EP1216030A1 - Preparations pharmaceutiques anti-inflammatoires - Google Patents

Preparations pharmaceutiques anti-inflammatoires

Info

Publication number
EP1216030A1
EP1216030A1 EP00964434A EP00964434A EP1216030A1 EP 1216030 A1 EP1216030 A1 EP 1216030A1 EP 00964434 A EP00964434 A EP 00964434A EP 00964434 A EP00964434 A EP 00964434A EP 1216030 A1 EP1216030 A1 EP 1216030A1
Authority
EP
European Patent Office
Prior art keywords
dosage form
granules
nsaid
phthalate
mixture
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Withdrawn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
EP00964434A
Other languages
German (de)
English (en)
Inventor
Austen John Woolfe
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.)
Norton Healthcare Ltd
Original Assignee
Norton Healthcare Ltd
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 GBGB9923139.1A external-priority patent/GB9923139D0/en
Priority claimed from GB0000483A external-priority patent/GB0000483D0/en
Application filed by Norton Healthcare Ltd filed Critical Norton Healthcare Ltd
Publication of EP1216030A1 publication Critical patent/EP1216030A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/14—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
    • 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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

  • This invention relates to pharmaceutical formulations of anti -inflammatory drugs, particularly non-steroidal anti- inflammatory drugs (NSAIDs) .
  • NSAIDs non-steroidal anti- inflammatory drugs
  • NSAIDs are used for the treatment of inflammatory conditions such as osteoarthritis or rheumatoid arthritis.
  • NSAID induced ulcers in the stomach are potentially dangerous because few or no symptoms may be detected until significant damage has been caused.
  • Certain prostaglandins for example misoprostol have been shown to reduce and even prevent such ulcers .
  • misoprostol with immediate release drugs for example GB-A- 2135881 (Farmitalia Carlo Erba) , 091/16896 (G D Searle) , or where a gastric resistant coating is put over the NSAID in an attempt to reduce further gastric erosion due to release in the stomach of the NSAID, for example 091/16895, 091/16886 (G D Searle) .
  • an oral pharmaceutical dosage form includes a mixture of a delay release formulation of a NSAID and a mixture containing one or more excipients and a prostaglandin, wherein the delay release NSAID formulation preferably comprises coated granules .
  • the prostaglandin mixture may be provided in the form of a powder which is mixed with the NSAID formulation within the dosage form.
  • the dosage form may comprise a tablet, capsule, granule or other commonly used configuration.
  • preferred dosage forms comprise a capsule containing multi-particulate granules of the NSAID formulation together with the powdered prostaglandin mixture.
  • the NSAID granules preferably have coatings adapted to provide programmed release according to the position in the gastrointestinal tract. Use of such coated granules provides a more repeatable release along the gastrointestinal tract and may reduce gastric erosion because the small pellets or granules are easily moved and do not adhere readily to the folds of the gastric wall .
  • Granules for use in accordance with this invention may have a single slowly erodible coat or may comprise mixtures of granules with differing levels or types of coating adapted to provide a continuous or distributed release profile through the gastrointestinal tract .
  • the delay afforded may range from a minimal delay to several hours, dependent on the pH of the gastrointestinal tract in the immediate vicinity.
  • the NSAID is preferably but not exclusively one of reasonably low weight per standard dose, that is 200 mg or below.
  • suitable NSAIDs include tiaprofenic acid, piroxicam, flubiprofen, tenoxicam, meloxicam or similar molecules. Salts or other derivatives of these drugs may be employed in a conventional manner. Most preferably the drug is diclofenac sodium, ketoprofen or indomethacin. Mixtures may be used.
  • Drug delivery using capsules avoids a further compression step as may be necessary during tablet manufacture .
