WO1996029994A1 - Formulations solides mecaniquement stables de principes actifs - Google Patents

Formulations solides mecaniquement stables de principes actifs Download PDF

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Publication number
WO1996029994A1
WO1996029994A1 PCT/EP1996/001156 EP9601156W WO9629994A1 WO 1996029994 A1 WO1996029994 A1 WO 1996029994A1 EP 9601156 W EP9601156 W EP 9601156W WO 9629994 A1 WO9629994 A1 WO 9629994A1
Authority
WO
WIPO (PCT)
Prior art keywords
coating
active ingredient
plasticizer
active substances
acid
Prior art date
Application number
PCT/EP1996/001156
Other languages
German (de)
English (en)
Inventor
Reinhard Spengler
Joerg Rosenberg
Jörg Breitenbach
Original Assignee
Basf Aktiengesellschaft
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 Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to AU51453/96A priority Critical patent/AU5145396A/en
Publication of WO1996029994A1 publication Critical patent/WO1996029994A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer

Definitions

  • the present invention relates to mechanically stable, solid active substance preparation forms which have a coating.
  • an active ingredient preparation form e.g. a tablet, a capsule, a pellet, a granulate or also crystals
  • an active ingredient preparation form e.g. a tablet, a capsule, a pellet, a granulate or also crystals
  • Protection against moisture e.g. can accelerate a decomposition reaction of the active ingredient
  • a functional varnish can e.g. transfer the following properties to the painted product:
  • Production of a diffusion-controlled system which releases the active substance into the environment of the gastrointestinal tract in a time-controlled manner through the undestroyed lacquer membrane.
  • Production of a quickly soluble coating which should not impair the absorption of the active ingredient as far as possible, but instead protects the product until it is taken, for example from light, oxygen, access to moisture or for other reasons.
  • a lubricious coating also makes it easier to swallow the dosage form.
  • coatings must have the following basic properties so that the function is preserved:
  • the coating must have a certain flexibility so that it can be used in the storage process of the dosage form, e.g. Temperature change, moisture change, mech. Stress when filling in containers, no mechanical damage and e.g. Cracks. Cracks or generally defects would override the function of a protective lacquer or at least severely interfere with it. In the case of diffusion coating, it would mean the risk of a dose dumping effect and thus serious damage to the patient through immediate release of an excessive amount of active ingredient.
  • the varnish must not move on a drug surface or be pressed together so that its mechanical integrity is guaranteed.
  • the layer thickness of the lacquer must remain constant over the storage time of the dosage form, so that desired and set properties, such as Diffusion permeability for the active ingredient or the dissolution rate of the lacquer are maintained.
  • the solution or dispersion of a lacquer substance has a complex composition so that the aforementioned properties are achieved and are preserved over the planned / tested storage time of the medication.
  • Solid oral pharmaceutical forms in particular are produced by mixing the active ingredient together with one or more polymers and optionally other pharmaceutically customary auxiliaries and tabletting them by extrusion and shaping or compacting.
  • the group of active ingredient preparation forms mentioned include, for example Tablets, pellet, granules.
  • the coating can be one or more layers.
  • the active substance is preferably in the form of a molecularly disperse distribution in a polymer matrix (“solid solution”).
  • the proportion of plasticizer in the coating is preferably 0 to 10% by weight, in particular 0 to 5% by weight, very preferably 0 to 20 3% by weight.
  • the active ingredient is in particular a pharmaceutical ingredient, but it can also be other active compounds such as e.g. Trade vitamins. 25
  • the active substance preparation form can also have one or more functional coatings over the first, plasticizer-free or low-plasticizer coating.
  • the active substance preparations are in the form of "solid solutions"
  • the pharmacologically acceptable polymers can be used, for example: polyvinylpyrrolidone (PVP), Copolymers of
  • N-vinylpyrrolidone (NVP) and vinyl esters in particular vinyl acetate, copolymers of vinyl acetate and crotonic acid, partially saponified polyvinyl acetate, polyvinyl alcohol, ethylene / vinyl acetate, copolymers, polyhydroxyethyl methacrylate, copolymers of methyl methacrylate and acrylic acid, cellulose esters, cellulose ethers,
  • hydroxypropyl cellulose especially hydroxypropyl cellulose, polyethylene glycol or polyethylene, preferably NVP copolymers with vinyl acetate, hydroxypropyl cellulose and polyethylene glycols / polyethylene oxides.
  • the K values (according to H Fikentscher, Cellulose-Chemie 13 (1932), pages 58 to 64 and 71 and 74) of the polymers are in the range from 10 to
  • the polymeric binder must soften or melt in the range from 50 to 180, preferably 60 to 130 ° C., so that the composition can be extruded.
  • the glass transition temperature of the mixture must in any case be below 180, preferably below 130 ° C.
  • plasticizing auxiliaries such as long-chain alcohols, ethylene glycol, propylene glycol, trimethylolpropane, triethylene glycols, butanediols, pentanols, hexanols, polyethylene glycols, silicones, aromatic carboxylic acid esters (for example dialkyl phthalate, benzoic acid ester). Terephthalic acid ester) or aliphatic dicarboxylic acid esters (eg dialkyl adipates, sebacic acid esters, azelaic acid esters, citric and tartaric acid esters) or fatty acid esters.
  • aromatic carboxylic acid esters for example dialkyl phthalate, benzoic acid ester.
