WO2014075692A1 - Comprimé dispersible - Google Patents

Comprimé dispersible Download PDF

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Publication number
WO2014075692A1
WO2014075692A1 PCT/DK2013/050384 DK2013050384W WO2014075692A1 WO 2014075692 A1 WO2014075692 A1 WO 2014075692A1 DK 2013050384 W DK2013050384 W DK 2013050384W WO 2014075692 A1 WO2014075692 A1 WO 2014075692A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
tablet
nimorazole
water
composition according
Prior art date
Application number
PCT/DK2013/050384
Other languages
English (en)
Inventor
Nilesh TANHAJI DUMBRE
Mahesh MOHANRAO BHADGALE
Vardhaman CHANDRAKANT BAFNA
Original Assignee
Azanta A/S
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
Priority claimed from US13/680,216 external-priority patent/US8703188B1/en
Priority claimed from DK201270714A external-priority patent/DK177906B1/en
Priority to CA2888856A priority Critical patent/CA2888856A1/fr
Priority to BR112015011408A priority patent/BR112015011408A2/pt
Priority to AU2013347264A priority patent/AU2013347264B2/en
Priority to JP2015542166A priority patent/JP2015537013A/ja
Priority to MX2015006217A priority patent/MX2015006217A/es
Priority to EA201590732A priority patent/EA201590732A1/ru
Application filed by Azanta A/S filed Critical Azanta A/S
Priority to RU2015117921A priority patent/RU2015117921A/ru
Priority to NZ707033A priority patent/NZ707033A/en
Priority to US14/443,262 priority patent/US20150283083A1/en
Priority to EP13798918.2A priority patent/EP2919754A1/fr
Publication of WO2014075692A1 publication Critical patent/WO2014075692A1/fr
Priority to TNP2015000156A priority patent/TN2015000156A1/fr
Priority to ZA2015/02896A priority patent/ZA201502896B/en
Priority to SA515360445A priority patent/SA515360445B1/ar
Priority to MA38211A priority patent/MA38211A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/1635—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
    • A61K9/14—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
    • A61K9/2022—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
    • A61K9/2072—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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical composition comprising Nimorazole, which disintegrates in water.
  • the invention concerns a pharmaceutical composition such as a tablet comprising Nimorazole or a pharmaceutically acceptable salt thereof, for dispersion in water and administration via a tube to a patient with swallowing difficulties.
  • the patent US 4371540 describes the use of radiosensitizers for hypoxic cells. Administration is performed via an intravenous route or suggested to be done orally using a prodrug, wherein the prodrug is the acetate ester of the compound.
  • the patent US 4462992 suggests administration parenterally, subcutaneously, intravenously, intramuscularly or intraperitoneally, or alternatively oral administration.
  • Nimorazole is inter alia used to improve the efficacy of irradiation treatment for cancer patients.
  • cancer patients may suffer from swallowing difficulties.
  • Nimorazole treatment may have difficulties swallowing Nimorazole tablets, and thus have a need for having Nimorazole administered via an alternative route.
  • the amount of Nimorazole necessary for an effective treatment such as about 2 g for each treatment, aggravates this problem, as it implies the use of large tablets or a high number of tablets.
  • Nimorazole is slightly soluble in water (The Merck Index, 14 th Edition). Experiments indicate that the solubility in water is about 5 mg/ml. Further, in order to achieve a reasonable dissolution rate, it is usually necessary to apply excessive amounts of liquid in order to obtain sink conditions. Preparing a bulky solution of Nimorazole for further distribution creates additional problems in terms of storage stability and difficulties distributing a large container comprising liquid. There is a need for providing a liquid medium comprising an amount of Nimorazole exceeding the solubility limit of Nimorazole in water, in order to be able to administer effective amounts of Nimorazole via a feeding tube while avoiding the intake of excessive amounts of liquid medium.
  • the invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, for disintegration in water or an aqueous medium and administration via a tube.
  • a feeding tube may suitably be used.
  • the invention concerns a pharmaceutical composition which allows administration using a feeding tube to a patient with swallowing difficulties.
  • the pharmaceutical formulation or tablet according to the invention preferably disintegrates upon contact with water, forming a dispersion.
  • the forming of the dispersion may be aided by stirring in the water, or shaking a container comprising the tablet and water.
  • the invention concerns a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: a disintegrant; optionally one or more additional excipients; and a coating; said pharmaceutical composition allowing administration via at least two different routes: i) oral administration, or
  • a pharmaceutical formulation or tablet which may be used directly for oral administration, and which alternatively may be dispersed in water in a short time frame for administration via a feeding tube.
  • the pharmaceutical formulation or tablet may be dispersed in a small volume of water.
  • the dispersed particles are sufficiently small to provide a slow sedimentation rate, allowing administration of the particles in dispersed state from e.g. a bottle via a feeding tube.
  • a pharmaceutical formulation in the form of a tablet is easy to handle and dosage may easily be measured and subsequently checked.
  • Using a powder from individual sachets makes a dosing of several sachets cumbersome.
  • the use of a powder makes a dosage check after measurement of the intended dosage cumbersome, while a small number of tablets are easily counted for verification of dosage.
  • a tablet provides a smaller surface area than a powder, thus potentially increasing the storage stability of the product.
  • the invention concerns a kit of parts comprising a pharmaceutical composition according to the invention, and instructions for preparing a dispersion of said pharmaceutical composition for administration via a tube.
