WO2004024128A2 - Modified release ketoprofen dosage form - Google Patents

Modified release ketoprofen dosage form Download PDF

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Publication number
WO2004024128A2
WO2004024128A2 PCT/SI2003/000033 SI0300033W WO2004024128A2 WO 2004024128 A2 WO2004024128 A2 WO 2004024128A2 SI 0300033 W SI0300033 W SI 0300033W WO 2004024128 A2 WO2004024128 A2 WO 2004024128A2
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WO
WIPO (PCT)
Prior art keywords
ketoprofen
composition according
pellets
hours
coated pellets
Prior art date
Application number
PCT/SI2003/000033
Other languages
French (fr)
Other versions
WO2004024128A3 (en
Inventor
Judita Sirca
Milojka Mohar
Original Assignee
Lek Pharmaceuticals D.D.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lek Pharmaceuticals D.D. filed Critical Lek Pharmaceuticals D.D.
Priority to AU2003261067A priority Critical patent/AU2003261067A1/en
Priority to EP03795550A priority patent/EP1539113A2/en
Publication of WO2004024128A2 publication Critical patent/WO2004024128A2/en
Publication of WO2004024128A3 publication Critical patent/WO2004024128A3/en

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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
    • A61K31/185—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
    • A61K9/14—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
    • A61K9/48—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
    • 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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention belongs to the field of pharmaceutical technology and relates to a modified release pharmaceutical composition of ketoprofen.
  • Ketoprofen [2-(3-benzoylphenyl)propionic acid] is a non-steroidal, anti-inflammatory drug which exhibits analgesic and anti-rheumatic properties.
  • non-steroidal anti-inflammatory agents there is a constant need for pharmaceutical compositions that would have an immediate analgesic effect and a prolonged anti-rheumatic effect. This is difficult to achieve with conventional pharmaceutical compositions which release the entire active substance quickly, have an immediate analgesic effect and an anti-rheumatic effect is lost. Contrary, with controlled release pharmaceutical compositions due to prolonged release of the active substance from a pharmaceutical composition an anti-rheumatic effect is obtained but the concentration of the active substance released initially is too low to provide an analgesic effect.
  • compositions containing pellets or granules of ketoprofen or other non- steroidal anti-inflammatory drugs, are known from prior art.
  • US 4980170 describes pharmaceutical compositions of the active substances from the group of non-steroid anti-inflammatory agents, which comprise two types of the pellets.
  • the first pellets comprising a two-layer coating membrane are resistant to gastric juices.
  • the second pellets have a retard permeable diffusion membrane.
  • US 5043167 relates to programmed release pharmaceutical compositions comprising non-steroidal anti-inflammatory drug substances, which contain two types of the granulates, the immediate release granulate and the controlled release granulate.
  • the release rate of active substances is governed by the granulate composition.
  • WO 99/12542 describes modified release multiple-units pharmaceutical compositions of non-steroidal anti-inflammatory drug substances which comprise two fractions of the particles with the different release profile.
  • the first fraction which may be in the form of granules or coated pellets, provides a very quick onset of the therapeutic effect. At least 50% w/w of the active substance is released from the first fraction within the first 20 minutes.
  • the second fraction is in a form of three-layer coated pellets adjusting release of the active substance for a relatively long period of time.
  • the composition is also suitable for once-a-day administration.
  • the present invention thus relates to a modified release pharmaceutical composition of ketoprofen which comprises uncoated pellets (pellet cores) which are designed to an immediate release of ketoprofen, and coated pellets which are designed to a delayed and prolonged release of ketoprofen.