  • Granules for example composed of diclofenac sodium and a methyl methacrylate (eg Eudragit L 30 D-55) may be prepared by blending the ingredients in a planetary mixer with slow addition of water to produce granules. In a preferred process very fine granules are produced to avoid a need for milling before compaction into tablets or incorporation into capsules. Use of granules with the dimension of 200 - 1000 ⁇ m, preferably 300 to 500 ⁇ m is particularly suitable. Tablets may be produced by coating these granules with a barrier coating material for example a cellulosic material such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose. Tablets may be produced by coating these granules .
  • a barrier coating material for example a cellulosic material such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose. Tablets may be produced by coating these granules .
  • An alternative method of forming coated granules is by spraying a solution of Eudragit onto a bed of diclofenac sodium or other drug and any necessary excipients for example using a fluid bed coating apparatus.
  • the process is preferably controlled to produce fine granules which do not require milling before incorporation into tablets or capsules .
  • the coating for the granules may include cellulose derivatives eg hydroxypropyl methyl cellulose, methacrylic acid and derivatives eg methyl methacrylates for example, Eudragrit ® (Rhom Pharm) , especially Eudragrit L or S .
  • Other standard enteric coating materials may be used for example phthalates, eg cellulose acetate phthalate or preferably hydroxypropylacetate phthalate or polyvinylacetate phthalate. Mixtures of these and other materials may be used to produce delay release coated beads.
  • the coating will include plasticisers eg polyethylene glycol, triacetin or phthalate esters.
  • the prostaglandin component preferably contains misoprostol optionally together with one or more inert excipients.
  • the prostaglandin is normally provided as a 1:10 or 1:100 dilution on an inert cellulose or other binder or filler.
  • Especially useful material for this invention is hydroxypropyl methyl cellulose.
  • the dosage of prostaglandin may be chosen to be suitable to prevent or reduce stomach ulceration caused by the NSAID.
  • a suitable dose of misoprostol is between 10 - 50 ⁇ g preferably 50 - 200 ⁇ g per dosage form but this may be increased or decreased depending on the NSAID used.
  • Preferred dosage forms comprise capsules, preferably hard gelatin capsules.
  • Tablets where the prostaglandin is mixed with one or more binding agents may be bi-layer tablets wherein the NSAID is formed into a first layer and the prostaglandin is then compressed onto it.
  • a tri- layer tablet with an inert intermediate barrier layer between the NSAID and prostaglandin layers may be employed.
  • the potential for gastric erosion is reduced by ensuring that the prostaglandin is released before the NSAID.
  • Any beads for immediate or rapid release are coated with an inert coating which defer solubility in gastric fluid, for example for a period of 30 minutes.
  • Such materials include cellulose derivatives for example hydroxypropyl methyl cellulose, methyl or ethyl celluloses or other sealants eg Zein. Thin coatings of methacrylate derivatives eg polyhydroxymethacrylate or other materials such as hardened gelatine, waxes, starches or polyvinyl pyrrolidone may be used. Other portions of the granules may be coated with methacrylate derivatives, phthalate, for example hydroxypropyl methyl cellulose phthalate or similar materials to give an appropriate release profile as is well known in the art .
  • the granules were dried and compacted into layered tablets having the following composition:
  • diclofenac-containing granules 26.0% microcrystalline cellulose 73.5% magnesium stearate 0.5%
  • a two layer tablet was made as follows:
  • the mixture was blended, dried and milled to give diclofenac-containing granules.
  • the granules (25%) were mixed with microcrystalline cellulose (Avicel pH 200 and pH 112) to give a total of 69%.
  • Dry Eudragit 1100 powder (5%) and hydrogenated castor oil (1%) were added.
  • the mixture was pressed into half tablets with a tablet weight of 400 mg.
  • a misoprostol layer was formed as follows:
  • a misoprostol dispersion (1:100) 6.7% was combined with microcrystalline cellulose (Avicel pH 112) 88.33%, croscarmelose sodium (4%) and hydrogenated castor oil to give a tablet weight of 300 mg .
  • the combined bi- layered tablet had a total weight of 700 mg .
  • Dissolution properties were determined by exposure to acid medium for two hours followed by measurement of dissolution in alkaline buffer. The following results were obtained.

