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
  • A61K9/0012—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
  • 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
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/40—Cyclodextrins; Derivatives thereof
• • 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
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • 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
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; 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
  • A61K9/2013—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
  • A61K9/205—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
  • 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
  • C07D307/93—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 condensed with a ring other than six-membered

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 um 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 jam 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
• patent document 2 JP-A-2005-523253
• patent document 3 JP-A-2007-182440
• 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 or buccal administration.
• Such preparations have benefits over oral (but not sublingual or buccal) administration of the same medicament, including improving bioavailability, providing a lower ratio of metabolite to medicament, increasing Cmax, decreasing Tmax, increasing AUC(O-tlqc) and increasing the coefficient of variance for Cmax and AUC(O-tlqc).
• preparations also are useful for treating bipolar disorder generally, as well as the remission and depression phases of the disorder.
• Another object of the present invention is to provide a novel formulation technique capable of improving
• Another object of the present invention is to provide a preparation useful as an orally rapidly disintegrating preparation. Such objects are not limiting to the invention and are merely exemplary.
• 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
• a component that prevents disintegration 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.
• the present invention provides the following.
• a rapidly disintegrating preparation comprising granules comprising a medicament coated with a coating layer containing sugar or sugar alcohol; and a disintegrant
• 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.
• oral-mucosal and oral-mucosa in the context of drug delivery, as used herein connotes administration of a medicament directly to the mucosal lining of the oral cavity, e.g., by a sublingual or buccal route, such that the medicament enters the systemic circulation and substantially bypasses hepatic first pass metabolism.
• oral in the context of drug delivery, as used herein connotes administration of a medicament to the oral cavity but not directly to the mucosa lining the oral cavity. The medicament that is delivered by the oral route (in contrast to the oral-mucosal route) enters the systemic
• a method of producing a rapidly disintegrating preparation comprising a step of producing granules comprising a
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide as a medicament; which shows a higher ratio of the medicament in an unchanged form and a metabolite of the medicament (i.e., medicament in unchanged
• a metabolite of the medicament means, in particular, (2S) -2-hydroxy-N- ⁇ 2- [ (8S) -1, 6, 7, 8-tetrahydro-2H- indeno [5, 4-b] furan-8-yl] ethyl ⁇ propanamide, which is known as M- II.)
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide 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, and a disintegration time of not more than 30 sec.
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide 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, a disintegration time of not more than 30 sec, and absolute hardness of not less than 1.0 N/mm 2 .
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide and a masking agent; which shows not less than about 10-fold improved bioavailability of (S)-N-[2-
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide and a masking agent; which shows not less than about 10-fold improved bioavailability of (S)-N-[2- (1, 6,7, 8-tetrahydro-2H-indeno [5, -b] furan-8- yl) ethyl] propionamide, as compared to that by oral
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide and a masking agent; which shows not less than about 10-fold improved bioavailability of (S)-N-[2- (1,6,7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide, as compared to that by oral
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide, sugar or sugar alcohol, and a
• disintegrant which shows not less than about 10-fold improved bioavailability of (S) -N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4- b] furan-8-yl) ethyl] propionamide, as compared to that by oral administration, and a disintegration time of not more than 30 sec .
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide, sugar or sugar alcohol, and a
• disintegrant which shows not less than about 10-fold improved bioavailability of (S) -N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4- b] furan-8-yl) ethyl] propionamide, as compared to that by oral administration, a disintegration time of not more than 30 sec, and absolute hardness of not less than 1.0 N/mm 2 .
• the present invention also relates to a method of use of compound A for prophylaxis and/or treatment of a bipolar disorder by administering it to a human in need thereof oral- mucosally.
• a method for the prophylaxis and/or treatment of a bipolar disorder comprising administering (S) -N- [2- ( 1 , 6, 7 , 8- tetrahydro-2H-indeno [5, 4-b] furan-8-yl) ethyl] propionamide oral- mucosally to a human.
• bipolar disorder is bipolar disorder I.
• prophylaxis and/or treatment of a bipolar disorder is a
• a drug for the prophylaxis and/or treatment of a bipolar disorder which comprises, as an active ingredient, (S)-N-[2- (1,6,7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide to be oral-mucosally administered to a human .
• prophylaxis and/or treatment of a bipolar disorder is a
• N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide is administered as the preparation of the above-mentioned [5] - [7], or [9] - [18].
• Formulation A preparation for oral-mucosal absorption of compound A (2) Another aspect of the present invention relates to the following "formulations with limitation by dose and/or PK profile" .
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno[5, 4-b] furan-8- yl) ethyl] propionamide (compound A); wherein (1) the dose of compound A is 0.1 mg a day, and (2) the preparation provides to a human subject in a fasting state Cmax for compound A falling within the range of about 0.43 to about 3.13 ng/ml and AUC (0-tlqc) for compound A falling within the range of about 0.48 to about 2.26 ng.hr/ml.