  • This composition is able to maintain therapeutically effective blood levels of ketoprofen over 12 hours and is suitable for twice daily administration. It solves the problem of managing pain relief and inflammation in patients in need thereof.
  • the novel pharmaceutical composition is patient-friendly. In the stomach it disintegrates very quickly and the pellets are distributed inside the stomach. Local gastric irritation is thus greatly decreased in comparison with a conventional pharmaceutical composition, e.g., tablet comprising the entire dose of the active substance in a single unit and causes a strong local irritation that may also damage the mucous membrane. Coated pellets additionally protect the mucosa.
  • the release rate of ketoprofen from the composition of present invention is governed by the composition of the pellet cores, the ratio of the uncoated pellets to the coated pellets and the composition and thickness of the coating.
  • the uncoated pellets comprise ketoprofen and excipients which are conventionally used for the production of pellets.
  • Pellet cores may comprise one or more diluents, such as lactose, saccharose, glucose, starch, microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate and others, one or more binding agents, such as starch, gelatin, polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose, carboxymethylcellulose, low-substituted hydroxypropyl cellulose and others, one or more disintegrants, such as starch, croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium starch glycollate and others.
  • diluents such as lactose, saccharose, glucose, starch, microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate and others
  • binding agents such as starch, gelatin, polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose, carboxymethylcellulose, low-substituted hydroxypropyl cellulose
  • the pellet cores may further comprise one or more surfactants, such as ionic surfactants, e.g., sodium lauryl sulfate, nonionic surfactants, such as natural or synthesized lecithins and esters of sorbitan and fatty acids (such as Span ® ), esters of polyoxyethylenesorbitan and fatty acids (such as, Polysorbates or Tween ® ), polyoxyethylated hydrogenated castor oil (such as Cremophor ® ) or any combination of the herein above mentioned surfactants
  • ionic surfactants e.g., sodium lauryl sulfate
  • nonionic surfactants such as natural or synthesized lecithins and esters of sorbitan and fatty acids (such as Span ® ), esters of polyoxyethylenesorbitan and fatty acids (such as, Polysorbates or Tween ® ), polyoxyethylated hydrogenated castor oil (such as Cremophor
  • Pellet cores may optionally be composed of inert seed to which ketoprofen is applied on together with a binding agent, selected from the group consisting of starch, gelatin, polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose, carboxymethylcellulose, low-substituted hydroxypropyl cellulose and others.
  • a binding agent selected from the group consisting of starch, gelatin, polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose, carboxymethylcellulose, low-substituted hydroxypropyl cellulose and others.
  • the proportion of ketoprofen in the pellet cores is from 5 to 95% w/w, preferably 60 to 90 % w/w.
  • Delayed release coated pellets are the pellet cores coated with a pH independent semi-permeable polymer.
  • the coating preferably comprises copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • a preferred coating comprises the combination of ammonio methacrylate copolymer type A and ammonio methacrylate copolymer type B (according to USP 25-NF 20) in the ratio of 7:3 to 3:7, preferably 1:1.
  • the polymers are commercially available in the form of 30% aqueous dispersion as Eudragit RS 30 D and Eudragit RL 30 D from Rohm Pharma.
  • the coating may further comprise one or more plasticizers, such as polyethylene glycol with different molecular weights, triethyl citrate, dibutyl sebacate, tributyl sebacate, cetyl alcohol, olive or castor oil, monoglycerides and other conventional pharmaceutically acceptable ingredients which are used for the production of coatings, such as talc, Polysorbate 80, pigments and magnesium stearate.