  • the invention concerns a method for manufacturing a pharmaceutical formulation or tablet according to the invention, comprising wet granulation of Nimorazole.
  • the invention concerns a method of treatment of cancer, wherein irradiation treatment is combined with the administration of at least one pharmaceutical formulation or tablet according to the invention, wherein said at least one pharmaceutical formulation or tablet is allowed to disintegrate in water or an aqueous medium and administered via a tube.
  • irradiation treatment is combined with the administration of at least one pharmaceutical formulation or tablet according to the invention, wherein said at least one pharmaceutical formulation or tablet is allowed to disintegrate in water or an aqueous medium and administered via a tube.
  • the invention concerns a method of radiosensitizing hypoxic tumor cells comprising administering Nimorazole, wherein the administration comprises: providing a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof; dispersing said solid pharmaceutical composition in water or an aqueous medium to obtain a dispersion; and administering said dispersion via a tube.
  • the invention concerns a use of a tablet according to the invention, wherein said tablet is dispersed in water and administered via a tube.
  • the invention concerns an aqueous pharmaceutical composition
  • aqueous pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, wherein at least part of said Nimorazole or pharmaceutically acceptable salt thereof is dispersed in an aqueous medium in form of solid particles.
  • the invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, for disintegration in water or an aqueous medium and administration via a tube.
  • a feeding tube may suitably be used.
  • water or an aqueous medium covers the possibility of using water or water comprising one or more salts, such as a saline solution, and/or any (other) components for the patient, such as at least one active ingredient. It also covers the possibility of water comprising one or more nutrients, optionally with one or more active ingredients.
  • the pharmaceutical composition or tablet according to the invention preferably disintegrates upon contact with water, forming a dispersion. The forming of the dispersion may be aided by stirring in the water, or shaking a container comprising at least one tablet and water.
  • the invention concerns a pharmaceutical composition or a tablet for administration to a patient with swallowing difficulties.
  • the invention concerns a pharmaceutical composition or tablet for administration to a patient with little, insufficient or no saliva, such as a patient with non-normal salivary function.
  • the invention concerns a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: a disintegrant; optionally one or more additional excipients, such as a binder; and a coating; said pharmaceutical composition allowing administration via at least two different routes: oral administration, or disintegration in water or an aqueous medium to provide a dispersion, and subsequent administration of said dispersion via a tube.
  • the solid pharmaceutical composition is preferably a tablet.
  • the pharmaceutical composition is preferably provided in a solid form which is stable over time.
  • the pharmaceutical composition is stable for 6 months, preferably 12 months, more preferred 18 months, preferably 24 months, more preferred 30 months, preferably 36 months, or even longer.
  • the pharmaceutical composition retains its dispersibility upon storage, i.e. during storage for 6 months, preferably 12 months, more preferred 18 months, preferably 24 months, more preferred 30 months, preferably 36 months, or even longer.
  • the disintegrant makes it possible to provide a dispersion in a short time interval.
  • the solid pharmaceutical composition allows the provision of a dispersion comprising an amount of Nimorazole or a pharmaceutically acceptable salt thereof, wherein the amount of Nimorazole or a pharmaceutically acceptable salt thereof exceeds the solubility limit of Nimorazole in the water or the aqueous medium.
  • the solid pharmaceutical composition allows the provision of a dispersion comprising an amount of Nimorazole or a pharmaceutically acceptable salt thereof, wherein the amount of Nimorazole or a pharmaceutically acceptable salt thereof exceeds the 5 mg / ml of water or the aqueous medium.
  • the coating may serve as taste-masking, as Nimorazole has an unpleasant taste. An unpleasant taste may lower patient compliance. Additionally, a coating may improve storage stability of the pharmaceutical formulation.
  • Having a pharmaceutical composition which allows two different routes of administration carries a number of advantages. Firstly, patient compliance is improved, as the patient is already used to the pharmaceutical composition if or when the patient needs to change route of administration. Secondly, the costs associated with production and obtaining marketing approval are lowered, as only one product needs to be produced and approved.
  • the dispersion of the solid pharmaceutical composition may be done by the patient. It is further preferred that administration of the dispersion may be performed by the patient. This allows out-patient or ambulatory use.
  • An excipient is generally a pharmacologically inactive substance. Examples include, but are not limited to, diluents, disintegrants, binders, glidants, lubricants, and coatings. Other examples of suitable excipients may be found in Handbook of Pharmaceutical Excipients, 7 th Ed. by owe, Raymond C. et al., Pharmaceutical Press, London.
  • Diluents are inactive ingredients that are added to tablets and capsules in addition to the active drug. Some very common diluents in tablets include starch, cellulose derivatives, and magnesium stearate (also a lubricant). Diluents fill out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use. By increasing the bulk volume, diluents make it possible for the final product to have the proper volume for patient handling. A good diluent must be inert, compatible with the other components of the formulation, non-hygroscopic, relatively cheap, compactible, and preferably tasteless or pleasant tasting. Plant cellulose (pure plant Diluent) is a popular diluent in tablets or hard gelatin capsules.
  • Dibasic calcium phosphate is another popular tablet diluent.
  • a range of vegetable fats and oils can be used in soft gelatin capsules.
  • Other examples of diluents include: lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate.
  • Disintegrants expand and dissolve when wet causing the tablet to break apart. They ensure that when the tablet is in contact with water, it rapidly breaks down into smaller fragments, facilitating dissolution or dispersion.
