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
  • A61K9/48—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
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • 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

Definitions

• This invention relates to a new oral controlled release ketoprofen pharmaceutical formulations for once daily administration.
• Ketoprofen which is chemically 2-(3-benzoylphenyl) propionic acid, is a non- steroidal anti-inflammatory drug with a ⁇ ti-inflammatory, analgesic and antipyretic properties. Ketoprofen is a weak acid, almost insoluble in water. It is quickly absorbed from the upper gastrointestinal tract and is rapidly eliminated from the body.
• ketoprofen controlled release formulations are known in the art. Among those are also multi-unit dosage forms, e.g. capsules containing granules, pellets or tablets, covered by a release-controlling coating.
• EP 403 383 discloses pharmaceutical ketoprofen dosage form containing granules, in which the extruded core contains ketoprofen and microcrystalline cellulose, while the coating contains a water-soluble cellulose derivative and 60 to 90% of cellulose derivative, which is insoluble in water.
• the coating contains preferably ethyl cellulose and hydroxypropyl methylcellulose.
• US 6197347 describes pellets having an inert core to which ketoprofen has been applied, and a coating which contains ethyl cellulose and shellac. Described are also capsules containing these pellets.
• WO 00/64433 and WO 00/64432 describe ketoprofen prolonged release microgranules containing an inert core to which ketoprofen is applied and a coating comprising acrylic polymers Eudragit RL and Eudragit SR in the ratio of 50:50 or 90:10. Capsules containing 200 mg of ketoprofen are described.
• EP 653935 describes peiletised sustained release pharmaceutical compositions of poorly soluble non-steroidal anti-inflammatory ingredients, preferably diclofenac, ketorolac and indomethacin.
• the active ingredient layer is applied to the inert pellet core.
• the coating layer contains an insoluble polymer, an acidoresistant polymer, and a plasticiser. The ratio of the acidoresistant polymer present in the coating is at least 30%.
• EP 288138 describes multi-unit controlled release pharmaceutical dosage forms of non-steroidal anti-inflammatory ingredients, in which the spheroid cores contain at least 70% of microcrystalline cellulose and at least one water-soluble and/or swelling cellulose derivative, e.g. hydroxypropy! cellulose or hydroxypropyl methylcellulose.
• the object of the present invention is to provide a safe controlled release pharmaceutical formulation that can provide suitable ketoprofen therapeutic levels for 24 hours and is suitable for once daily administration.
• This invention provides for a novel controlled release multi-unit pharmaceutical formulation comprising ketoprofen, used for once daily administration.
• the subject of the invention is a hard gelatine capsule comprising ketoprofen pellets, consisting of an extruded core and a coating. Coated pellets are designed to prevent release of acidic ketoprofene in the stomach, and therefore to protect gastric mucosa against the acid ingredient. After passage of the pellets into neutral environment of the duodenum and small intestine, they gradually release ketoprofen and provide adequate plasma concentrations of ketoprofen over an extended period of time.
• This invention relates also to pellets comprising ketoprofen.
• the composition of the pellet cores is very simple and allows incorporation of a high amount of the active ingredient in the core.
• Pellet cores may contain only ketoprofen and microcrystalline cellulose.
• Ketoprofen may be present in an amount from about 50 to about 97 % w/w of the pellet core.
• Microcrystalline cellulose may be any commercially available form of microcrystalline cellulose, e.g. various types of Avicel ® , Emocel ® , Vivacel ® , and the like. Particularly suitable is Avicel ® PH 101. Appropriate is also silicified microcrystalline cellulose, e. g. Prosolv ® . Pellet cores may comprise from about 3 to about 50 % w/w of microcrystalline cellulose.
• Pellet cores may optionally contain other excipients, such as e. g. binders (e. g. various types of polyvinylpyrrolidone, gelatine, various types of starch, different carboxymethyl celluloses, mono- and disaccharides, etc.), various surfactants (polysorbate 80, sodium lauryl sulphate, etc.), fillers (e. g. lactose and other mono- and disaccharides, calcium phosphate, calcium hydrogen phosphate), disintegrants (various starches, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and the like).
• binders e. g. various types of polyvinylpyrrolidone, gelatine, various types of starch, different carboxymethyl celluloses, mono- and disaccharides, etc.
• various surfactants polysorbate 80, sodium lauryl sulphate, etc.
• fillers e. g
• the coating applied to the core comprises at least one acidoresistant polymer and at least one insoluble polymer. Only one coating is used that provides delayed release of ketoprofen depending on the pH, and an prolonged release over a prolonged period of time.
• the coating contains preferably only talc besides the polymers and the colouring agent, if needed.
• One coating is of technological advantage, as it is prepared once and applied once.
• the manufacturing process is environment friendly because it does not require usage of organic solvents. Water is the only solvent used.
• the acidoresistant polymer may be any acidoresistant polymer which is available in the form of aqueous dispersion, e. g. acrylic polymers (Eudragit ® ), cellulose acetate phthalate (Aquateric ® ), hydroxypropyl methylcellulose acetate succinate (Aqoat ® ), carboxymethylethyl cellulose ether (Duodcell ® ), polyvinyl acetate phthalate (Sureteric ® ).
• Eudragit ® L 30 D-55 is a particularly suitable acidoresistant polymer; it is anionic copolymer of methacrylic acid and methylmethacrylate in the ratio 1 :1 , which is available in the form of aqueous dispersion 30 %.
• the insoluble polymer may be any insoluble polymer available in the form of aqueous dispersion, e. g. ethyl cellulose (Surelease ® , Aquacoat ® ) and acrylic polymers used for controlled release, such as Eudragit ® NE 30 D or Eudragit ® RS 30 D.