  • plasticizers such as polyethylene glycol with different molecular weights, triethyl citrate, dibutyl sebacate, tributyl sebacate, cetyl alcohol, olive or castor oil, monoglycerides and other conventional pharmaceutically acceptable ingredients which are used for the production of coatings, such as talc, Polysorbate 80, pigments and magnesium stearate.
  • the coated pellets may comprise from 3 to 50% w/w of the coating, preferably 5 to 15% w/w.
  • the composition of the uncoated pellets may be the same as the composition of the pellet cores of coated pellets.
  • the composition of the uncoated pellets may be different from the composition of the pellet cores of coated pellets.
  • Pellet cores may be produced in the manner conventional in the pharmaceutical industry. A wet mixture of ketoprofen and excipients is extruded in a screw extruder and the resulting extrudate is spheronized into pellets in a spheronizer. The pellets thus produced are dried in a fluidized bed. The pellet cores are coated with a polymer coating by the methods conventional in the pharmaceutical technology.
  • Pellet cores may optionaly be prepared by coating the inert core seeds with ketoprofen and binding agent.
  • Uncoated pellets and coated pellets in the desired ratio may be encapsulated into gelatin capsules. They may be also compressed into tablets together with the excipients such as, for example, lactose, saccharose, glucose, starch microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, neutral pellet cores and others.
  • excipients such as, for example, lactose, saccharose, glucose, starch microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, neutral pellet cores and others.
  • the ratio of uncoated pellets to the coated pellets in the formulation of the present invention may be from 80:20 to 20:80, preferably about 60:40 to the dose of ketoprofen in the pharmaceutical composition. It means that 60% w/w of the ketoprofen dose is in a form of the pellet cores and 40% w/w of the ketoprofen dose in a form of the coated pellets.
  • the pharmaceutical composition of the present invention may contain from 50 to 250 mg of ketoprofen, preferably 150 mg.
  • the object of the present invention is a modified release composition of ketoprofen wherefrom 15 to 35% w/w of ketoprofen is released within the first two hours, 50 to 80%) w/w of ketoprofen after 6 hours and at least 80% w/w after 8 hours, measured 2 hours in 1000 ml of simulated gastric juice having a pH of 1.2, 4 hours in 1000 ml of phosphate buffer having a pH of 4.5 and 2 hours in 1000 ml of phosphate buffer having a pH of 6.8, in he rotating basket (USP 25) at 50 rpm.
  • the object of the present invention is a hard gelatine capsule containing 150 mg of ketoprofen. 60% w/w of the ketoprofen dose is in the form of uncoated pellets and 40% w/w of the ketoprofen dose is in the form of coated pellets.
  • Ketoprofen, microcrystalline cellulose, lactose and polyvinylpyrrolidone were mixed and 140 g of demineralized water was added.
  • the wet mixture was extruded in a screw extruder and the resulting extrudate was spheronized into pellets in a spheronizer.
  • the wet pellets thus obtained were dried in a fluidized bed. 60% w/w of the dry pellets (pellet cores) was set aside to be capsulated, and the remainder 40% w/w was coated.
  • Te pellet cores were placed in a fluidized bed apparatus and sprayed with an aqueous dispersion Eudragit RS 30 D and Eudragit RL 30 D by further added triethyl citrate, Polysorbate and talc.
  • the pellet cores and the coated pellets were dosed into capsules using a capsule filling machine. Each capsule contained 60% w/w pellet cores and 40% w/w coated pellets.
  • Ketoprofen, microcrystalline cellulose, lactose and polyvinylpyrrolidone were mixed and 140 g of demineralized water was added.
  • the wet mixture was extruded on a screw extruder and resulting extrudate was spheronized into pellets in a spheronizer.
  • the wet pellets thus obtained were dried in a fluidized bed. 60% w/w of the dry pellets (pellet cores) was set aside to be capsulated, and the remainder 40% w/w was coated.
  • Te pellet cores were placed in a fluidized bed apparatus and sprayed with an aqueous dispersion Eudragit RS 30 D and Eudragit RL 30 D by further added triethyl citrate, Poysorbate and talc.
  • the pellet cores and the coated pellets were dosed into capsules using a capsule filling machine. Each capsule contained 60% w/w pellet cores and 40% w/w coated pellets.