• a preparation for oral-mucosal absorption comprising (S) -N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (compound A); wherein (1) the dose of compound A is 0.1 mg a day, (2) the preparation provides to a human subject in a fasting state Cmax for compound A falling within the range of about 0.43 to about 3.13 ng/ml and AUC (0- tlqc) for compound A falling within the range of about 0.48 to about 2.26 ng.hr/ml, and (3) the average Tmax value of plasma level of compound A after administration to a human is not more than about 0.4 hrs, preferably, not more than about 0.3 hrs, and more preferably, not more than about 0.25 hrs.
• preparation provides to a human subject in a fasting state Cmax for compound A falling within the range of about 0.66 to about 2.05 ng/ml and AUC (0-tlqc) for compound A falling within the range of about 0.67 to about 1.62 ng.hr/ml.
• preparation provides to a human subject in a fasting state Cmax for compound A falling within the range of about 0.66 to about 2.05 ng/ml and AUC (0-tlqc) for compound A falling within the range of about 0.67 to about 1.62 ng.hr/ml, and (3) the average Tmax value of plasma level of compound A after administration to a human is not more than about 0.4 hrs, preferably, not more than about 0.3 hrs, and more preferably, not more than about 0.25 hrs.
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (compound A); wherein (1) the dose of compound A is 0.4 mg a day, and (2) the preparation provides to a human subject in a fasting state Cmax for compound A falling within the range of about 2.04 to about 6.89 ng/ml and AUC (0-tlqc) for compound A falling within the range of about 1.52 to about 6.68 ng.hr/ml.
• a preparation for oral-mucosal absorption comprising (S) -N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (compound A); wherein (1) the dose of compound A is 0.4 mg a day, (2) the preparation provides to a human subject in a fasting state Cmax for compound A falling within the range of about 2.04 to about 6.89 ng/ml and AUC (0- tlqc) for compound A falling within the range of about 1.52 to about 6.68 ng.hr/ml, and (3) the average Tmax value of plasma level of compound A after administration to a human is not more than about 0.4 hrs, preferably, not more than about 0.3 hrs, and more preferably, not more than about 0.25 hrs.
• preparation provides to a human subject in a fasting state Cmax for compound A falling within the range of about 2.54 to about 5.54 ng/ml and AUC (0-tlqc) for compound A falling within the range of about 1.98 to about 5.12 ng.hr/ml.
• preparation provides to a human subject in a fasting state Cmax for compound A falling within the range of about 2.54 to about 5.54 ng/ml and AUC (0-tlqc) for compound A falling within the range of about 1.98 to about 5.12 ng.hr/ml, and (3) the average Tmax value of plasma level of (S) -N- [2- (1, 6, 7, 8- tetrahydro-2H-indeno [5, 4-b] furan-8-yl) ethyl] propionamide after administration to a human is not more than about 0.4 hrs, preferably, not more than about 0.3 hrs, and more preferably, not more than about 0.25 hrs.
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno[5, -b] furan-8- yl) ethyl] propionamide (compound A); wherein (1) the dose of compound A is 0.8 mg a day, and (2) the preparation provides to a human subject in a fasting state Cmax for compound A falling within the range of about 3.63 to about 14.06 ng/ml and AUC (0-tlqc) for compound A falling within the range of about 2.48 to about 14.43 ng.hr/ml.
• a preparation for oral-mucosal absorption comprising (S) -N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (compound A); wherein (1) the dose of compound A is 0.8 mg a day, (2) the preparation provides to a human subject in a fasting state Cmax for compound A falling within the range of about 3.63 to about 14.06 ng/ml and AUC (0-tlqc) for compound A falling within the range of about 2.48 to about 14.43 ng.hr/ml, and (3) the average Tmax value of plasma level of (S) -N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4- b] furan-8-yl) ethyl] propionamide after administration to a human is not more than about 0.4 hrs, preferably, not more than about 0.3 hrs, and more preferably, not more than about 0.
• preparation provides to a human subject in a fasting state Cmax for compound A falling within the range of about 4.85 to about 10.54 ng/ml and AUC (0-tlqc) for compound A falling within the range of about 3.60 to about 9.91 ng.hr/ml.
• preparation provides to a human subject in a fasting state Cmax for compound A falling within the range of about 4.85 to about 10.54 ng/ml and AUC (0-tlqc) for compound A falling within the range of about 3.60 to about 9.91 ng.hr/ml, and (3) the average Tmax value of plasma level of (S) -N- [2- (1, 6, 7, 8- tetrahydro-2H-indeno [5, 4-b] furan-8-yl) ethyl] propionamide after administration to a human is not more than about 0.4 hrs, preferably, not more than about 0.3 hrs, and more preferably, not more than about 0.25 hrs.
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (compound A); wherein (1) the dose of compound A is 0.05 - 1.0 mg a day; and (2) the AUC ratio of the metabolite of compound A (M-II) to compound A in an unchanged form after administration to a human is not more than about 20.
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (compound A); wherein (1) the dose of compound A is 0.1 - 0.8 mg a day; and (2) the AUC ratio of the metabolite of compound A (M-II) to compound A in an unchanged form after administration to a human is not more than about 20
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide; wherein the AUC ratio of (S)-N-[2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide in an unchanged form to a metabolite of (S) -N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (M-II) after administration to a human is not less than about 5-fold than that by oral administration.
