WO2008037795A1 - Formulations orodispersibles, gastroprotectrices et masquant le goût contenant au moins un principe actif gastrique anti-irritant - Google Patents

Formulations orodispersibles, gastroprotectrices et masquant le goût contenant au moins un principe actif gastrique anti-irritant Download PDF

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Publication number
WO2008037795A1
WO2008037795A1 PCT/EP2007/060312 EP2007060312W WO2008037795A1 WO 2008037795 A1 WO2008037795 A1 WO 2008037795A1 EP 2007060312 W EP2007060312 W EP 2007060312W WO 2008037795 A1 WO2008037795 A1 WO 2008037795A1
Authority
WO
WIPO (PCT)
Prior art keywords
active principle
formulations
ibuprofen
gastrolesive
hydrogenated
Prior art date
Application number
PCT/EP2007/060312
Other languages
English (en)
Inventor
Celestino Ronchi
Giancarlo Ceschel
Manuela Astulfoni
Original Assignee
Monteresearch S.R.L.
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 Monteresearch S.R.L. filed Critical Monteresearch S.R.L.
Publication of WO2008037795A1 publication Critical patent/WO2008037795A1/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • the present invention relates to orodispersible, gastroprotective and taste- masking formulations containing at least one gastrolesive active principle.
  • the principal pharmaceutical forms for oral cavity administration are, for example, conventional oral formulations whereby drug absorption takes place by direct ingestion (such as tablets, capsules, aqueous suspensions etc.) or subsequent to mastication such as chewable tablets, or else tablets that enable absorption of the active principle directly in the required site (buccal or sublingual tablets), or orodispersible tablets that disintegrate rapidly in the oral cavity before being swallowed with possible absorption of the active principle in the oral cavity and/or in the gastrointestinal system.
  • Orodispersible tablets can be more useful and, in particular, rapidly dissolving orodispersible tablets disintegrate rapidly and spontaneously in the mouth as soon as they come into contact with saliva, allowing the active principle to dissolve rapidly in the saliva and to be hence absorbed rapidly across the membranes with which it comes into contact during and after swallowing.
  • Lyophilization renders the final product very porous but poorly resistant to handling and is used in few formulations e.g. ZydisTM (US patent 4,305,502) and Feldene Melt which contains 20 mg of piroxicam (Pfizer) or Claritin Reditabs containing 10 mg of Loratidine (Schering Plough Corp).
  • ZydisTM US patent 4,305,502
  • Feldene Melt which contains 20 mg of piroxicam (Pfizer) or Claritin Reditabs containing 10 mg of Loratidine (Schering Plough Corp).
  • the LyocTM technique uses an oil-in-water emulsion which is introduced into a honeycomb mould, cooled and lyophilized. The rapid disintegration achieved is, however, accompanied by poor mechanical strength.
  • the excipients e.g. starch, saccharose etc.
  • the drug can be dispersed in the molten phase (PEG, lecithin, hydrogenated oils) with other excipients such as flavourings, sweeteners etc.
  • FlashDoseTM EP552777A2 (1993) Hisakadzu and Yunxia, 2002; Rong-Kun et al. 2000; Seager, 1998; WaNd et al. 2000).
  • FlashDoseTM EP552777A2 (1993) Hisakadzu and Yunxia, 2002; Rong-Kun et al. 2000; Seager, 1998; WaNd et al. 2000).
  • Direct compression was used to prepare rapidly dispersing tablets containing ibuprofen while seeking to minimize gastrolesivity of the drug and to improve palatability.
  • Direct compression involves a reduced number of operations and has a relatively low cost; however, the active principle and the excipients are often in high concentrations, so water-soluble and/or effervescent disintegrants must be used while at the same time ensuring the tablets have sufficient mechanical strength.
  • mechanical strength counteracts disintegration and the patents obtained are aimed at reconciling these opposing needs (examples of patented products include OrasolvTM, PacksolveTM, DurasolvTM, WowtabTM, FlashtabTM).
  • FIGURES Figure 1 is a graph of ibuprofen gastrolesivity, expressed as ulcer index, induced by the tested substances whose composition is given in table 1.
  • Figure 2 is a graph showing a curve of dose-response to gastric damage with the tested substances as given in table 2.
  • the term "gastrolesive active principle” means an active principle belonging to the class of anti-inflammatory analgesics and other active principle classes whose administration is able to induce gastric damage of a greater or lesser severity.