Abstract

The present invention relates to a modified release pharmaceutical composition of ketoprofen which comprises uncoated pellets designed to an immediate release of ketoprofen, and coated pellets release designed to a delayed and prolonged release. This composition is suitable for twice daily administration.

Description

Lek Pharmaceuticals d. d.
Modified release pharmaceutical composition
The present invention belongs to the field of pharmaceutical technology and relates to a modified release pharmaceutical composition of ketoprofen.
Ketoprofen, [2-(3-benzoylphenyl)propionic acid], is a non-steroidal, anti-inflammatory drug which exhibits analgesic and anti-rheumatic properties.
In the group of the active substances known as the non-steroidal anti-inflammatory agents there is a constant need for pharmaceutical compositions that would have an immediate analgesic effect and a prolonged anti-rheumatic effect. This is difficult to achieve with conventional pharmaceutical compositions which release the entire active substance quickly, have an immediate analgesic effect and an anti-rheumatic effect is lost. Contrary, with controlled release pharmaceutical compositions due to prolonged release of the active substance from a pharmaceutical composition an anti-rheumatic effect is obtained but the concentration of the active substance released initially is too low to provide an analgesic effect.
A number of compositions, containing pellets or granules of ketoprofen or other non- steroidal anti-inflammatory drugs, are known from prior art.
US 4980170 describes pharmaceutical compositions of the active substances from the group of non-steroid anti-inflammatory agents, which comprise two types of the pellets. The first pellets comprising a two-layer coating membrane are resistant to gastric juices. The second pellets have a retard permeable diffusion membrane.
US 5043167 relates to programmed release pharmaceutical compositions comprising non-steroidal anti-inflammatory drug substances, which contain two types of the granulates, the immediate release granulate and the controlled release granulate. The release rate of active substances is governed by the granulate composition. WO 99/12542 describes modified release multiple-units pharmaceutical compositions of non-steroidal anti-inflammatory drug substances which comprise two fractions of the particles with the different release profile. The first fraction, which may be in the form of granules or coated pellets, provides a very quick onset of the therapeutic effect. At least 50% w/w of the active substance is released from the first fraction within the first 20 minutes. The second fraction is in a form of three-layer coated pellets adjusting release of the active substance for a relatively long period of time. The composition is also suitable for once-a-day administration.
Thus it is the object of the present invention to provide improved modified release composition of ketoprofen.
Description of the invention
The present invention thus relates to a modified release pharmaceutical composition of ketoprofen which comprises uncoated pellets (pellet cores) which are designed to an immediate release of ketoprofen, and coated pellets which are designed to a delayed and prolonged release of ketoprofen. This composition is able to maintain therapeutically effective blood levels of ketoprofen over 12 hours and is suitable for twice daily administration. It solves the problem of managing pain relief and inflammation in patients in need thereof.
The novel pharmaceutical composition is patient-friendly. In the stomach it disintegrates very quickly and the pellets are distributed inside the stomach. Local gastric irritation is thus greatly decreased in comparison with a conventional pharmaceutical composition, e.g., tablet comprising the entire dose of the active substance in a single unit and causes a strong local irritation that may also damage the mucous membrane. Coated pellets additionally protect the mucosa.
The release rate of ketoprofen from the composition of present invention is governed by the composition of the pellet cores, the ratio of the uncoated pellets to the coated pellets and the composition and thickness of the coating. The uncoated pellets (pellet cores) comprise ketoprofen and excipients which are conventionally used for the production of pellets. Pellet cores may comprise one or more diluents, such as lactose, saccharose, glucose, starch, microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate and others, one or more binding agents, such as starch, gelatin, polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose, carboxymethylcellulose, low-substituted hydroxypropyl cellulose and others, one or more disintegrants, such as starch, croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium starch glycollate and others. The pellet cores may further comprise one or more surfactants, such as ionic surfactants, e.g., sodium lauryl sulfate, nonionic surfactants, such as natural or synthesized lecithins and esters of sorbitan and fatty acids (such as Span®), esters of polyoxyethylenesorbitan and fatty acids (such as, Polysorbates or Tween®), polyoxyethylated hydrogenated castor oil (such as Cremophor®) or any combination of the herein above mentioned surfactants
Pellet cores may optionally be composed of inert seed to which ketoprofen is applied on together with a binding agent, selected from the group consisting of starch, gelatin, polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose, carboxymethylcellulose, low-substituted hydroxypropyl cellulose and others.