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide; wherein the AUC ratio of the metabolite of (S) -N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (M-II) to (S) -N- [2- ( 1, 6, 7 , 8-tetrahydro- 2H-indeno [5, 4-b] furan-8-yl) ethyl] propionamide in an unchanged form after administration to a human is not more than about 20.
• the preparation for oral-mucosal absorption of aforementioned [50] wherein the AUC ratio is not more than about 10, more preferably, not more than about 5.
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, -b] furan-8- yl) ethyl] propionamide; wherein the bioavailability of (S)-N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide is improved not less than about 10-fold than that by oral administration, more specifically, is
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide, wherein the average Tmax value of plasma level of (S) -N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4- b] furan-8-yl) ethyl] propionamide after administration to a human is not more than about 0.4 hrs, preferably, not more than about 0.3 hrs, and more preferably, not more than about 0.25 hrs.
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide, wherein the coefficient of variation (CV) of pharmacokinetic parameters including Cmax and AUC of (S) -N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide after administration to a human is not more than about 45%, preferably, not more than about 35%, and more preferably, not more than about 30%.
• CV coefficient of variation
• a preparation for oral-mucosal absorption comprising (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide; wherein the dose of (S) -N- [2- (1, 6, 7, 8- tetrahydro-2H-indeno [5, 4-b] furan-8-yl) ethyl] propionamide is 0.05 - 1.0 mg a day.
• Another aspect of the present invention relates to the following "method of use of compound A with limitation by dose and/or PK profile”.
• a method for the prophylaxis and/or treatment of a bipolar disorder comprising administering daily 0.05 to 1.0 mg of (S) -N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide to the oral mucosa of a human in need thereof.
• a method for the prophylaxis and/or treatment of a bipolar disorder comprising administering daily 0.1 mg of (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (compound A) to the oral mucosa of a human in need thereof, wherein in the fasting state, Cmax for compound A falls within the range of about 0.43 to about 3.13 ng/ml and AUC (0-tlqc) for compound A falls within the range of about 0.48 to about 2.26 ng.hr/ml.
• a method for the prophylaxis and/or treatment of a bipolar disorder comprising administering daily 0.1 mg of (S) N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (compound A) to the oral mucosa of a human in need thereof, wherein in the fasting state, Cmax for compound A falls within the range of about 0.43 to about 3.13 ng/ml and AUC (0-tlqc) for compound A falls within the range of about 0.48 to about 2.26 ng.hr/ml; and the average Tmax value of plasma level of compound A after administration to a human is not more than about 0.4 hrs, preferably, not more than about 0.3 hrs, and more preferably, not more than about 0.25 hrs.
• bipolar disorder is bipolar disorder I.
• prophylaxis and/or treatment of a bipolar disorde is a treatment of a depression symptom associated with the bipolar disorder or maintenance of a remission phase of the bipolar disorder.
• a method for the prophylaxis and/or treatment of a bipolar disorder comprising administering daily 0.4 mg of (S) N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, -b] furan-8- yl) ethyl] propionamide (compound A) to the oral mucosa of a human in need thereof, wherein in the fasting state, Cmax for compound A falls within the range of about 2.04 to about 6.89 ng/ml and AUC (0-tlqc) for compound A falls within the range of about 1.52 to about 6.68 ng.hr/ml.
• a method for the prophylaxis and/or treatment of a bipolar disorder comprising administering daily 0.4 mg of (S) N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (compound A) to the oral mucosa of a human in need thereof, wherein in the fasting state, Cmax for compound A falls within the range of about 2.04 to about 6.89 ng/ml and AUC (0-tlqc) for compound A falls within the range of about 1.52 to about 6.68 ng.hr/ml; and the average Tmax value of plasma level of compound A after administration to a human is not more than about 0.4 hrs, preferably, not more than about 0.3 hrs, and more preferably, not more than about 0.25 hrs.
• bipolar disorder is bipolar disorder I.
• prophylaxis and/or treatment of a bipolar disorder is a treatment of a depression symptom associated with the bipolar disorder or maintenance of a remission phase of the bipolar disorder.
• bipolar disorder is bipolar disorder I.
• prophylaxis and/or treatment of a bipolar disorder is a treatment of a depression symptom associated with the bipolar disorder or maintenance of a remission phase of the bipolar disorder.
• a method for the prophylaxis and/or treatment of a bipolar disorder comprising administering daily 0.8 mg of (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (compound A) to the oral mucosa of a human in need thereof, wherein in the fasting state, Cmax for compound A falls within the range of about 3.63 to about 14.06 ng/ml and AUC (0-tlqc) for compound A falls within the range of about 2.48 to about 14.43 ng.hr/ml.