  • disintegrants include, but are not limited to: crosslinked polymers, such as crosslinked polyvinylpyrrolidone (crospovidone), and crosslinked sodium carboxymethyl cellulose (croscarmellose sodium); and the modified starch sodium starch glycolate. Specific examples further include Indion 414, L-HPC, and pregelatinised starch.
  • Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to tablets.
  • binders include: saccharides and their derivatives: disaccharides, sucrose, lactose; polysaccharides and their derivatives, such as starches, cellulose or modified cellulose, such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); sugar alcohols such as xylitol, sorbitol or maltitol; further Protein: gelatin; and Synthetic polymers: polyvinylpyrrolidone (PVP), polyethylene glycol (PEG). Examples include gelatin, cellulose, cellulose derivatives,
  • polyvinylpyrrolidone starch, sucrose and polyethylene glycol.
  • Other examples include cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol.
  • Glidants are used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce die wall friction.
  • Examples include fumed silica, talc, and magnesium carbonate.
  • Lubricants are agents added to tablet and capsule formulations to improve certain processing characteristics. Lubricants inter alia prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall. Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are examples of lubricants used in tablets or hard gelatin capsules.
  • Coatings protect ingredients from deterioration by moisture in the air and make large or unpleasant-tasting tablets easier to swallow.
  • a cellulose ether hydroxypropyl methylcellulose (HPMC) film coating is used which is free of sugar and potential allergens.
  • other coating materials are used, for example synthetic polymers, shellac, corn protein zein or other polysaccharides.
  • a specific example is Opadry.
  • Capsules are coated with gelatin.
  • the invention concerns a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: diluent; disintegrant; binder; glidant; lubricant; and optionally one or more additional excipients; and a coating.
  • the invention concerns a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: diluent, 1 - 50 %; disintegrant, 0.5 - 15%; binder, 0.5 - 15 %; glidant, 0.5 - 3 %; lubricant, 0.5 - 3 %; and optionally one or more additional excipients; and a coating, 0.5 - 5 %.
  • the invention concerns a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: diluent, 2 - 25 %, preferably 4 - 15%, more preferred 6 - 10%, preferably 7-9%; disintegrant, 1 - 12 %, preferably 3 - 10%, more preferred 5 - 9%, preferably 7-8%; binder, 1 - 10 %, preferably 2 - 8%, more preferred 3 - 6%, preferably 4 - 5%; glidant, 0.6 - 2.5 %, preferably 0.8 - 2%, more preferred 0.9 - 1.8%, preferably 1 - 1.5%; lubricant, 0.6 - 2.5 %, preferably 0.8 - 2%, more preferred 0.9 - 1.8%, preferably 1 - 1.5%; and optionally one or more additional excipients; and a coating, 0.7 - 4 %, preferably 1 - 3%, more preferred 1.5 - 2.5%,
  • the invention concerns a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: a) An intragranular part, comprising: diluent, 1 - 50 %; disintegrant, 0.5 - 15%; and binder, 0.5 - 15 %; and
  • An extragranular part comprising: diluent, 0.5 - 50%; disintegrant, 0.5 - 15%; glidant, 0.5 - 3 %; and lubricant, 0.5 - 3 %; and
  • the invention concerns a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: a) An intragranular part, comprising: diluent, 2 - 25 %, preferably 4 - 15%, more preferred 6 - 10%, preferably 7 - 8%; disintegrant, 0.7 - 10 %, preferably 1 - 8%, more preferred 1.5 -
  • binder 1 - 10 %, preferably 2 - 8%, more preferred 3 - 6%, preferably 4-5%;
  • An extragranular part comprising: diluent, 0.7 - 25 %, preferably 0.8 - 10%, more
  • disintegrant 1 - 10 %, preferably 2 - 8%, more preferred 4 - 7%, preferably 5-6%
  • glidant 0.6 - 2.5 %, preferably 0.8 - 2%, more preferred 0.9 - 1.8%, preferably 1 - 1.5%
  • lubricant 0.6 - 2.5 %, preferably 0.8 - 2%, more preferred 0.9 - 1.8%, preferably 1 - 1.5%; and
  • a coating 0.7 - 4 %, preferably 1 - 3%, more preferred 1.5 - 2.5%, preferably 2 - 2.2%.
  • the invention concerns a pharmaceutical composition which is an immediate release tablet.
  • An immediate release tablet disintegrates in water within 30 minutes.
  • the invention concerns a pharmaceutical composition or a tablet for disintegration in water within 15 minutes, preferably 10 minutes, more preferred 5 minutes, preferably within 3 minutes to produce a dispersion for administration to a patient via a tube.
  • the invention concerns a pharmaceutical composition or a tablet, wherein said dispersion passes through a sieve screen with a nominal mesh aperture of 710 ⁇ .
  • the invention concerns a pharmaceutical composition or a tablet, which disintegrates within 10 min., preferably within 5 min., using water at 25°C, preferably 20°C, more preferred at 15°C.
  • the invention concerns a pharmaceutical composition which is a dispersible tablet.
  • dispersible tablet refers to a tablet, which may be dispersed in water before administration, providing a homogeneous dispersion. Dispersible tablets disintegrate within 3 minutes using water at 15 - 25°C. The fineness of dispersion should comply with a test comprising placing 2 tablets in 100 ml water and stirring until completely dispersed. A smooth dispersion is produced, which passes through a sieve screen with a nominal mesh aperture of 710 ⁇ .