The proportion of ketoprofen in the pellet cores is from 5 to 95% w/w, preferably 60 to 90 % w/w.
Delayed release coated pellets are the pellet cores coated with a pH independent semi-permeable polymer. The coating preferably comprises copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. A preferred coating comprises the combination of ammonio methacrylate copolymer type A and ammonio methacrylate copolymer type B (according to USP 25-NF 20) in the ratio of 7:3 to 3:7, preferably 1:1. The polymers are commercially available in the form of 30% aqueous dispersion as Eudragit RS 30 D and Eudragit RL 30 D from Rohm Pharma.
The coating may further comprise one or more plasticizers, such as polyethylene glycol with different molecular weights, triethyl citrate, dibutyl sebacate, tributyl sebacate, cetyl alcohol, olive or castor oil, monoglycerides and other conventional pharmaceutically acceptable ingredients which are used for the production of coatings, such as talc, Polysorbate 80, pigments and magnesium stearate.
The coated pellets may comprise from 3 to 50% w/w of the coating, preferably 5 to 15% w/w.
The composition of the uncoated pellets may be the same as the composition of the pellet cores of coated pellets. The composition of the uncoated pellets may be different from the composition of the pellet cores of coated pellets.
Pellet cores may be produced in the manner conventional in the pharmaceutical industry. A wet mixture of ketoprofen and excipients is extruded in a screw extruder and the resulting extrudate is spheronized into pellets in a spheronizer. The pellets thus produced are dried in a fluidized bed. The pellet cores are coated with a polymer coating by the methods conventional in the pharmaceutical technology.
Pellet cores may optionaly be prepared by coating the inert core seeds with ketoprofen and binding agent.
Uncoated pellets and coated pellets in the desired ratio may be encapsulated into gelatin capsules. They may be also compressed into tablets together with the excipients such as, for example, lactose, saccharose, glucose, starch microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, neutral pellet cores and others.
The ratio of uncoated pellets to the coated pellets in the formulation of the present invention may be from 80:20 to 20:80, preferably about 60:40 to the dose of ketoprofen in the pharmaceutical composition. It means that 60% w/w of the ketoprofen dose is in a form of the pellet cores and 40% w/w of the ketoprofen dose in a form of the coated pellets.
The pharmaceutical composition of the present invention may contain from 50 to 250 mg of ketoprofen, preferably 150 mg. The object of the present invention is a modified release composition of ketoprofen wherefrom 15 to 35% w/w of ketoprofen is released within the first two hours, 50 to 80%) w/w of ketoprofen after 6 hours and at least 80% w/w after 8 hours, measured 2 hours in 1000 ml of simulated gastric juice having a pH of 1.2, 4 hours in 1000 ml of phosphate buffer having a pH of 4.5 and 2 hours in 1000 ml of phosphate buffer having a pH of 6.8, in he rotating basket (USP 25) at 50 rpm.
The object of the present invention is a hard gelatine capsule containing 150 mg of ketoprofen. 60% w/w of the ketoprofen dose is in the form of uncoated pellets and 40% w/w of the ketoprofen dose is in the form of coated pellets.
The present invention is illustrated but in no way limited by the following examples:
Example 1
Figure imgf000006_0001
Ketoprofen, microcrystalline cellulose, lactose and polyvinylpyrrolidone were mixed and 140 g of demineralized water was added. The wet mixture was extruded in a screw extruder and the resulting extrudate was spheronized into pellets in a spheronizer. The wet pellets thus obtained were dried in a fluidized bed. 60% w/w of the dry pellets (pellet cores) was set aside to be capsulated, and the remainder 40% w/w was coated. Te pellet cores were placed in a fluidized bed apparatus and sprayed with an aqueous dispersion Eudragit RS 30 D and Eudragit RL 30 D by further added triethyl citrate, Polysorbate and talc.
The pellet cores and the coated pellets were dosed into capsules using a capsule filling machine. Each capsule contained 60% w/w pellet cores and 40% w/w coated pellets.
Dissolution test Medium:
Figure imgf000007_0001
Apparatus: Rotating basket (USP 25) Rotations per minute: 50
Figure imgf000007_0002
Example 2
Figure imgf000008_0001
Ketoprofen, microcrystalline cellulose, lactose and polyvinylpyrrolidone were mixed and 140 g of demineralized water was added. The wet mixture was extruded on a screw extruder and resulting extrudate was spheronized into pellets in a spheronizer. The wet pellets thus obtained were dried in a fluidized bed. 60% w/w of the dry pellets (pellet cores) was set aside to be capsulated, and the remainder 40% w/w was coated. Te pellet cores were placed in a fluidized bed apparatus and sprayed with an aqueous dispersion Eudragit RS 30 D and Eudragit RL 30 D by further added triethyl citrate, Poysorbate and talc.
The pellet cores and the coated pellets were dosed into capsules using a capsule filling machine. Each capsule contained 60% w/w pellet cores and 40% w/w coated pellets.
Dissolution test Medium:
Figure imgf000009_0001
Apparatus: Rotating basket (USP 25) Rotations per minute: 50
Figure imgf000009_0002