• aqueous dispersion e. g. ethyl cellulose (Surelease ® , Aquacoat ® ) and acrylic polymers used for controlled release, such as Eudragit ® NE 30 D or Eudragit ® RS 30 D.
• a particularly suitable insoluble polymer is Eudragit ® NE 30 D, not soluble, but swellable in water, which is a copolymer of ethylacrylate and methylmetacrylate in the ratio 2:1 , which is available in the form of 30 % aqueous dispersion.
• the ratio of the insoluble polymer and of acidoresistant polymer may be between 7:3 and 19:1 , preferably 3:1.
• the amount of the coating may be from about 5 to about 20 % w/w of the total weight of the coated pellets, preferably from about 8 to about 12 % w/w of the coated pellets.
• the coating may also contain other excipients, such as e. g. plasticisers (triethyl citrate, tributhyl citrate, triacetin, dibuthyl phthalate, polyethylene glycols (200, 400, 600, 6000), glycerol), antiadhesives (talc, magnesium stearate, glycerol monostearate), pigments, colouring agents, and dispersion agents.
• plasticisers triethyl citrate, tributhyl citrate, triacetin, dibuthyl phthalate, polyethylene glycols (200, 400, 600, 6000), glycerol), antiadhesives (talc, magnesium stearate, glycerol monostearate), pigments, colouring agents, and dispersion agents.
• plasticisers triethyl citrate, tributhyl citrate, triacetin, dibuthyl phthalate
• polyethylene glycols 200, 400, 600
• the size of the coated pellets may be from about 0.2 to about 2.0 mm, preferably between about 0.7 and about 1.3 mm.
• Pellets according to the present invention may be prepared by processes well known in the art. Ketoprofen and microcrystalline cellulose powders are mixed homogeneously and granulated with demineralised water in which optionaly the binder has been dissolved. The granulated mixture is extruded and spheronized. The prepared pellet cores are dried in a fluid bed dryer.
• Film coating shall be applied preferably by spraying the dispersion of polymers in fluid-bed devices, such as: Wurster chamber, Huettlin Kugelcoater, etc. Coating parameters vary from device to device, but it is important, however, that product temperature is below 30 °C. After the coating process, the film forming process shall be applied to pellets prepared in this fashion during 2 to 24 hours at temperatures from 40 to 60 °C.
• the pellets thus obtained may be filled into capsules or sachets, or compressed into tablets.
• the pharmaceutical formulation according to the present invention may also be a tablet.
• Pellets of the invention may be mixed with the excipients and compressed into tablets.
• Suitable excipients may be fillers (microcrystalline cellulose, calcium hydrogen phosphate), disintegrants (various starches, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, glidants (talc, magnesium stearate, etc.).
• the subject of this invention are also sachets comprising the pellets of the invention.
• ketoprofen according to this invention may contain between about 100 mg and about 300 mg of ketoprofen, preferably about 200 mg of ketoprofen.
• the pharmaceutical formulation according to the present invention may contain other active ingredients instead of ketoprofen, which are weak acids that are almost insoluble in water.
• Such ingredients are e. g. naproxen and indomethacin.
• Example 1 The invention is illustrated by, but not limited to, the following examples: Example 1
• the mixture of ketoprofen and of microcrystalline cellulose powders was mixed homogeneously and granulated for 1 minute at 100 rpm with demineralised water in a high shear mixer.
• the granulate was extruded in a screw extruder through the die plate with 1 mm openings at 95 rpm.
• the extrudate was spheronised for 60 seconds in the spheroniser on a cross hatch plate (spheronising speed 12 m/s).
• Pellet cores prepared in this fashion were dried in a fluid bed apparatus, at moderate fluidisation, at a temperature of the inlet air 30 °C, until a loss on drying under 2 %.
• Pellets were sifted through sieves 0.7 mm and 1.2 mm, respectively.
• Pellets with particle size between 0.7 and 1.2 mm were used for film coating.
• the film coating dispersion was prepared so as to combine and mix individual components. During the coating process the dispersion was mixed thoroughly.
• Pellet cores were coated in a fluid-bed machine.
• the coating dispersion was sprayed on the pellet cores, with moderate fluidisation of pellets; the coating parameters were adjusted so as to preserve the product temperature between 20 and 25 °C.
• the mixture of ketoprofen and of microcrystalline cellulose powders was mixed homogeneously and granulated for 1 minute at 100 rpm with demineralised water in a high shear mixer.
• the granulate was extruded in a screw extruder through the die plate with 1 mm openings at 95 rpm.
• the extrudate was spheronised for 60 seconds in the spheroniser on a cross hatch plate (spheronising speed 12 m/s).
• Pellet cores prepared in this fashion were dried in a fluid bed apparatus using moderate fluidisation, at a temperature of the inlet air 30 °C, until a loss on drying under 2 %.
• Pellets were sifted through sieves 0.7 and 1.2 mm.
• pellets with particle size between 0.7 and 1.2 mm were used.
• the coating dispersion was prepared so as to combine and mix the individual components. During the coating process the dispersion was mixed thoroughly.
• Pellet cores were coated in a fluid-bed machine.
• the coating dispersion was sprayed on the pellet cores, at moderate fluidisation of pellets; the coating parameters were adjusted so as to preserve the product temperature between 20 and 25 °C.
• the film forming step was performed for 12 hours at 40 °C. Pellets were filled in capsules No. 1.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)

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• 2003
  • 2003-11-12 SI SI200300275A patent/SI21638A/sl not_active IP Right Cessation
• 2004
  • 2004-11-11 EP EP04800455A patent/EP1703900A1/de not_active Withdrawn
  • 2004-11-11 WO PCT/SI2004/000037 patent/WO2005046652A1/en active Search and Examination

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