  • the invention concerns a pharmaceutical composition or a tablet, which allows complete dispersion of one or more pharmaceutical compositions or tablets comprising a total of at least 1000 mg Nimorazole in 100 ml water at 25°C upon stirring, thereby providing a dispersion; said dispersion passing through a sieve screen with a nominal mesh aperture of 710 ⁇ .
  • complete dispersion covers the case wherein at least 90%, more preferred at least 95%, preferably at least 98%, more preferred 99%, preferably 100% Nimorazole is dispersed or dissolved.
  • the invention concerns a pharmaceutical composition or a tablet for administration via a feeding tube.
  • the invention concerns a pharmaceutical composition or a tablet for administration via a feeding tube selected among the group consisting of a percutaneous endoscopic gastrostomy tube, a nasogastric feeding tube, a nasojejunal feeding tube, a gastric feeding tube, and a jejunostomy feeding tube.
  • the invention concerns a pharmaceutical composition or a tablet for administration via a percutaneous endoscopic gastrostomy (“PEG”) tube or a nasogastric (“NG”) feeding tube.
  • PEG percutaneous endoscopic gastrostomy
  • NG nasogastric
  • the invention concerns a pharmaceutical composition or a tablet for treatment of bedridden or geriatric patients. These patient groups often suffer from difficulties swallowing tablets. According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for treatment of patients undergoing irradiation treatment, particularly irradiation treatment of the head and/or neck region.
  • the invention concerns a pharmaceutical composition or a tablet for treatment of intubated patients, such as patients having inserted a tube into the
  • the invention concerns a pharmaceutical composition or a tablet for treatment of patients having received at least a number selected among 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 irradiation treatments for cancer of the head and/or neck region.
  • Nimorazole is usually administered from the first irradiation treatment, using a tube becomes particularly relevant when the patient begins to experience problems swallowing, usually from the 5th or 6th irradiation treatment.
  • the need for administration of Nimorazole via a feeding tube does usually not occur before after the 4 th or 5 th irradiation treatment, as the swallowing difficulties is usually not present early.
  • direct oral administration is preferred, i.e. in the form of a tablet taken orally, while the need for administration via a feeding tube usually occurs later, i.e. from the 5 th or 6 th irradiation treatment.
  • Nimorazole tablet for a Nimorazole tablet to be used with concurrent radiotherapy, it is convenient to have a tablet which may both be administered directly orally, and which may be used for making a dispersion or solution for administration via a feeding tube.
  • the tablet due to the unpleasant taste of Nimorazole, it is preferable that the tablet comprises a coating, masking the taste.
  • the invention concerns a pharmaceutical composition or a tablet for swallowing or for disintegration in water or an aqueous medium and administration via a tube.
  • This tablet is specifically adapted to allow swallowing or allow disintegration in water or an aqueous medium at the discretion of a person administering the tablet.
  • the invention concerns a pharmaceutical composition or a tablet further comprising a coating facilitating swallowing and masking the taste of Nimorazole.
  • Nimorazole The taste of Nimorazole is unpleasant to most patients. Thus, without a coating, many patients will feel the swallowing of Nimorazole tablets objectionable. However, a coating tends to impede the disintegration of the tablet in water. Surprisingly, it has been possible to device a coating, which facilitates swallowing, and masks the taste of Nimorazole, and still allows producing a dispersion in water quickly.
  • the invention concerns a pharmaceutical composition or a tablet for curative treatment or reirradiation of cancer.
  • the invention concerns a pharmaceutical composition or a tablet for 1 st line irradiation treatment of cancer with curative intent or 2 nd line reirradiation treatment of cancer with curative and/or palliation intent.
  • the invention concerns a pharmaceutical composition or a tablet for curative or palliative treatment of cancer in patients undergoing radiotherapy, particularly for patients with cancer in the head and/or neck region.
  • the invention concerns a pharmaceutical composition or a tablet for treatment of patients with hypoxic cancer. Methods for testing whether cancers are hypoxic are known in the art.
  • the invention concerns a pharmaceutical composition or a tablet for treatment of an indication selected among breast cancer, head/neck cancer, esophagus cancer, lymphoma, cervical cancer, colorectal cancer, brain cancer, lung cancer, bladder cancer, and prostate cancer.
  • the invention is particularly relevant for patients with a swallowing problem, which may or may not be caused by irradiation treatment.
  • the cancer treatment may be with or without concurrent chemotherapy.
  • the invention concerns a pharmaceutical composition or a tablet for treatment of head/neck cancer.
  • the invention concerns a pharmaceutical composition or a tablet for treatment of cervical cancer or inoperable lung cancer.
  • the invention concerns a pharmaceutical composition or a tablet for treatment of non-smokers.
  • Nimorazole may appear to have reduced or little influence on the efficacy of irradiation treatment of cancer among patients who have not stopped smoking during treatment.
  • cessation of smoking during therapy is warranted.
  • the invention concerns a pharmaceutical composition, comprising at least 250 mg Nimorazole or a pharmaceutically acceptable salt thereof. According to an embodiment, the invention concerns a pharmaceutical composition, comprising 10 - 2500 mg, more preferred 100 - 2000 mg, preferably 300 - 1500 mg, more preferred 400 - 1000 mg, preferably 500 mg Nimorazole or a pharmaceutically acceptable salt thereof.
  • the invention concerns a pharmaceutical composition or a tablet, subject to the proviso that 3 - 5 of said pharmaceutical compositions or tablets may be dispersed in 2 dl water at 25°C, preferably 20°C, more preferred 15°C within 15, preferably 10, more preferred 5, preferably within 3 minutes.