  • Terephthalic acid ester or aliphatic dicarboxylic acid esters (eg dialkyl adipates, sebacic acid esters, azelaic acid esters, citric and tartaric acid esters) or fatty acid esters.
  • Active ingredients that can be used in the manufacture of solid solutions include:
  • Metildigoxin o- (beta-hydroxyethyl) rutoside, propicillin, acicovir mononitrate, paracetamol, naftidrofuryl, pentoxyfylline, propafenone, acebutolol, L-thyroxine, tramadol, bromocriptine, loperamide, ketotifen, fenoterol, pro-phenol , Minocycline, nicergoline, ambroxol, metoprolol, beta-sitosterol, enalaprilhy- drug maleate, bezafibrate, ISDN, gallopamil, xantinol nicotinate, digitoxin, flunitrazepan, bencyclan, dexapanthenol, pindolol, lorazepam, diltiazem, furamamzepinamomethylaminomamzepam, pirolamamapin
  • Vitamins can also be formulated according to the invention. These include the vitamins of the A group and the B group, whereby besides B1, B2, B6 and B12 and nicotinic acid and nicotinamide, compounds with vitamin B properties are also understood, such as Adenine, choline, pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-ionite and ⁇ -lipoic acid. Furthermore vitamins of the C group, D group, E group, F group, H group, I and J group, K group and P group.
  • active ingredients for the preparation of solid solutions are ibuprofen, acetylsalicylic acid, para-cetamol, phenazone, flurbiprofen, captopril, nifedipine, acetylcystone, naftidrofuryl, verapamil and furosemide.
  • Combinations of active ingredients can also be used.
  • the amount of active ingredient, based on the solid pharmaceutical form, can be varied within wide limits depending on the effectiveness and rate of release.
  • the active ingredient content can be in the range from 0.1 to 90, preferably 0.5 to 60,% by weight.
  • the mechanical stabilization of moldings such as tablets, granules or pellets on the basis of the abovementioned polymers is successful if these have been processed into solid solutions with the abovementioned active substances or if these polymers have been processed with softening active substances, e.g. Acetylsalicylic acid, fenofibrate, naftidofuryl, furosemide, ibuprofen, anipamil, benzoic acid, indomethacin. Otherwise, the products are deformed, bonded and also melt away, so that individual removal from a container is no longer possible and that if individual moldings are stored separately, they are in a form which is no longer suitable for consumption.
  • softening active substances e.g. Acetylsalicylic acid, fenofibrate, naftidofuryl, furosemide, ibuprofen, anipamil, benzoic acid, indomethacin.
  • the coatings for the active substance preparations according to the invention can be produced in the following way:
  • Suitable coating polymers are:
  • plasticizers if they are used, the following can be used:
  • These polymers include:
  • the moldings are coated with a coating as described under 1 or 2 and thus sufficiently solidified.
  • a plasticizer-containing coating possibly a functional coating, is applied, which contains plasticizer components, as are common in pharmaceutics.
  • a stronger mechanical solidification is achieved and it is also possible to cover the forming with a functional coating (enteric coating, diffusion coating, saliva-resistant coating).
  • the functional covering is represented by the 2nd layer.
  • the functional cover is protected against additional, migrating, softening components from the molding and can thus retain its function and quality over the intended storage period.
  • the coating layers are applied in the known manner.
  • Macrogol 6000 polyethylene glycol 0.070 mg
  • Titanium dioxide E 171 1.840 mg
  • the mechanical stability is guaranteed with a coating over 3 years at ⁇ .30 ° C. At 30 ° C, the tablet is deformed after 4 months of storage if no lacquer coating is used.
  • Klucel EF hydroxypropylmethyl 200 mg cellulose
  • the mechanical stability of the coated pellets can be guaranteed for 3 years at up to + 30 ° C. Without coating, the pellets deform and stick after 2 months, stored at + 30 ° C. With a triethyl citrate content of 22 mg (to 80 mg ethyl cellulose dispersion), this corresponds to the pharmaceutically Chen concentration in the processing of the paint, the
  • the mechanical stability is given with a varnish coating for> 3 years at up to + 30 ° C. Without a coating, the tablet deforms at + 30 ° C after 7 months.
  • Titanium dioxide 1.8 mg iron oxide yellow 0.015 mg
  • the mechanical stability with the stabilizing coating is given at a storage temperature of ⁇ + 30 ° C for> 3 years, without the stabilizing coating only 1.5 months.
  • Titanium dioxide 1.8 mg
  • the mechanical stability with the stabilizing coating is at a storage temperature of ⁇ . + 30 ° C for> 3 years.
  • the uncoated tablet dissolves within a week at + 30 ° C.
  • Aerosil o. 005 mg gastro-resistant function lsöü LubJe ⁇ Srzug
  • the stability of the coated indomethacin tablet is guaranteed for 3 years at a storage temperature of up to + 30 ° C. Without a coating, the tablet dissolves within 3 weeks of storage at + 30 ° C.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des formulations solides mécaniquement stables de principes actifs, contenant au moins un principe actif et au moins un polymère, et dont le revêtement a une teneur en plastifiant de 6 à 16 % en poids. Ces formulations de principes actifs permettent une stabilisation mécanique de produits moulés - comprimés, granulés ou pastilles - sur la base des polymères susmentionnés, lorsque ces derniers sont transformés en solutions solides avec les principes actifs susmentionnés ou lorsque ces polymères sont traités avec des principes actifs plastifiants, comme par exemple: acide acétylsalicylique, fénofibrate, naftidrofuryle, furosémide, ibuprofène, anipamile, acide benzoïque ou indométacine.
PCT/EP1996/001156 1995-03-27 1996-03-18 Formulations solides mecaniquement stables de principes actifs WO1996029994A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU51453/96A AU5145396A (en) 1995-03-27 1996-03-18 Mechanically stable solid formulations of active substances