Landscapes

  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Medicinal Preparation (AREA)
  • Pain & Pain Management (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme de dosage pharmaceutique à usage buccal comprenant un mélange d'une préparation à libération différée d'un médicament anti-inflammatoire non stéroïdien (NSAID) et un mélange renfermant une prostaglandine et au moins un excipient.
EP00964434A 1999-10-01 2000-09-29 Preparations pharmaceutiques anti-inflammatoires Withdrawn EP1216030A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GBGB9923139.1A GB9923139D0 (en) 1999-10-01 1999-10-01 Anti-inflammatory pharmaceutical formulations
GB9923139 1999-10-01
GB0000483A GB0000483D0 (en) 2000-01-11 2000-01-11 Anti-inflammatory pharmaceutical formulations
GB0000483 2000-01-11
PCT/GB2000/003729 WO2001024778A1 (fr) 1999-10-01 2000-09-29 Preparations pharmaceutiques anti-inflammatoires

Publications (1)

Publication Number Publication Date
EP1216030A1 true EP1216030A1 (fr) 2002-06-26

Family

ID=26243367

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00964434A Withdrawn EP1216030A1 (fr) 1999-10-01 2000-09-29 Preparations pharmaceutiques anti-inflammatoires

Country Status (6)

Country Link
EP (1) EP1216030A1 (fr)
JP (1) JP2003510347A (fr)
KR (1) KR20020063871A (fr)
AU (1) AU7537000A (fr)
CA (1) CA2387288A1 (fr)
WO (1) WO2001024778A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008146178A2 (fr) 2007-05-30 2008-12-04 Wockhardt Research Centre Nouvelle forme posologique de comprimé

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6387410B1 (en) 1998-09-10 2002-05-14 Norton Healthcare Ltd Anti-inflammatory pharmaceutical formulations
JPWO2004004738A1 (ja) * 2002-07-02 2005-11-04 わかもと製薬株式会社 角結膜上皮細胞障害治療薬又は予防薬
WO2004091579A1 (fr) * 2003-04-16 2004-10-28 Pharmacia Corporation Formulation de prostaglandine stabilisee
EP1987820A1 (fr) * 2007-05-04 2008-11-05 Christian Fiala, Ph. D. Misoprostole à libération lente pour applications obstétriques et/ou gynécologiques
CN110893174A (zh) * 2019-12-04 2020-03-20 仁和堂药业有限公司 双氯芬酸钠肠溶片的制备方法

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016895A1 (fr) * 1990-05-03 1991-11-14 G.D. Searle & Co. Composition pharmaceutique
AU8089091A (en) * 1990-05-03 1991-11-27 G.D. Searle & Co. Pharmaceutical composition containing ibuprofen and a prostaglandin
US5232704A (en) * 1990-12-19 1993-08-03 G. D. Searle & Co. Sustained release, bilayer buoyant dosage form
GB9814215D0 (en) * 1998-07-01 1998-09-02 Norton Healthcare Ltd Anti-inflammatory pharmaceutical formulations
GB9819685D0 (en) * 1998-09-10 1998-11-04 Norton Healthcare Ltd Anti-inflammatory pharmaceutical formulations
CA2259727A1 (fr) * 1999-01-18 2000-07-18 Bernard Charles Sherman Pastille pharmaceutique a deux couches comprenant un ains et du misoprostol
US6183779B1 (en) * 1999-03-22 2001-02-06 Pharmascience Inc. Stabilized pharmaceutical composition of a nonsteroidal anti-inflammatory agent and a prostaglandin
CA2277407A1 (fr) * 1999-07-14 2001-01-14 Bernard Charles Sherman Comprime comprenant un ains et du misoprostol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0124778A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008146178A2 (fr) 2007-05-30 2008-12-04 Wockhardt Research Centre Nouvelle forme posologique de comprimé

Also Published As

Publication number Publication date
AU7537000A (en) 2001-05-10
WO2001024778A1 (fr) 2001-04-12
CA2387288A1 (fr) 2001-04-12
KR20020063871A (ko) 2002-08-05
JP2003510347A (ja) 2003-03-18

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