• a method for the prophylaxis and/or treatment of a bipolar disorder comprising administering daily 0.8 mg of (S)- N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (compound A) to the oral mucosa of a human in need thereof, wherein in the fasting state, Cmax for compound A falls within the range of about 3.63 to about 14.06 ng/ml and AUC (0-tlqc) for compound A falls within the range of about 2.48 to about 14.43 ng.hr/ml; and the average Tmax value of plasma level of compound A after administration to a human is not more than about 0.4 hrs, preferably, not more than about 0.3 hrs, and more preferably, not more than about 0.25 hrs.
• bipolar disorder is bipolar disorder I.
• a method for the prophylaxis and/or treatment of a bipolar disorder comprising administering daily 0.05 to 1.0 mg of (S) -N- [2- (1, 6,7, 8-tetrahydro-2H-indeno [5, -b] furan-8- yl) ethyl] propionamide (compound A) to the oral mucosa of a human in need thereof, wherein the AUC ratio of a metabolite of compound A (M-II) to compound A in an unchanged form after administration is not more than 20.
• a method for the prophylaxis and/or treatment of a bipolar disorder comprising administering daily 0.1 to 0.8 mg of (S) -N- [2- (1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl) ethyl] propionamide (compound A) to the oral mucosa of a human in need thereof, wherein the AUC ratio of a metabolite of compound A (M-II) to compound A in an unchanged form after administration is not more than 20.
• administration is not more than about 20.
• bipolar disorder is bipolar disorder I.
• a drug for the prophylaxis and/or treatment of a bipolar disorder comprising daily 0.1 mg of (S) -N- [2- (1, 6, 7, 8- tetrahydro-2H-indeno [5, 4-b] furan-8-yl) ethyl] propionamide
• compound A to be administered to the oral mucosa of a human in need thereof, wherein in the fasting state, Cmax for compound A falls within the range of about 0.43 to about 3.13 ng/ml and AUC (0-tlqc) for compound A falls within the range of about 0.48 to about 2.26 ng.hr/ml.
• a drug for the prophylaxis and/or treatment of a bipolar disorder comprising daily 0.4 mg of (S) -N- [2- (1, 6, 7, 8- tetrahydro-2H-indeno [5, 4-b] furan-8-yl) ethyl] propionamide (compound A) to be administered to the oral mucosa of a human in need thereof, wherein in the fasting state, Cmax for compound A falls within the range of about 2.04 to about 6.89 ng/ml and AUC (0-tlqc) for compound A falls within the range of about 1.52 to about 6.68 ng.hr/ml.
• a drug for the prophylaxis and/or treatment of a bipolar disorder comprising daily 0.8 mg of (S) -N- [2- ( 1, 6, 7 , 8- tetrahydro-2H-indeno [5, 4-b] furan-8-yl) ethyl] propionamide
• compound A to be administered to the oral mucosa of a human in need thereof, wherein in the fasting state, Cmax for compound A falls within the range of about 3.63 to about 14.06 ng/ml and AUC (0-tlqc) for compound A falls within the range of about 2.48 to about 14.43 ng.hr/ml.
• oral-mucosal administration is sublingual administration or buccal administration.
• 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
• 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
• 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
• 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 above-mentioned effects can be produced.
• Figure 1 demonstrates the mean serum concentration of compound A after oral-mucosal delivery at different concentrations.
• Figure 2 demonstrates the mean serum concentration of compound A after oral-mucosal delivery compared to the concentration of compound A after oral delivery.
• 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 .
• 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 used.
• 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
• the invention is particularly effective when a medicament having poor compatibility with the disintegrant (e.g. compound A, etc) is used as a medicament.
• the disintegrant e.g. compound A, etc
• Compound A is a known therapeutic agent for sleep
• 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,
• 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, micro
• microcrystalline cellulose are preferable.
• 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 polyvinylpyrrolidone, gelatin, starch, gum arabic powder, tragacanth, carmellose, sodium alginate, pullulan, glycerol and the like, and partly pregelatinized starch,
• hydroxypropylcellulose and pregelatinized starch are
• 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 receptors (thaumatin, sucralose, saccharin, aspartame, xylitol, citric acid, L-sodium glutamate etc. ) , various receptors (thaumatin, sucralose, saccharin, aspartame, xylitol, citric acid, L-sodium glutamate etc. ) , various receptors (thaumatin, sucralose, saccharin, aspartame, xylitol, citric acid, L-sodium glutamate etc. ) , various receptors (thaumatin, sucralose, saccharin, aspartame, xylitol, citric acid, L-sodium glutamate etc. ) , various receptors (thaumatin, sucralose
• BENECOAT sodium chloride etc.
• various cation channel antagonists L-arginine etc.
• various clathration agents a-cyclodextrin, ⁇ -cyclodextrin etc.
• various flavors strawberry flavor, mint flavor, orange flavor, vanillin etc. 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.
• the solubilizer include various aqueous solvents (polyethylene glycol, propylene glycol, glycerol etc.), various clathration agents (a-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
• 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 solubilizer
• disintegration property can be improved by
• the preparation can achieve high disintegration property by ensuring the invasion route of water into the preparation by coating the 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
• 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
• 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 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
• comprising a medicament coated with a coating layer containing sugar or sugar alcohol is generally 50 ⁇ - 500 ⁇ ,
• the average particle size is a value measured by a laser diffraction particle size analyzer, SYMPATEC: HELOS&RODOS and the like.