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19511131.1 1995-03-27
DE1995111131 DE19511131A1 (de) 1995-03-27 1995-03-27 Mechanisch stabile feste Wirkstoffzubereitungsformen

Publications (1)

Publication Number Publication Date
WO1996029994A1 true WO1996029994A1 (fr) 1996-10-03

Family

ID=7757830

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/001156 WO1996029994A1 (fr) 1995-03-27 1996-03-18 Formulations solides mecaniquement stables de principes actifs

Country Status (3)

Country Link
AU (1) AU5145396A (fr)
DE (1) DE19511131A1 (fr)
WO (1) WO1996029994A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998056355A1 (fr) * 1997-06-12 1998-12-17 Hexal Ag Preparations pharmaceutiques a liberation controlee contenant un inhibiteur de l'enzyme de conversion de l'angiotensine comme principe actif
US5902632A (en) * 1995-01-31 1999-05-11 Mehta; Atul M. Method of preparation of controlled release nifedipine formulations
US9089492B2 (en) 2000-11-20 2015-07-28 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1311915B1 (it) * 1999-04-12 2002-03-20 Pharmexcel S R L Compressa anidra di cloridrato di ranitidina con rivestimento a doppiostrato e sua composizione.
US20100151035A1 (en) * 2007-03-13 2010-06-17 Sandoz Ag Pharmaceutical compositions of poorly soluble drugs

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4155993A (en) * 1977-01-13 1979-05-22 Lipha, Lyonnaise Industrielle Pharmaceutique Prolonged-release pharmaceutical compositions for oral administration, their methods of making and use
EP0137198A2 (fr) * 1983-08-11 1985-04-17 Fujisawa Pharmaceutical Co., Ltd. Préparation solide à libération rapide à base d'un composé de la dihydropyridine A et procédé de sa préparation
US4693896A (en) * 1985-10-07 1987-09-15 Fmc Corporation Ethylcellulose-coated, gastric-disintegrable aspirin tablet
EP0240904A2 (fr) * 1986-04-11 1987-10-14 BASF Aktiengesellschaft Procédé pour la préparation de formes pharmaceutiques solides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4155993A (en) * 1977-01-13 1979-05-22 Lipha, Lyonnaise Industrielle Pharmaceutique Prolonged-release pharmaceutical compositions for oral administration, their methods of making and use
EP0137198A2 (fr) * 1983-08-11 1985-04-17 Fujisawa Pharmaceutical Co., Ltd. Préparation solide à libération rapide à base d'un composé de la dihydropyridine A et procédé de sa préparation
US4693896A (en) * 1985-10-07 1987-09-15 Fmc Corporation Ethylcellulose-coated, gastric-disintegrable aspirin tablet
EP0240904A2 (fr) * 1986-04-11 1987-10-14 BASF Aktiengesellschaft Procédé pour la préparation de formes pharmaceutiques solides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PORTER S.C.: "The effect of additives on the properties of an aqueous film coating. Part II", PHARM. TECHNOL., vol. 4, no. 3, 1980, pages 67 - 75, XP002007037 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5902632A (en) * 1995-01-31 1999-05-11 Mehta; Atul M. Method of preparation of controlled release nifedipine formulations
WO1998056355A1 (fr) * 1997-06-12 1998-12-17 Hexal Ag Preparations pharmaceutiques a liberation controlee contenant un inhibiteur de l'enzyme de conversion de l'angiotensine comme principe actif
AU736357B2 (en) * 1997-06-12 2001-07-26 Hexal Ag Controlled-release pharmaceutical preparation comprising an ACE inhibitor as active ingredient
US6267990B1 (en) 1997-06-12 2001-07-31 Hexal Ag Controlled-release pharmaceutical preparation comprising an ACE inhibitor as active ingredient
US9089492B2 (en) 2000-11-20 2015-07-28 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures

Also Published As

Publication number Publication date
AU5145396A (en) 1996-10-16
DE19511131A1 (de) 1996-10-02

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