WO2008049657A2 - Utilisation de copolymères de (méth)acrylate dans des formes de médicaments à délivrance retardée pour diminuer les effets de l'éthanol sur la libération de la subtance active - Google Patents

Utilisation de copolymères de (méth)acrylate dans des formes de médicaments à délivrance retardée pour diminuer les effets de l'éthanol sur la libération de la subtance active Download PDF

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Publication number
WO2008049657A2
WO2008049657A2 PCT/EP2007/058100 EP2007058100W WO2008049657A2 WO 2008049657 A2 WO2008049657 A2 WO 2008049657A2 EP 2007058100 W EP2007058100 W EP 2007058100W WO 2008049657 A2 WO2008049657 A2 WO 2008049657A2
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WIPO (PCT)
Prior art keywords
meth
ethanol
release
acrylate
active ingredient
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PCT/EP2007/058100
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German (de)
English (en)
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WO2008049657A3 (fr
Inventor
Hans-Ulrich Petereit
Brigitte Skalsky
Diego Gallardo
Manfred Assmus
Andreas Gryczke
Wolfgang Weisbrod
Felix Hofmann
Hans BÄR
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Evonik Röhm Gmbh
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Publication of WO2008049657A2 publication Critical patent/WO2008049657A2/fr
Publication of WO2008049657A3 publication Critical patent/WO2008049657A3/fr

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    • 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
    • A61K9/20—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