  • the formulations of the present invention preferably contain at least one of the following active principles chosen from: ibuprofen, ketoprofen, diclofenac sodium, indomethacin, acetylsalicylic acid, paracetamol, nimesulide, piroxicam.
  • the hydrogenated phosphatidylcholine is contained within a hydrogenated lecithin in a quantity of preferably at least 60%, more preferably at least 80% by weight.
  • hydrogenated lecithin is preferably present relative to the active principle in weight ratios of between 1 :6 and 1 :1 , more preferably 1 :4.
  • the formulations of the present invention are preferably in the form of orodispersible tablets, more preferably being rapidly dissolving.
  • excipients normally used for preparing this type of tablets for example disintegrants such as cross-linked polyvinylpyrrolidone (Kollidon® CL), sodium starch glycolate (Explotab®), lubricants such as colloidal silica, mono-, di-, triglyceryl behenate or mixtures thereof, binders such as polyvinylpyrrolidone with an average molecular weight of 40000 (Kollidon® K30) flavourings, sweeteners etc.
  • disintegrants such as cross-linked polyvinylpyrrolidone (Kollidon® CL), sodium starch glycolate (Explotab®)
  • lubricants such as colloidal silica, mono-, di-, triglyceryl behenate or mixtures thereof
  • binders such as polyvinylpyrrolidone with an average molecular weight of 40000 (Kollidon® K30) flavourings, sweeteners etc.
  • the orodispersible formulations of the present invention mask the taste of the active principle and hence present an improved palatability (taste-masking effect).
  • the best results are obtained by coating to create intimate contact between the granules of active principle and the hydrogenated phosphatidylcholine by the technique of granulation or coating before undertaking compression.
  • the formulations of the present invention have an improved active principle bioavailability.
  • the bioavailability of the active principle can be increased by the presence of hydrogenated phosphatidylcholine in the formulation.
  • said component has an absorption promotion capacity, increasing active principle absorption at the oromucosal level and in the gastrointestinal system.
  • Tablet formulation expressed in % w/w, is the following:
  • Hydrogenated lecithin 8.34 (cont. 80% by weight of hydrogenated phosphatidylcholine)
  • Stage 1 This is on a two-stage basis: one of granulation for pre-compaction and one of compression. Stage 1
  • the accurately weighed active principle is added to the hydrogenated lecithin, colloidal silica and Kollidon K30. These are mixed and sized with a 600 micron mesh screen.
  • the mixture obtained is compacted in a suitable compactor for 15 minutes and subsequently sized by means of an oscillating granulator equipped with 2.5 and 1 mm meshes. Finally the entire mixture is sieved through a 180 micron mesh.
  • flavouring, aspartame, glyceryl behenate and Kollidon CL are sieved by means of an oscillating granulator equipped with 600 micron mesh.
  • the mixture obtained in this stage is added to the product derived from stage 1 and mixed in a suitable mixer for 20 minutes.
  • the mixture obtained is compressed with a suitable compressing machine to a hardness of between 5 and 8 Kp.
  • test solutions containing the active principle ibuprofen together with phospholipids i.e. hydrogenated lecithin containing 80% by weight of hydrogenated phosphatidylcholine.
  • the tested substances were administered as solutions at a dose-volume of 10 ml/kg.
  • the UD 5 O parameter i.e. the dose of substance able to cause 50% lesion severity, was calculated by nonlinear regression in accordance with a dose-response curve having as the x-axis the concentrations of substances used and as the y-axis the severity of lesions.
  • the rat stomachs were fixed onto suitable supports and photographed by high resolution digital camera; this enabled the thus obtained images to be enlarged on a computer so as to evaluate as accurately as possible the number and severity of the lesions observed.
  • P 1.25% is significantly less than that of the lesions produced with ibuprofen alone (I 0.5%) and is completely analogous to the severity of lesions caused by water (H 2 O) or by 1.25% phospholipids alone (P 1.25%).
  • ibuprofen with 1.25% phospholipids is analogous to that caused by 0.5% ibuprofen, though at concentrations which are respectively 2.5 and 5 times lower than the two tested substances.
  • the UD 50 parameter indicates the dose of substance at which 50% severity of lesions consequent to treatment is observed.