  • the invention concerns a pharmaceutical composition or a tablet allowing dispersion of 1500 - 2500 mg, preferably 2000 mg, Nimorazole in 2 dl water at 25°C, preferably 20°C, more preferred 15°C within 15, preferably 10, more preferred 5, preferably within 3 minutes.
  • the invention concerns a pharmaceutical composition or a tablet for treatment alone or combined with chemotherapy.
  • the invention concerns a tablet for treatment alone or combined with chemotherapy for patients undergoing irradiation of a total of > 40 Grey during a course of treatment.
  • the invention concerns a kit of parts comprising a pharmaceutical composition according to the invention, and instructions for preparing a dispersion of said pharmaceutical composition for administration via a tube.
  • the invention concerns a method for manufacturing a
  • composition comprising wet granulation of Nimorazole.
  • the invention concerns a method for manufacturing a
  • the invention concerns a method for manufacturing a
  • the invention concerns a method for manufacturing a
  • composition comprising drying the wet granular mass resulting from a wet granulation until a pre-determined loss on drying (%LOD) is obtained.
  • the invention concerns a method for manufacturing a
  • composition comprising drying the wet granular mass resulting from a wet granulation until said %LOD is in the range of 0 to 10%, preferably 0.5 to 5.0%, more preferred within 1.5 to 3.0%.
  • the invention concerns a method for manufacturing a
  • the invention concerns a method for manufacturing a
  • composition comprising sifting all extragranular ingredients through a 20#, preferably 25#, more preferred 30# sieve or finer prior to compression.
  • the invention concerns a method of treatment of cancer, wherein irradiation treatment is combined with the administration of at least one tablet according to the invention, wherein said at least one tablet is allowed to disintegrate in water or an aqueous medium and administered via a tube.
  • This method is particularly preferred for patients with swallowing difficulties undergoing treatment with Nimorazole.
  • the invention concerns a method of radiosensitizing hypoxic tumor cells comprising administering Nimorazole, wherein the administration comprises: Providing a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof; Dispersing said solid pharmaceutical composition in water or an aqueous medium to obtain a dispersion; and Administering said dispersion via a tube.
  • Patients receiving Nimorazole in form of tablets may have difficulties swallowing.
  • a new route or way of administration of Nimorazole particularly suitable for these patients is suggested.
  • the dispersion to be administered may easily be prepared by the patient, in particular without the need to crush tablets.
  • the invention concerns a use of a tablet according to the invention, wherein said tablet is dispersed in water and administered via a tube.
  • the invention concerns an aqueous pharmaceutical composition
  • aqueous pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, wherein at least part of said Nimorazole or pharmaceutically acceptable salt thereof is dispersed in water or an aqueous medium in form of solid particles.
  • the invention concerns an aqueous pharmaceutical composition obtainable by dispersing a pharmaceutical composition in water or an aqueous medium.
  • the invention concerns an aqueous pharmaceutical composition, wherein said Nimorazole or pharmaceutically acceptable salt is present in a concentration exceeding 5 mg / ml water or an aqueous medium.
  • concentration refers to the abundance of a constituent divided by the total volume of a mixture.
  • concentration can be applied to any kind of mixture, and is not confined to solutes and solvents in solutions.
  • the invention concerns a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising: i) Nimorazole or a pharmaceutically acceptable salt thereof; ii) a disintegrant; iii) optionally one or more additional excipients; and iv) a coating; said pharmaceutical composition allowing oral administration, preferably as a tablet, and further allowing, as an alternative, administration via a feeding tube, wherein prior to administration via a feeding tube the pharmaceutical composition is disintegrated in water or an aqueous medium to provide a dispersion which is administered via the feeding tube.
  • the invention concerns the pharmaceutical composition wherein the additional excipients comprise a diluent, a binder, a glidant, and a lubricant.
  • the invention concerns the pharmaceutical composition comprising: diluent, 1 - 50 wt%; disintegrant, 0.5 - 15 wt%; binder, 0.5 - 15 wt%; glidant, 0.5 - 3 wt%; lubricant, 0.5 - 3 wt%; optionally one or more additional excipients; and a coating, 0.5 - 5 wt%.
  • the invention concerns the pharmaceutical composition
  • the pharmaceutical composition comprising: diluent, 7 - 9 wt%; disintegrant, 7 - 8 wt%; binder, 4 - 5 wt%; glidant, 1 - 1.5 wt%; lubricant, 1 - 1.5 wt%; optionally one or more additional excipients; and a coating, 2 - 2.2 wt%.
  • the invention concerns the pharmaceutical composition
  • a pharmaceutical composition comprising: an intragranular part, comprising a diluent, a disintegrant, and a binder; an extragranular part, comprising a diluent, a disintegrant, a glidant, and a lubricant; and a coating.
  • the invention concerns the pharmaceutical composition that is formulated as a tablet, an immediate release tablet or a dispersible tablet.
  • the invention concerns the pharmaceutical composition that disintegrates in water at 20°C within 5 minutes. According to an embodiment, the invention concerns the pharmaceutical composition that after disintegration in water or an aqueous medium passes through a sieve screen with a nominal mesh aperture of 710 ⁇ .
  • the invention concerns the pharmaceutical that can be dispersed to provide at least 1000 mg Nimorazole in 100 ml water at 25°C within 5 minutes upon stirring, wherein said dispersion passes through a sieve screen with a nominal mesh aperture of 710 ⁇ .