Definitions

  • the invention relates to the use of (meth) acrylate copolymers in sustained-release dosage forms for reducing the influence of ethanol on the release of active ingredient.
  • US 2003/0118641 A1 describes a method for reducing the abuse potential of oral dosage forms containing extractable opioids.
  • a resistance to the extraction of active ingredient by means of common household solvents such as isopropyl alcohol, vodka, white wine vinegar, hot water or peroxide, 0.01 HCl in dilute alcohol, is to be effected.
  • the active ingredient with a matrix-forming polymer and an ion exchange material, for.
  • stryrene-divinylbenzene Polymehsaten to formulate in micronized form.
  • the ion exchange material is crucial.
  • the matrix-forming polymer obviously serves as a structurant for the drug core.
  • Preferred matrix formers are C 1 -C 6 -hydroxyalkylcelluloses.
  • US 2004/0052731 A1 describes a dosage form, in particular suitable for opioid active substances, which is intended to contribute to the reduction of the abuse potential by improper administration. It is proposed to use a lipophilic active ingredient variant with a water-insoluble additive such. As a fatty acid or crosslinked water-soluble polysaccharides to combine.
  • US 2005/0163856 A1 describes a therapeutic method for the treatment of patients suffering from pain with an oxycodone-containing dosage form with reduced potential for abuse by dissolution in a solvent and subsequent improper administration.
  • the active ingredient is said to be formulated with a matrix-forming polymer selected from the group of hydroxypropyl cellulose, hydroxypropylmethyl cellulose or hydroxyethyl cellulose.
  • WO 2006/002884 A1 describes anti-abuse oral dosage forms containing a polymer, in particular a polyalkylene oxide, having a breaking strength of at least 500 N.
  • WO 2006/094083 A1 describes a dosage form with controlled release of venlafaxine.
  • As additives may further hydrophobic polymers, u.a. also polymethacrylates, are added.
  • the present invention is based on sustained release veterinary forms for oral administration (oral sustained-release dosage forms).
  • This type of dosage form is intended for a prolonged release of an active ingredient mostly during intestinal transit. Attempted by appropriate retardant formulations of the drug form to achieve that after initial increase in the blood level concentration of the active ingredient it remains as long as possible in the therapeutically optimal range. Too high a blood level concentration of the drug, which usually has toxic effects, or too low, subliminal blood level of the drug, the no or no sufficient therapeutic effect, should be avoided.
  • the purpose of the present invention is expressly not to stimulate, promote or permit the ingestion of ethanol-containing beverages together with sustained release dosage forms, but to mitigate or avoid the potentially fatal consequences of deliberate or accidental abuse.
  • the present invention is based on in vitro conditions as objectively comprehensible measurement basis.
  • the object of the invention is to provide an oral sustained-release pharmaceutical form in which the release of active ingredient in acidic USP Paddle at pH 1, 2 and 37 0 C with a content of 5, 10 or 40% ethanol (v / v) at the time is not increased or decreased by more than 20%, preferably by not more than 10%, compared to the medium without ethanol after 2 hours.
  • This requirement concerns the prevention or reduction of the effect of an undesirable or high-risk release of an unintentional dose of active ingredient in the stomach.
  • This situation primarily affects the more or less simultaneous intake the oral sustained release drug form and an alcoholic beverage within the residence time in the stomach, z. B. within a time window of about 2 hours.
  • the object of the present invention is to provide an oral sustained-release pharmaceutical form in which the release of active ingredient in buffered medium according to USP Paddle at pH 6.8 and 37 0 C with a content of 5, 10 or 40% ethanol (v / v) at the time is increased or decreased by not more than 20%, preferably not more than 10%, after 4 hours compared to the medium without ethanol.
  • This requirement relates to the prevention or reduction of the effect of accelerating or slowing down the release of active substance in the intestine.
  • This situation essentially relates to the subsequent intake of an alcoholic beverage at a time interval from taking the oral sustained-release dosage form, so that the dosage form is first exposed to an ethanol-containing environment in the intestine.
  • the measurement of the percentage released amount of active ingredient may, for. B. by on-line UV spectroscopy at a suitable wavelength for the respective drug.
  • a specialist is familiar with the methodology.
  • Drug release may be performed according to USP, especially USP 28-NF23, General Chapter ⁇ 711>, Dissolution, Apparatus 2 (Paddle), Method ⁇ 724>, "Delayed Release (Enteric Coated) Articles-General General Drug Release Standard", Method B (50th Edition) Upm, 37 0 C) are determined with the following modification:
  • the dosage forms are first tested for 120 min in artificial gastric juice (USP) at pH 1, 2, then buffered with phosphate buffer to pH 6.8, which corresponds to an artificial intestinal milieu Measurement carried out in ethanolic medium with the appropriate amount of ethanol (v / v) in the medium.
  • USP artificial gastric juice
  • An oral sustained-release dosage form in which the drug release in acidic USP Paddle at pH 1, 2 and 37 0 C with a content of 5% ethanol (v / v) at the time after 2 hours compared to the medium without ethanol to not is increased or decreased by more than 20%, preferably by not more than 10%, in vivo by the simultaneous ingestion of alcoholic beverages with low ethanol content, such as. B. beer (about 4.8% ethanol content), relatively little influenced compared to a non-inventively designed dosage form.
  • An oral sustained-release pharmaceutical form in which the drug release, measured according to USP paddle at 37 0 C in acidic medium at pH 1, 2 for 2 hours and subsequent buffering on buffered medium according to USP Paddle pH 6.8 with a content of the media % Ethanol (v / v) at the time after a total of 6 hours compared to the medium without ethanol increased by not more than 20%, preferably by not more than 10% or decreased, is in vivo by the subsequent ingestion of alcoholic beverages with low ethanol content, such.
  • B. beer (about 4.8% ethanol content) relatively little influenced compared to a non-inventively designed dosage form.
  • alcoholic drinks patient group is expected to consume mostly drinks with low ethanol content, which often corresponds to common food intake habits. Just think of the more southern regions of Germany, where beer is still regarded as a staple food and consumed regularly in large parts of the population. Dosage forms that meet these requirements, develop their beneficial effect in patient groups who consume predominantly or exclusively drinks with low ethanol content.