• extragranule component include amino acid, starch, corn starch, carmellose, carmellose sodium, carmellose calcium,
• 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%,
• 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 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.
• a component that prevents disintegration as described above.
• 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 rapidly disintegrating preparation of the present invention can be produced by a method conventionally used in the pharmaceutical-technical field.
• the pharmaceutical-technical field for example, 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
• step (1) producing granules comprising a medicament
• step (2) forming a coating layer containing sugar or sugar alcohol on the obtained granules
• step (3) mixing the coated granules with a disintegrant and molding the mixture.
• steps (1) - (3) 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. are mixed to give a mixture.
• the obtained mixture is granulated while spraying the coating solution thereon, and dried to give a granulated powder
• 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; PO REX 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
• a preparation machine for example, V-type mixer, tumbler mixer (TM-30, TM
• Coating is carried out by using, for example, a
• 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 Karlsui Seisakusho Ltd.
• rotary tableting machine AQUARIUS 36K, AQUARIUS 2L; Kikusui Seisakusho Ltd.
• AUTOGRAPH AG-5000B, SHIMADZU Corporation
• 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 metabolism effect when administered orally is used.
• a medicament e.g., compound A etc.
• the rapidly disintegrating preparation for oral-mucosal absorption of the present invention can afford a low dose medicament with the potential for fewer side effects when it is used for the treatment of a bipolar
• 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 to 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 an effect in that the ratio of the medicament in an unchanged form to a metabolite of the medicament after transfer into blood is higher than that by oral administration.
• the present invention also relates to a
• preparation (A) of the present invention (hereinafter sometimes to be abbreviated as preparation (A) of the present invention) .
• the disintegration time is preferably not more than 30 sec.
• the dosage form in preparation (A) is a tablet, more
• 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
• preparation (B) of the present invention (preparations [12] to [18]) (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 25-fold. In other words, the bioavailability is improved within the range from not less than about 10-fold to not more than about 30-fold, more
• 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
• AUC concentration time curve
• Bioavailability (BA) is calculated according to the following formula (absolute bioavailability) .
• BA (%) ((oral or oral-mucosal administration AUC/dose in oral or oral-mucosal administration) / (intravenous administration AUC/dose in intravenous
• BA ratio Metal A
• 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 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])
• preparation (C) of the present invention (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
• AUC plasma concentration time curve
• AUC(O-tlqc) is area under the serum concentration-time curve from time 0 to time of the last quantifiable concentration (tlqc) , calculated using the linear trapezoidal rule.
• AUC(O-inf) is area under the serum
• Both AUC values can be used for evaluation of improvement of bioavailability, but in principle, the evaluation thereof is made based on AUC(O-inf) value.
• the ratio of the unchanged form and metabolite, (i.e., AUC of unchanged form/AUC of metabolite) in each preparation is calculated.
• 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
• 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.
• the present invention also relates to a preparation for oral-mucosal absorption (preparations [37] to [59] )
• preparation (D) of the present invention (hereinafter sometimes to be abbreviated as preparation (D) of the present invention) .
• preparation (D) in principle, definitions of the terms specifying each preparation [37] to [59] and concrete examples thereof can be referred to those exemplified for preparations (A) to (C) above.
• the AUC ratio is not less than about 5-fold than that by oral administration, preferably, not less than about 10-fold than that by oral administration. In general, the AUC ratio is not more than about 30-fold than that by oral administration, more specifically, not more than about 25-fold than that by oral administration.
• "about” means 5% error range.
• the AUC ratio is not more than about 25, preferably, not more than about 10, and more preferably, not more than about 5. In general, the AUC ratio is not less than about 1.
• the test method As for the test method, the examples of specific preparations to be subjected to a test, the below-mentioned Experimental Example 4 can be referred to. However, when a substantially similar evaluation is possible, the method is not limited to that of Experimental Example 4.
• the bioavailability is not less than about 10-fold improved, as compared to that by oral administration.
• "about” means 5% error range.
• the bioavailability is improved within the range from not less than about 10-fold to not more than about 30-fold, more specifically, within the range from not less than about 10-fold to not more than about 25-fold than that by oral administration.
• Tmax value of plasma level of (S) -N- [2- (1, 6, 7, 8- tetrahydro-2H-indeno [5, 4-b] furan-8-yl) ethyl] propionamide after administration to a human Tmax means time to reach Cmax, wherein Cmax means maximum observed serum concentration, after a preparation is administered to a human.
• the average Tmax value is not more than about 0.4 hrs, preferably, not more than about 0.3 hrs, and more preferably, not more than about 0.25 hrs.
• Individual variability is not more than about 45%, more preferably, not more than about 35%, and most preferably, not more than about 30%.
• "about” means 5% error range.
• Preparations (A) - (D) can be produced, for example, according to the production method explained for "the rapidly disintegrating preparation of the present invention".
• the dosage form of preparations (A) - (D) 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
• a coating solution solution or suspension, solvent is, for example, purified water
• solvent is, for example, purified water
• the preparation can be produced according to a conventional method as follows.