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

Abstract

La présente invention concerne des formulations orodispersibles, gastroprotectrices et masquant le goût qui contiennent au moins un principe actif anti-irritant en association avec une phosphatidylcholine hydrogénée.
PCT/EP2007/060312 2006-09-29 2007-09-28 Formulations orodispersibles, gastroprotectrices et masquant le goût contenant au moins un principe actif gastrique anti-irritant WO2008037795A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2006A001883 2006-09-29
ITMI20061883 ITMI20061883A1 (it) 2006-09-29 2006-09-29 Formulazioni orodispersibili, gastroprotettive e taste- masking contenenti almeno un principio attivo gastrolesivo

Publications (1)

Publication Number Publication Date
WO2008037795A1 true WO2008037795A1 (fr) 2008-04-03

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/060312 WO2008037795A1 (fr) 2006-09-29 2007-09-28 Formulations orodispersibles, gastroprotectrices et masquant le goût contenant au moins un principe actif gastrique anti-irritant

Country Status (2)

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IT (1) ITMI20061883A1 (fr)
WO (1) WO2008037795A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0032556A1 (fr) * 1979-12-22 1981-07-29 A. Nattermann & Cie. GmbH Complexes acide rosmarinique phospholipide, procédé pour leur préparation et médicament les contenant
US20050053655A1 (en) * 2003-09-05 2005-03-10 Pharmaceutical Industry Technology And Development Center Rapid disintegrating tablets (RDTs) for pharmaceutical use and method for preparing the same
US20060078574A1 (en) * 2004-10-12 2006-04-13 The Board Of Regents Of The University Of Texas System Purified phospholipid-non-steroidal anti-inflammatory drug associated compositions and methods for preparing and using same
WO2006061142A1 (fr) * 2004-12-10 2006-06-15 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Composition pharmaceutique orodispersible et procede de preparation de celle-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0032556A1 (fr) * 1979-12-22 1981-07-29 A. Nattermann & Cie. GmbH Complexes acide rosmarinique phospholipide, procédé pour leur préparation et médicament les contenant
US20050053655A1 (en) * 2003-09-05 2005-03-10 Pharmaceutical Industry Technology And Development Center Rapid disintegrating tablets (RDTs) for pharmaceutical use and method for preparing the same
US20060078574A1 (en) * 2004-10-12 2006-04-13 The Board Of Regents Of The University Of Texas System Purified phospholipid-non-steroidal anti-inflammatory drug associated compositions and methods for preparing and using same
WO2006061142A1 (fr) * 2004-12-10 2006-06-15 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Composition pharmaceutique orodispersible et procede de preparation de celle-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LEYCK S ET AL: "IMPROVEMENT OF THE GASTRIC TOLERANCE OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS BY POLYENE PHOSPHATIDYLCHOLINE (PHOSPHOLIPON 100)", EUROPEAN JOURNAL OF PHARMACOLOGY, AMSTERDAM, NL, vol. 117, no. 1, October 1985 (1985-10-01), pages 35 - 42, XP001027916, ISSN: 0014-2999 *

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