Claims

1. A modified release pharmaceutical composition of ketoprofen comprising uncoated pellets designed to an immediate release of ketoprofen and coated pellets designed to a controlled release of ketoprofen, wherein from said composition 15 to 35% w/w of ketoprofen is released within the first two hours, 50 to 80% w/w of ketoprofen after 6 hours, and at least 80% w/w after 8 hours, measured by the method of a rotating basket at 50 rpm, 2 hours in 1000 ml of simulated gastric juice ml having a pH of 1.2, 4 hours in 1000 ml of phosphate buffer having a pH of 4.5 and 2 hours in 1000 ml of phosphate buffer having a pH of 6.8.
2. The composition according to claim 1 , which comprises from 50 to 250 mg of ketoprofen.
3. The composition according to claims 1, which comprises 150 mg of ketoprofen.
4. The composition according to claim 1 , wherein the coated pellets comprise a pellet core and a pH independent semi-permeable polymer coating.
5. The composition according to claim 1 and 4, wherein the composition of uncoated pellets is the same as composition of pellet cores of coated pellets
6. The composition according to claim 4, wherein the pellet cores contain from 5 to 90% w/w of ketoprofen.
7. The composition according to claims 4, wherein the pellet cores contain from 60 to 90% w/w of ketoprofen.
8. The composition according to claim 4, wherein the coating comprises copolymers of acrylic and methacrylic acid esters
9. The composition according to claim 4, wherein the coating comprises the combination of ammonio methacrylate copolymer type A and ammonio methacrylate copolymer type B in the ratio of 7:3 to 3:7.
10. The I composition according to claims 8, wherein the ratio of ammonio methacrylate copolymer type A and ammonio methacrylate copolymer type B in the coating is 1 :1.
11. The composition according to claims 1 and 4, wherein the coated pellets contain from 3 to 50% w/w of the coating.
12. The composition according to claims 1 and 4, wherein the coated pellets contain from 5 to 15% w/w of the coating.
13. The pharmaceutical composition according to claim 1 , wherein the ratio of the uncoated pellets to the coated pellets is from 80:20 to 20:80.
14. The pharmaceutical composition according to claims 1 and 13, wherein the ratio of the uncoated pellets to the coated pellets is 60:40.
15. The composition according to claim 1 , which is a hard gelatine capsule.
PCT/SI2003/000033 2002-09-11 2003-09-10 Modified release ketoprofen dosage form WO2004024128A2 (en)

Priority Applications (2)

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AU2003261067A AU2003261067A1 (en) 2002-09-11 2003-09-10 Modified release ketoprofen dosage form
EP03795550A EP1539113A2 (en) 2002-09-11 2003-09-10 Modified release ketoprofen dosage form

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SI200200220A SI21301A (en) 2002-09-11 2002-09-11 Pharmaceutical form with controlled release
SIP-200200220 2002-09-11