• the preparation can be produced according to a conventional method as follows.
• preparation can be produced by mixing a medicament, a polymer, sugars and the like, and dissolving and lyophilizing them (Manufacturing Chemist, Feb. 36 (1990)).
• the preparation can be produced according to a
• the preparation can be produced by adding a medicament, additive such as sweetener, flavor, colorant, softening agent, flavoring
• 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
• the preparation can be produced according to a general
• 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,
• 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,
• the dose of compound A is 0.05 - 1.5 mg (preferably, 0.05 - 1.0 mg, more preferably, 0.1 - 1.0 mg, much more preferably, 0.1 - 0.8 mg and most preferably, 0.1 mg, 0.4 mg and 0.8 mg) a day, which can be administered once a day.
• the solubility of compound A is about 0.2 mg/ml
• the compound In order for this compound to be absorbed oral-mucossally, the compound should be dissolved in saliva first. When it is taken into consideration that the amount of saliva in the oral cavity is about 1 ml, the reduction of amount of compound A which the present invention brings in is quite advantageous from practical viewpoint.
• the dose of compound A can be reduced with keeping its efficacy. Therefore, if necessary, the size of the preparation can be made smaller. This feature would be also one of the advantages of the present invention.
• Compound A is quite similar to that of the endogenous
• compound A can regulate the circadian rhythm, which is thought to be disturbed in bipolar patients, better than existing drugs indicated for a bipolar disorder.
• compound A is expected to show
• this circadian rhythm regulating effect can also translate into better normalizing circadian rhythm and/or sleep/awake cycle in bipolar patients.
• the present invention provides a preparation showing superior absorption of compound A from the oral mucosa and improved bioavailability thereof and
• 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 compound A in the form of the preparation of the present invention (preparations (A) to (D))to humans.
• the various kinds of PK profiles mentioned in the methods [59] to [71] can be achieved by administering compound A to a human in the forms of preparations [37] to [58] .
• sublingual administration or buccal administration preferably sublingual administration or buccal administration, and sublingual administration is particularly preferable.
• the sublingual and buccal administration is advantageous for providing a quick onset of therapy and a quick offset of therapy. This is in contrast to oral administration, in which onset and offset is slower due to gastro-intestinal transit time.
• the sublingual and buccal administrations result in a lower ratio of the metabolite M-II to Compound A.
• formulation provides a therapeutic effect by achieving a blood level above a certain therapeutic level for, a certain period of time.
• the duration and blood level should correspond to an endogenous
• a tablet containing 0.05 - 1.5 mg (preferably, 0.05 - 1.0 mg, more preferably, 0.1 - 1.0 mg, much more preferably, 0.1 - 0.8 mg and most preferably, 0.1 mg, 0.4 mg and 0.8 mg) of compound A per tablet is preferably administered to
• the invention is effective for bipolar disorders including bipolar disorder I, bipolar disorder II (recurrent major depressive episodes with bipolar disorder I), bipolar disorder II (recurrent major depressive episodes with bipolar disorder I, bipolar disorder II (recurrent major depressive episodes with bipolar disorder I), bipolar disorder II (recurrent major depressive episodes with bipolar disorder I, bipolar disorder II (recurrent major depressive episodes with bipolar disorder II), and bipolar disorder II (recurrent major depressive episodes with
• invention is particularly effective in the treatment of 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”.
• bipolar disorders by oral-mucosal administration of compound A
• other 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.
• one or more SSRI selective serotonin reuptake inhibitors
• fluvoxamine paroxetine
• escitalopram may also be included in the escitalopram, fluoxetine, citalopram, etc.
• fluoxetine may also be included in the escitalopram, fluoxetine, citalopram, etc.
• the administration mode of the "combination medicament” is not particularly restricted, and it is sufficient that "compound A” and “combination medicament” be combined in administration.
• Examples of such 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.
• microcrystalline cellulose CEOLUS PH-101, Asahi Kasei
• crospovidone Kerdon CL-F, BASF
• sodium stearyl fumarate PRUV, JRS PHARMA
• microcrystalline cellulose 0. 75 mg
• 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 ⁇ ) .
• the obtained compound A solution was divided into small fraction
• Copovidone (4.5 g) were dissolved in purified water (198 g) and dispersed therein to give dispersion I. Titanium oxide (25 g) and yellow ferric oxide (0.5 g) were dispersed in purified water (450 g) to give dispersion II. Dispersion II was added to dispersion I, and the mixture was stirred to give a coating solution. The coating solution was sprayed on the core tablet obtained in (3) until the weight of the core tablet increased by 5 mg per tablet by using a coater (High Coater HC-LABO, Freund Corporation) to give a film-coated tablet having the following composition.
• a coater High Coater HC-LABO, Freund Corporation
• magnesium stearate 1. 0 mg
• microcrystalline cellulose 0. 75 mg
• PEG400 (Wako Pure Chemical Industries, Ltd.) (60 g) was dissolved in purified water (110 g) to give PEG400 solution.
• Hydroxypropylcellulose HPC-L, NIPPON SODA CO., LTD.
