EP1539113A2 - Modified release ketoprofen dosage form - Google Patents

Modified release ketoprofen dosage form

Info

Publication number
EP1539113A2
EP1539113A2 EP03795550A EP03795550A EP1539113A2 EP 1539113 A2 EP1539113 A2 EP 1539113A2 EP 03795550 A EP03795550 A EP 03795550A EP 03795550 A EP03795550 A EP 03795550A EP 1539113 A2 EP1539113 A2 EP 1539113A2
Authority
EP
European Patent Office
Prior art keywords
ketoprofen
composition according
pellets
hours
coated pellets
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03795550A
Other languages
German (de)
French (fr)
Inventor
Judita Sirca
Milojka Mohar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lek Pharmaceuticals dd
Original Assignee
Lek Pharmaceuticals dd
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 dd filed Critical Lek Pharmaceuticals dd
Publication of EP1539113A2 publication Critical patent/EP1539113A2/en
Withdrawn legal-status Critical Current

Links

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
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:
Apparatus: Rotating basket (USP 25) Rotations per minute: 50
Example 2
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:
Apparatus: Rotating basket (USP 25) Rotations per minute: 50

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EP03795550A 2002-09-11 2003-09-10 Modified release ketoprofen dosage form Withdrawn EP1539113A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SI200200220A SI21301A (en) 2002-09-11 2002-09-11 Pharmaceutical form with controlled release
SI200200220 2002-09-11
PCT/SI2003/000033 WO2004024128A2 (en) 2002-09-11 2003-09-10 Modified release ketoprofen dosage form

Publications (1)

Publication Number Publication Date
EP1539113A2 true EP1539113A2 (en) 2005-06-15

Family

ID=31989658

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03795550A Withdrawn EP1539113A2 (en) 2002-09-11 2003-09-10 Modified release ketoprofen dosage form

Country Status (4)

Country Link
EP (1) EP1539113A2 (en)
AU (1) AU2003261067A1 (en)
SI (1) SI21301A (en)
WO (1) WO2004024128A2 (en)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8802139B2 (en) 2003-06-26 2014-08-12 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
ES2434072T3 (en) * 2005-06-09 2013-12-13 Norgine Bv Solid preparation of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxacin-4-one
US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
KR100762847B1 (en) * 2006-01-27 2007-10-04 씨제이 주식회사 Multiple unit type sustained release oral formulation and process for the preparation thereof
CA2648280C (en) 2006-04-03 2014-03-11 Isa Odidi Controlled release delivery device comprising an organosol coat
CA2648278C (en) * 2006-04-03 2019-05-28 Isa Odidi Drug delivery composition
US10960077B2 (en) 2006-05-12 2021-03-30 Intellipharmaceutics Corp. Abuse and alcohol resistant drug composition
PE20130574A1 (en) 2010-06-16 2013-06-01 Takeda Pharmaceuticals Usa Inc NEW MODIFIED RELEASE DOSAGE FORMS OF A XANTHINE OXIDOR REDUCTASE INHIBITOR OR XANTHINE OXIDASE INHIBITORS
ES2394888B1 (en) * 2011-06-15 2013-09-23 Farmalider, S.A. PHARMACEUTICAL FORM OF MODIFIED RELEASE OF DEXKETOPROPHENE AND INHIBITOR OF THE PUMP OF PROTONS AND USE OF THE SAME.

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6144811A (en) * 1984-08-10 1986-03-04 Ss Pharmaceut Co Ltd Sustained release diclofenac sodium pharmaceutical
DE3822095A1 (en) * 1988-06-30 1990-01-04 Klinge Co Chem Pharm Fab NEW MEDICAMENT FORMULATION AND METHOD FOR THE PRODUCTION THEREOF
IE66933B1 (en) * 1990-01-15 1996-02-07 Elan Corp Plc Controlled absorption naproxen formulation for once-daily administration
US6599529B1 (en) * 1997-09-11 2003-07-29 Nycomed Danmark A/S Modified release multiple-units compositions of non-steroid anti-inflammatory drug substances (NSAIDs)
FR2792527B1 (en) * 1999-04-22 2004-08-13 Ethypharm Lab Prod Ethiques KETOPROFENE MICROGRANULES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004024128A2 *

Also Published As

Publication number Publication date
WO2004024128A3 (en) 2004-07-08
AU2003261067A1 (en) 2004-04-30
AU2003261067A8 (en) 2004-04-30
SI21301A (en) 2004-04-30
WO2004024128A2 (en) 2004-03-25

Similar Documents

Publication Publication Date Title
AU2006297477B2 (en) Pharmaceutical dosage forms having immediate release and/or controlled release properties
CA2297832C (en) Pellet-type formulation intended for treating the intestinal tract
CA2277017C (en) Rapidly releasing and taste-masking pharmaceutical dosage form
EP1734933B1 (en) Gastroresistant pharmaceutical dosage form comprising n-(2-(2-phthalimidoethoxy)-acetyl)-l-alanyl-d-glutamic acid (lk-423)
TWI483748B (en) Pharmaceutical compositions comprising hydromorphone and naloxone
KR20080033354A (en) Extended release solid pharmaceutical composition containing carbidopa and levodopa
JP2001526213A (en) Oral drug pulse release dosage form
JP2002532425A (en) New pharmaceutical formulations
AU783911B2 (en) Coated solid dosage forms
JP5687185B2 (en) Solid oral dosage forms with a two-stage release profile containing multiparticulate systems
WO2004024128A2 (en) Modified release ketoprofen dosage form
EP2533766A2 (en) Pharmaceutical mini-tablets for sustained release of flecainide acetate
JP2004512298A (en) Delayed and sustained release formulations and methods of using them
US20050220873A1 (en) Pharmaceutical dosage forms having immediate and controlled release properties that contain a GABAB receptor agonist
HRP970004A2 (en) Pharmaceutically controlled release of beads comprising furosemide and a formulation containing said controlled release beads
AU732210B2 (en) Colonic delivery of weak acid drugs
WO2009065130A2 (en) Modified release formulations of diltiazem
US20050220874A1 (en) Pharmaceutical dosage forms having immediate release and controlled release properties that contain a GABAB receptor agonist
US20050220863A1 (en) Pharmaceutical dosage forms having controlled release properties that contain a GABAB receptor agonist
US20050220864A1 (en) Pharmaceutical dosage forms having controlled release properties that contain a GABAB receptor agonist
MX2008004282A (en) Pharmaceutical dosage forms having immediate release and/orcontrolled release properties

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20050411

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

17Q First examination report despatched

Effective date: 20080207

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20080819