  • the invention concerns the pharmaceutical composition, wherein the feeding tube is selected from the group consisting of a percutaneous endoscopic gastrostomy tube, a nasogastric feeding tube, a nasojejunal feeding tube, a gastric feeding tube, and a jejunostomy feeding tube.
  • the feeding tube is selected from the group consisting of a percutaneous endoscopic gastrostomy tube, a nasogastric feeding tube, a nasojejunal feeding tube, a gastric feeding tube, and a jejunostomy feeding tube.
  • the invention concerns the pharmaceutical composition, wherein the coating facilitates swallowing and masks the taste of Nimorazole.
  • the invention concerns the pharmaceutical composition, wherein the composition comprises at least 250 mg Nimorazole or a pharmaceutically acceptable salt thereof per dosing unit.
  • the invention concerns the pharmaceutical composition that can be dispersed to provide at least 2000 mg of Nimorazole or a pharmaceutically acceptable salt thereof in 2 dl of water at 25°C within 3 minutes.
  • the invention concerns a kit of parts comprising the pharmaceutical composition and instructions for preparing a dispersion of the pharmaceutical composition for administration to a patient via a feeding tube.
  • the invention concerns a kit of parts comprising: a) a solid pharmaceutical composition comprising: i) Nimorazole or a pharmaceutically acceptable salt thereof; ii) a disintegrant; iii) optionally one or more additional excipients; and iv) a coating; said pharmaceutical composition allowing administration to a patient via a feeding tube by disintegrating the solid pharmaceutical composition in water or an aqueous medium to provide a dispersion which is administered via the feeding tube; and b) instructions for disintegrating the solid pharmaceutical composition in water or an aqueous medium to form a dispersion and administering the dispersion via a feeding tube.
  • the invention concerns the pharmaceutical composition, made by a method comprising performing wet granulation of a composition comprising Nimorazole or a pharmaceutically acceptable salt thereof.
  • the invention concerns a method for manufacturing a
  • composition the method comprising performing wet granulation of Nimorazole or a pharmaceutically acceptable salt thereof.
  • the invention concerns a method of treating cancer by
  • radiosensitizing hypoxic tumor cells comprising performing radiation treatment combined with the administration of at least one solid pharmaceutical composition comprising: i) Nimorazole or a pharmaceutically acceptable salt thereof; ii) a disintegrant; iii) optionally one or more additional excipients; and iv) a coating; wherein said at least one solid pharmaceutical composition is allowed to disintegrate or is dispersed in water or an aqueous medium and administered to a patient via a feeding tube.
  • the invention concerns a method of treating cancer by
  • radiosensitizing hypoxic tumor cells comprising performing radiation treatment combined with the administration of at least one solid pharmaceutical composition, wherein said at least one solid pharmaceutical composition is allowed to disintegrate or is dispersed in water or an aqueous medium and administered to a patient via a tube.
  • the invention concerns the method, wherein the radiation treatment comprises: providing said solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof; dispersing the solid pharmaceutical composition in water or an aqueous medium to obtain a dispersion; administering the dispersion to a patient via a feeding tube; and administering radiation to the patient.
  • the invention concerns the method, wherein the dispersion contains said Nimorazole or pharmaceutically acceptable salt thereof at a concentration exceeding 5 mg / ml of water or the aqueous medium.
  • the invention concerns the method, further comprising
  • the invention concerns the method, wherein the cancer is selected from the group consisting of breast cancer, head/neck cancer, esophagus cancer, lymphoma, cervical cancer, colorectal cancer, brain cancer, lung cancer, bladder cancer, and prostate cancer.
  • the invention concerns a dispersion containing dispersed particulate Nimorazole or a pharmaceutically acceptable salt thereof in water or an aqueous medium, wherein the concentration of Nimorazole or its pharmaceutically acceptable salt exceeds the solubility limit in water or the aqueous medium, and wherein the dispersion is formulated for administration to a patient via a feeding tube.
  • the invention concerns the aqueous dispersion, wherein the particulate Nimorazole or its pharmaceutically acceptable salt has an average diameter of less than 710 ⁇ .
  • Purified water BP as. as. as. as.
  • Crospovidone (Kollidon Ph. Eur. 35 35 35 45.5 CL)
  • Purified water evaporates during process and does not appear in finished product.
  • Crospovidone was replaced with Sodium Starch Glycolate for Tablet Al. Tablets were manufactured using the following steps. i. Sifting with vibratory sifter: Crospovidone was mixed with cellulose microcrystalline PH 101 and finally mixed with Nimorazole. The material was sifted through a 30# sieve using vibratory sifter.
  • Binder preparation and binder addition Povidone K30 was dispersed into weighed quantity of purified water to prepare a 20% w/w dispersion under stirring.
  • step ii. The binder of step ii. was added into step iii. within 2 minutes with slow speed of impeller, keeping Chopper off. If required, additional sufficient quantity of purified water was added within one min.
  • step iv. The wet mass of step iv. was mixed up to 1 minute with slow speed of impeller and slow speed chopper to get uniform consistency of the wet mass.
  • the wet mass was discharged from Rapid Mixer Granulator with impeller at slow speed.
  • step v. The wet mass of step v. was passed through a 8.00 mm screen using co-mill at 700 RPM.
  • step vii. Drying in fluidized bed processor / dryer of the wet granular mass was performed with an inlet temperature of 60 ⁇ 10°C, ensuring uniform drying, until loss on drying (%LOD) was obtained.