• 660 g was dissolved in purified water (10230 g) to give a binding solution.
• Compound A (165.3 g)
• lactose DMV INTERNATIONAL
• corn starch Japan Corn Starch Co., Ltd.
• FD-S2, POWREX CORPORATION a fluid bed dryer granulator
• This granulation step was performed twice. A part of the obtained granulated powder was ground by a power mill grinding machine (P-3, SHOWA KAGAKU KIKAI CO., LTD.) using a 1.5 mm ⁇ j> punching screen to give a sieved powder.
• the mixed powder was tableted by a rotary tableting machine (AQUARIUS 36K, Kikusui Seisakusho Ltd.) by using a 7 ⁇ punch (tableting pressure: 7 kN, weight per tablet: 130 mg) to give a tablet (core tablet) .
• dispersion I Titanium oxide (207 g) and yellow ferric oxide (4.14 g) were dispersed in purified water (1822 g) to give dispersion II. Dispersion II was added to dispersion I, and the mixture was stirred to give a coating solution. Using a coater (High Coater HCF-100N, Freund Corporation) , the coating solution was sprayed on the core tablet obtained in (3) until the weight of the core tablet increased by 5 mg per tablet to give a film-coated tablet having the following composition.
• a coater High Coater HCF-100N, Freund Corporation
• D-mannitol (PEARLITOL 50C, Roquette) (120 g) was dissolved in purified water (680 g) to give a coating solution.
• Compound A (40 g) , D-mannitol (818 g) , macrocrystalline cellulose
• ⁇ - ⁇ -CyD Hydroxypropyl-p-cyclodextrin
• KLEPTOSE HPB Roquette
• 75 g was dissolved in purified water (422.5 g) .
• Compound A 2.5 g was dissolved in the obtained ⁇ - ⁇ -CyD aqueous solution to give a coating solution.
• D-Mannitol PEARLITOL 50C, Roquette
• CEOLUS PH-101 Asahi Kasei
• microcrystalline cellulose 3.0 mg
• Crospovidone (Kollidon CL-F, BASF) (90 g) and sodium stearyl fumarate (18 g) were added to the obtained sieved powder (1692 g) , and the mixture was mixed in a tumbler mixer (TM-15S, SHOWA KAGAKU KIKAI CO., LTD.) to give a mixed powder.
• the mixed powder was tableted by a rotary tableting machine (AQUARIUS 2L, Kikusui Seisakusho Ltd.) by using a 4 ⁇ punch (tableting pressure: 4 kN, weight per tablet: 30 mg) to give a core tablet with the following composition.
• D-mannitol PEARLITOL 50C, Roquette
• purified water 2550 g
• Compound A (150.5 g)
• microcrystalline cellulose CEOLUS PH-101, Asahi Kasei Corporation
• PCS partly pregelatinized starch
• Crospovidone (Kollidon CL-F, BASF) (90 g) and sodium stearyl fumarate (18 g) were added to the obtained sieved powder (1692 g) , and the mixture was mixed in a tumbler mixer (TM-15S, SHOWA KAGAKU KIKAI CO., LTD.) to give a mixed powder.
• the mixed powder was tableted by a rotary tableting
• Hydroxypropylcellulose (HPC-L, NIPPON SODA CO., LTD.) (660 g) was dissolved in purified water (10230 g) to give a binding solution.
• Compound A (1320 g)
• lactose (DMV INTERNATIONAL) (16104 g)
• corn starch (Japan Corn Starch Co., Ltd.) (2640 g) were uniformly mixed in a fluid bed dryer granulator (FD-S2, POWREX CORPORATION) , granulated while spraying the binding solution (10890 g) , and dried to give a granulated powder.
• This granulation step was performed twice. A part of the obtained granulated powder was ground by a power mill grinding machine (P-3, SHO A KAGAKU KIKAI CO., LTD.) using a 1.5 ⁇ punching screen to give a sieved powder.
• P-3 power mill grinding machine
• Dispersion II was added to dispersion I, and the mixture was stirred to give a coating solution.
• a coater High
• the mixed powder was tableted by a rotary tableting machine (AQUARIUS 2L, Kikusui Seisakusho Ltd.) using a 4 mm ⁇ j) punch (tableting pressure: 4 kN, weight per tablet: 30 mg) to give a core tablet with the following composition.
• D-mannitol in coating layer 3. 0 mg microcrystalline cellulose 0. 75 mg partly pregelatinized starch 3. 0 mg crospovidone 1. 5 mg sodium stearyl fumarate 0. 3 mg aspartame 3.0 mg
• D-mannitol in coating layer 3.0 mg microcrystalline cellulose 0.75 mg partly pregelatinized starch 3.0 mg crospovidone 1.5 mg sodium stearyl fumarate 0.3 mg aspartame 3.0 mg vanillin 0.03 mg total 30 mg
• BASF (375.0 g) , aspartame (750 g) , vanillin (7.5 g) and
• D-mannitol in coating layer 3.0 mg microcrystalline cellulose 0.75 mg partly pregelatinized starch 3.0 mg crospovidone 1.5 mg sodium stearyl fumarate 0.3 mg aspartame 3.0 mg vanillin 0.03 mg total 30 mg
• Example 1 The tablet obtained in Example 1 was measured for the tablet hardness and disintegration time.