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WO2004024128A2 true WO2004024128A2 (en) 2004-03-25
WO2004024128A3 WO2004024128A3 (en) 2004-07-08

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AU (1) AU2003261067A1 (en)
SI (1) SI21301A (en)
WO (1) WO2004024128A2 (en)

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EP1897558A1 (en) * 2005-06-09 2008-03-12 Takeda Pharmaceutical Company Limited Solid preparation
EP1976489A1 (en) * 2006-01-27 2008-10-08 CJ CheilJedang Corporation Multiple unit type sustained release oral formulation and process for the preparation thereof
EP2010162A1 (en) * 2006-04-03 2009-01-07 Isa Odidi Drug delivery composition
ES2394888A1 (en) * 2011-06-15 2013-02-06 Farmalider, S.A. Pharmaceutical form of modified release of dexketoprophene and inhibitor of the proton pump and use of the same. (Machine-translation by Google Translate, not legally binding)
EP2582812A1 (en) * 2010-06-16 2013-04-24 Takeda Pharmaceuticals U.S.A., Inc. Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors
US9078827B2 (en) 2006-05-12 2015-07-14 Isa Odidi Pharmaceutical composition having reduced abuse potential
US9561188B2 (en) 2006-04-03 2017-02-07 Intellipharmaceutics Corporation Controlled release delivery device comprising an organosol coat
US9636306B2 (en) 2003-06-26 2017-05-02 Intellipharmaceutics Corp. Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
US10624858B2 (en) 2004-08-23 2020-04-21 Intellipharmaceutics Corp Controlled release composition using transition coating, and method of preparing same

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US9636306B2 (en) 2003-06-26 2017-05-02 Intellipharmaceutics Corp. Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
US10624858B2 (en) 2004-08-23 2020-04-21 Intellipharmaceutics Corp Controlled release composition using transition coating, and method of preparing same
EP1897558A4 (en) * 2005-06-09 2012-09-12 Norgine Bv Solid preparation
EP1897558A1 (en) * 2005-06-09 2008-03-12 Takeda Pharmaceutical Company Limited Solid preparation
US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
EP1976489A1 (en) * 2006-01-27 2008-10-08 CJ CheilJedang Corporation Multiple unit type sustained release oral formulation and process for the preparation thereof
EP1976489A4 (en) * 2006-01-27 2011-04-13 Cj Cheiljedang Corp Multiple unit type sustained release oral formulation and process for the preparation thereof
US9561188B2 (en) 2006-04-03 2017-02-07 Intellipharmaceutics Corporation Controlled release delivery device comprising an organosol coat
EP2010162A4 (en) * 2006-04-03 2013-01-09 Isa Odidi Drug delivery composition
EP2010162A1 (en) * 2006-04-03 2009-01-07 Isa Odidi Drug delivery composition
US9078827B2 (en) 2006-05-12 2015-07-14 Isa Odidi Pharmaceutical composition having reduced abuse potential
US10632205B2 (en) 2006-05-12 2020-04-28 Intellipharmaceutics Corp Pharmaceutical composition having reduced abuse potential
US10960077B2 (en) 2006-05-12 2021-03-30 Intellipharmaceutics Corp. Abuse and alcohol resistant drug composition
US9248119B2 (en) 2010-06-16 2016-02-02 Takeda Pharmaceuticals U.S.A., Inc. Modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors
EP2582812A4 (en) * 2010-06-16 2013-12-04 Takeda Pharmaceuticals Usa Inc Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors
US9937157B2 (en) 2010-06-16 2018-04-10 Takeda Pharmaceuticals U.S.A., Inc. Modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors
EP2582812A1 (en) * 2010-06-16 2013-04-24 Takeda Pharmaceuticals U.S.A., Inc. Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors
ES2394888A1 (en) * 2011-06-15 2013-02-06 Farmalider, S.A. Pharmaceutical form of modified release of dexketoprophene and inhibitor of the proton pump and use of the same. (Machine-translation by Google Translate, not legally binding)

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WO2004024128A3 (en) 2004-07-08

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