  • the percent loss on drying (%LOD) of the granules was determined at 105°C in auto mode in moisture analyzer, and drying was continued until %LOD reached within the limit, in the range of 1.5 to 3.0%.
  • step vii. Sizing: The dried granules obtained in step vii. were sifted through a 20# sieve using Vibratory sifter to get uniform sized granules.
  • step viii. 20# retained granules of step viii. were sifted through 14#. 14# retained and 14# passed granules were collected separately.
  • step ix The 14# retained granules obtained in step ix. were milled through 2.0mm SS screen using co-mill at 700 PM. The milled granules were passed through 20# sieve using vibro sifter.
  • step xi Both the oversized granules obtained in step x. and 14# passed 20# retained fraction of step ix. were milled through 1.0mm SS screen using co-mill at 700 RPM. The milled granules were passed through 20# sieve using vibro sifter.
  • Blending & Lubrication in pillar type bin blender Extragranular cellulose
  • microcrystalline and crospovidone was sifted through 40# sieve using vibratory sifter. Subsequently, this was blended with the sifted granules for 10 minutes. Separately, silica colloidal anhydrous and magnesium stearate was sifted through 30# sieve using vibratory sifter. The mixture was added, and lubrication performed for 3 minutes.
  • Coating dispersion preparation in stirrer Opadry 03B57695 Grey was dispersed in to weighed quantity of purified water to prepare a 10% w/w dispersion under stirring. xvi.
  • Coating in autocoater The compressed core tablets were sprayed with the film
  • the coating dispersion was at 45°C inlet temperature.
  • Tablets Al, A2, A3 and A4 are all suitable for oral administration as well as dispersion in water before being administered via a feeding tube.
  • the tablets differed in terms of time necessary for dispersion and storage stability. Preliminary experiments indicate the amount of coating provides a trade-off between storage stability and dispersion time. More coating tend to provide improved storage time but also increased time for disintegration or dispersion.
  • Crospovidone (Kollidon CL)
  • Crospovidone (Kollidon CL)
  • This oral powder is less suited for direct oral administration without being dispersed in water.
  • Nimorazole Cellulose Microcrystalline, Silica Colloidal Anhydrous, Maize Starch, Hydroxypropylcellulose, Povidone granulated by spraying granulating fluid by using Top spray assembly. Granules further coated with basic butylated methacrylate copolymer hydro-alcoholic solution. Quantity equivalent to unit dose packed in sachet dispersed in 250 ml of water delivers 500 mg.
  • Tablets Al had a thickness of 5.61 to 5.65 mm. The disintegration time was measured to 2 - 3 min. Tablet A2
  • Tablets A2 had a thickness of 5.65 to 5.68 mm. The disintegration time was measured to 18 seconds.
  • the % Cumulative Drug Release was measured in 900 ml 0.1 N HCI in a USP type II apparatus at 50 RPM for 30 minutes, with measurements performed at 5, 10, 20, and 30 minutes.
  • Crospovidone as a disintegrant instead of Sodium Starch Glycolate decreased the disintegration time, and provided a significant increase in dissolution rate, wherein more than 85% of the drug was released within 5 minutes.
  • the tablet Al (500 mg) of the present invention was compared with the tablet F4 (200 mg) of the prior art (this tablet is described in the article "Formulation and In-Vitro Characterization of Nimorazole Mouth Dissolving Tablets", Ratnaparkhi, Mukesh R et al., Research Journal of
  • Dispersibility tests were performed using water at room temperature.
  • a tablet Al 500 mg was dispersed in 50 ml water in a glass beaker, while a tablet F4 (200 mg) was dispersed in 20 ml water glass beaker. Stirring was continued for 3 min.
  • Tablets of the invention Al (500 mg), were compared with prior art tablets, F4 (200 mg, Ibid.). Mixtures of water at room temperature and tablets were prepared as noted in the tablet below.
  • Mixture I provided a stable, homogenous dispersion, having a milky appearance (Fig. 3, right).
  • the dispersion of Mixture I showed long term stability.
  • Mixture II (Fig. 3, left) and Mixture III both provided non-homogenous mixtures, with a clear phase separation between solvent and precipitate.
  • Mixture I was a smooth dispersion, while Mixture II and Mixture III were not. Further, it was noted that for Mixture I negligible amounts of material was left behind in the bottle used for mixing, while for Mixture II and III clearly visible lumps of the tablets were left behind. This indicates that for Mixture II and Mixture III not all of the active ingredient would be present in the mixture poured from the bottle. Further, that the use of Mixture II and III would increase the risk of blocking a feeding tube, and that the release of active ingredient from the Mixtures II and III would be slower than for Mixture I, due to the larger particle sizes resulting from making mixtures of the prior art tablet.
  • the prior art tablet F4 exhibits slower dissolution rate expressed in percentage at all measured points in time than the tablets Al and A2 (see above) of the present invention. It is additionally surprisingly, since the prior art tablets F4 comprise 200 mg active ingredient, while the present tablets, Al and A2, comprise 500 mg active ingredient. This should favor the % cumulative drug release of the tablets F4 as the actual concentration of the active ingredient Nimorazole is lower in the USP apparatus for the 200 mg tablets. Thus, it is an advantage of the present tablet that higher dissolution rates are achieved in vitro, making it easier to achieve peak serum level of the active ingredient at a specific time, coinciding with irradiation treatment, and further increasing the serum peak level of the active ingredient.