• the tablet hardness was measured by a tablet hardness tester (TH-303MP, Toyama
• Example 2 The mixed powder obtained in Example 1 was measured for the dissolution property.
• the mixed powder (15 g)
• Macaca fascicularis under fasting conditions.
• AUC area under the plasma concentration time curve
• Example 3 28.0+4.5 38.5+12.8 3062.4+1129.9 18.1 sublingual Example 4 42.0+16.0 31.4+8.6 3206.91809.9 19.0
• Example 5 48.0+16.0 46.6113.8 4568.4+1286.3 27.0 buccal
• Example 7 36.0+12.0 87.1121.2 5862.0 ⁇ 1038.0 34.7
• AUC(O-tlqc) Area under the serum concentration-time curve from time 0 to time of the last quantifiable
• Tmax Time to reach Cmax.
• 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 ⁇ ) to give an oral spray preparation.
• ⁇ - ⁇ -CyD Hydroxypropyl-p-cyclodextrin ( ⁇ - ⁇ -CyD) (40 g) was dissolved in water (60 g) , and compound A (100 mg) was added to the obtained solution (10 ml), stirred and dissolved therein. The obtained solution was filled in a spray device (spray amount: 100 ⁇ L/time) to give an oral spray preparation.
• hydroxypropylcellulose 100 mg were added to a mixed solution (100 ml) of water and ethanol (4:1) and dissolved by stirring.
• the obtained solution (1 ml) was dispensed to a pocket of a blister pack with vinyl chloride resin as an inner film, frozen at -30°C, and dried by a vacuum dryer to give an orally rapidly dissolving freeze-dried preparation.
• test tablet was administered to a group of patients suffering from biopolar disorder and in the remission phase, once daily at bedtime for 6 months.
• a placebo was administered once daily at bedtime to a separate control group of patients in the remission phase of biopolar disorder for 6 months.
• This study was performed as a double-blind, randomized, placebo- controlled trial. The time from randomization to relapse over 6 months of treatment is determined by the Primary
• PI PI
• depression [Montgomery-Asberg Depression Rating Scale (MADRS) score ⁇ 16] ; mania/hypomania [Young Mania Rating Scale (YMRS) total score ⁇ 14] ; clinical global impressions bipolar version (CGI-BP) ; cumulative proportion of participants in each arm (placebo or Compound A) surviving without relapse [MADRS score 16 and YMRS total score ⁇ 14] , a medication initiation or change for manic/depressed/mixed symptoms, a hospitalization for manic/depressed/mixed symptoms and suicide risk or
• test tablet was administered once daily to a group of patients suffering from biopolar disorder and in the mania phase for up to 8 weeks.
• a placebo was administered to a separate control group of patients in the mania phase of biopolar disorder for up to 8 weeks.
• This study was performed as a double-blind, randomized, placebo-controlled trial.
• the time from randomization to relapse over 6 months of treatment is determined by the Primary Investigator (PI) or defined by any of the following criteria: clinical global impressions scale for biopolar disorder (CGI-BP) . 3. Test Result
• test was conducted in two parts: (1) a parallel-group design to evaluate the pharmacokinetic parameters of 3 doses of Compound A (0.25, 0.5 and 1 mg) in oral-mucosal tablets and (2) an open-label, randomized 2-period crossover design to assess the relative bioavailability (pharmacokinetic profile) of the oral-mucosal 0.5 mg tablet compared with the
• a total of 18 subjects were randomly assigned to 1 of the 3 dosing regimens (i.e., 0.25, 0.5 and 1 mg; 6 subjects per dose) and each subject received a single dose of Compound A at the assigned dose.
• a total of 24 subjects were randomly assigned to take either the oral-mucosal 0.5 mg tablet or the oral 8 mg tablet at a single dose during each of the two periods .
• Compound A were similar between the oral-mucosal and oral administrations. Also, the geometric mean Cmax and AUC(O-tlqc) values of M-II were much lower after oral-mucosal
• the 0.5 mg oral-mucosal dose provided an increase in maximum exposure (as measured by Cmax) and similar total exposure (as measured by AUC) to Compound A compared to the oral 8 mg tablet.
• the oral-mucosal administration provided a small fraction of exposure ( ⁇ 7%) to M-II compared to the approved oral 8 mg tablet. measurement Dose Cmax AUC(O-tlqc)
• a 2 compartment model for the unchanged form of compound A and 1 compartment model for its metabolite M-II was used to fit PK profiles after the administration of 0.25 mg, 0.5 mg and 1 mg doses, respectively.
• the Bayesian parameter estimates were subsequently mapped such that individual parameter estimates for 0.25 mg, 0.5 mg, and 1 mg doses corresponded to the 0.1 mg, 0.4 mg, and 0.8 mg doses, respectively, during simulation. Descriptive statistics were calculated based on the individual simulated Cmax and AUC values including

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• 2012
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