  • the tablet Al (500 mg) of the present invention was compared with the tablet F4 (200 mg) of the prior art (described in the article "Formulation and In-Vitro Characterization of Nimorazole Mouth Dissolving Tablets", atnaparkhi, Mukesh R et al., Research Journal of Pharmaceutical, Biological and Chemical Sciences (2012), Vol. 3, Issue 3, pp. 303-308.
  • Test Person 2 1 No taste during the 30 seconds. 7: Very unpleasant taste
  • the mouth dissolving tablet F4 would be unsuitable for patients having no saliva. Further, due to the very unpleasant taste, this tablet would not be suitable for combination with irradiation treatment, due to the large amounts of active ingredient and thus tablets required.
  • the suggested mode of administration of F4 i.e. mouth dissolving is hence not suitable for treatments of patients.

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Abstract

La présente invention concerne un comprimé comprenant du nimorazole. L'invention concerne en particulier une composition pharmaceutique ou un comprimé comprenant du nimorazole ou un sel pharmaceutiquement acceptable de celui-ci, à disperser dans l'eau et à administrer via un tube à un patient présentant des difficultés de déglutition.
PCT/DK2013/050384 2012-11-19 2013-11-18 Comprimé dispersible WO2014075692A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
US14/443,262 US20150283083A1 (en) 2012-11-19 2013-11-18 Dispersible Tablet
EP13798918.2A EP2919754A1 (fr) 2012-11-19 2013-11-18 Comprimé dispersible
RU2015117921A RU2015117921A (ru) 2012-11-19 2013-11-18 Диспергируемая таблетка
AU2013347264A AU2013347264B2 (en) 2012-11-19 2013-11-18 Dispersible tablet
JP2015542166A JP2015537013A (ja) 2012-11-19 2013-11-18 速崩性錠剤
MX2015006217A MX2015006217A (es) 2012-11-19 2013-11-18 Tableta dispersable.
EA201590732A EA201590732A1 (ru) 2012-11-19 2013-11-18 Диспергируемая таблетка
CA2888856A CA2888856A1 (fr) 2012-11-19 2013-11-18 Comprime dispersible
BR112015011408A BR112015011408A2 (pt) 2012-11-19 2013-11-18 comprimido dispersível
NZ707033A NZ707033A (en) 2012-11-19 2013-11-18 Dispersible nimorazole tablet
TNP2015000156A TN2015000156A1 (en) 2012-11-19 2015-04-22 Dispersible tablet
ZA2015/02896A ZA201502896B (en) 2012-11-19 2015-04-28 Dispersible tablet
SA515360445A SA515360445B1 (ar) 2012-11-19 2015-05-17 قرص قابل للتشتيت
MA38211A MA38211A1 (fr) 2012-11-19 2015-06-18 Comprimé dispersible

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DKPA201270714 2012-11-19
US13/680,216 2012-11-19
US13/680,216 US8703188B1 (en) 2012-11-19 2012-11-19 Dispersible tablet
DK201270714A DK177906B1 (en) 2012-11-19 2012-11-19 Dispersible tablet

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CA (1) CA2888856A1 (fr)
EA (1) EA201590732A1 (fr)
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TN (1) TN2015000156A1 (fr)
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AU2016212116B2 (en) * 2015-01-27 2021-07-15 Janssen Pharmaceutica Nv Dispersible compositions
US11324734B2 (en) 2015-04-01 2022-05-10 Akebia Therapeutics, Inc. Compositions and methods for treating anemia

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WO2008066716A2 (fr) * 2006-11-30 2008-06-05 Johnson & Johnson Consumer Companies, Inc. Forme galénique solide enrobée d'un film
WO2011127537A1 (fr) * 2010-04-14 2011-10-20 Phebra Pty Ltd Compositions radio-sensibilisatrices

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JP2008081448A (ja) * 2006-09-28 2008-04-10 Kowa Pharmaceutical Co Ltd 酒石酸ゾルピデムの苦味マスキング速放性粒子
EP2510950B1 (fr) * 2009-12-11 2018-11-28 Sumitomo Dainippon Pharma Co., Ltd. Comprimé enrobé à sec à désintégration orale

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WO2008066716A2 (fr) * 2006-11-30 2008-06-05 Johnson & Johnson Consumer Companies, Inc. Forme galénique solide enrobée d'un film
WO2011127537A1 (fr) * 2010-04-14 2011-10-20 Phebra Pty Ltd Compositions radio-sensibilisatrices

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2016212116B2 (en) * 2015-01-27 2021-07-15 Janssen Pharmaceutica Nv Dispersible compositions
AU2021204135B2 (en) * 2015-01-27 2023-10-05 Janssen Pharmaceutica Nv Dispersible compositions
IL253626B1 (en) * 2015-01-27 2024-04-01 Janssen Pharmaceutica Nv dispersible preparations
IL253626B2 (en) * 2015-01-27 2024-08-01 Janssen Pharmaceutica Nv dispersible preparations
US11324734B2 (en) 2015-04-01 2022-05-10 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US11844756B2 (en) 2015-04-01 2023-12-19 Akebia Therapeutics, Inc. Compositions and methods for treating anemia

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JP2015537013A (ja) 2015-12-24
AU2013347264B2 (en) 2016-10-27
EP2919754A1 (fr) 2015-09-23
BR112015011408A2 (pt) 2017-07-11
CA2888856A1 (fr) 2014-05-22
NZ707033A (en) 2016-11-25
TN2015000156A1 (en) 2016-10-03
EA201590732A1 (ru) 2016-01-29
MX2015006217A (es) 2015-11-16

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