  • An oral sustained-release pharmaceutical form in which the drug release in acidic USP Paddle at pH 1, 2 and 37 0 C containing 10% ethanol (v / v) at the time after 2 hours compared to the medium without ethanol to not is increased or decreased by more than 20%, preferably by not more than 10% is in vivo by the simultaneous intake of alcoholic beverages with moderate ethanol content, such.
  • alcoholic beverages with moderate ethanol content such.
  • a liquor taken before or after taking the oral sustained release (20 ml with about 45% ethanol content) would dilute in the stomach to a lower ethanol concentration, however, the dosage form could be locally exposed to a higher ethanol content in the short term.
  • An oral sustained-release pharmaceutical form in which the drug release, measured to USP paddle at 37 0 C in acidic medium at pH 1, 2 for 2 hours and then buffering on buffered medium to USP paddle pH 6.8 with a content of 10 media % Ethanol (v / v) at the time after a total of 6 hours compared to the medium without ethanol increased by not more than 20%, preferably not more than 10% or decreased, is in vivo by the simultaneous intake of alcoholic beverages with medium Ethanol content, such as. As wine or the ingestion of small amounts of alcoholic beverages with high ethanol content compared to a non-inventively designed drug form relatively little affected.
  • alcoholic drinks patient group drinks with medium ethanol content, such as. As wine, or occasionally consumed small amounts of alcoholic beverages with high ethanol content.
  • medium ethanol content such as. As wine, or occasionally consumed small amounts of alcoholic beverages with high ethanol content.
  • An oral sustained-release drug form in which the drug release in acidic medium to USP paddle at pH 1, 2 and 37 0 C containing 40% ethanol (v / v) at the time after 2 hours compared to the medium without ethanol to not more than 20% preferably not more than 10% is increased or decreased, offers a high protection against unwanted side effects when taking alcoholic beverages with low, medium or high ethanol content.
  • An oral sustained-release pharmaceutical form in which the drug release, measured according to USP paddle at 37 0 C in acidic medium at pH 1, 2 for 2 hours and subsequent buffering on buffered medium according to USP Paddle pH 6.8 with a content of 40 media % Ethanol (v / v) at the 6 hour time point is not increased or decreased by more than 20% as compared to the medium without ethanol offers a high level of protection against undesirable side effects when taking low, medium or high ethanol content alcoholic beverages ,
  • This high requirement is of importance in practice, since a small proportion of the alcoholic beverage consumed in the context of the invention consumes drinks with a high ethanol content.
  • This group of people is usually referred to as alcohol dependent and therefore often not inclined or able to dispense during the intake of drugs on the consumption of hard alcohol.
  • the abuse potential is highest in this numerically safe smallest patient group.
  • enteric-insoluble (meth) acrylate copolymers in sustained-release oral dosage forms as a matrix-forming agent for the active substance contained in order to reduce the effect of accelerating or slowing the release of active ingredient by the influence of ethanol under in-vitro conditions.
  • the invention relates to the
  • enteric-insoluble (meth) acrylate copolymers in sustained-release oral dosage forms as a matrix-forming agent for the active substance contained in order to reduce the effect of accelerating or slowing the release of active ingredient by the influence of ethanol under in-vitro conditions.
  • Neutral or essentially neutral methacrylate copolymers consist of at least 95, in particular at least 98, preferably at least 99, in particular to at least 99, more preferably to 100 wt .-% of (meth) acrylate monomers having neutral radicals, in particular C 1 to C 4 alkyl radicals.
  • Suitable (meth) acrylate monomers with neutral radicals are, for.
  • Preferred are methyl methacrylate, ethyl acrylate and methyl acrylate.
  • methacrylate monomers with anionic radicals for.
  • methacrylic acid may be included.
  • Suitable z. B. neutral or nearly neutral (meth) acrylate copolymers of 20 to 40 wt .-% ethyl acrylate, 60 to 80 wt .-% of methyl methacrylate and 0 to 5 wt .-% methacrylic acid type EUDRAGIT® NE, EUDRAGIT® NM or Kollicoat type ® EMM 3OD, BASF.
  • Suitable z. B. neutral (meth) acrylate copolymers of 20 to 40 wt .-% ethyl acrylate and 60 to 80 wt .-% methyl methacrylate (type EUDRAGIT® NE).
  • EUDRAGIT® NE is a copolymer of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate.
  • a nonionic emulsifier having an HLB value of from 15.2 to 17.3.
  • the latter offer the advantage that a phase separation under formation of crystal structures by the emulsifier is omitted (Eudragit® NM).
  • EUDRAGIT® NM is a copolymer of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate.
  • EP 1571164 A2 corresponding almost neutral (meth) acrylate copolymers, with small amounts, 0.05 to 1 wt .-% of monoolefinically unsaturated Cs-Cs carboxylic acids but also by emulsion polymerization in the presence of comparatively small amounts of anionic emulsifiers, eg. B. 0.001 to 1 wt .-%, are obtained as a dispersion.
  • anionic emulsifiers eg. B. 0.001 to 1 wt .-%
  • neutral or almost neutral (meth) acrylate copolymers are used in the process according to the invention, these should preferably be obtained first as a solid from the dispersions, for. B. by spray or freeze-drying.
  • Gastric juice-insoluble (meth) acrylate copolymers may, for. B. 40 to 100, preferably from 45 to 99, in particular from 85 to 95 wt .-% radically polymehstechnisch d- to C 4 -alkyl esters of acrylic or methacrylic acid and 0 to 60, preferably 1 to 55, in particular 5 bis 15% by weight of (meth) acrylate monomers having an anionic group.
  • the proportions mentioned add up to 100% by weight.
  • small amounts ranging from 0 to 10, e.g. B. 1 to 5 wt .-% of further vinylic copolymerizable monomers, such as.
  • As hydroxyethyl methacrylate or hydroxyethyl acrylate may be included.
  • C 1 -C 4 -alkyl esters of acrylic or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.
  • a (meth) acrylate monomer having an anionic group may e.g. As acrylic acid, but preferably be methacrylic acid. Also suitable are anionic (meth) acrylate copolymers of 40 to 60, wt .-% methacrylic acid and 60 to 40 wt .-% methyl methacrylate or 60 to 40 wt .-% ethyl acrylate (types EUDRAGIT® L or EUDRAGIT® L100-55).
  • EUDRAGIT® L is a copolymer of 50% by weight of methyl methacrylate and 50% by weight of methacrylic acid.
  • EUDRAGIT® L100-55 is a copolymer of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.
  • EUDRAGIT® L 30-55 is a dispersion containing 30% by weight EUDRAGIT® L 100-55.
  • anionic (meth) acrylate copolymers of from 20 to 40% by weight of methacrylic acid and from 80 to 60% by weight of methyl methacrylate (type EUDRAGIT® S).
  • (meth) acrylate copolymers consisting of 10 to 30 wt .-%, methyl methacrylate, 50 to 70 wt .-% of methyl acrylate and 5 to 15 wt .-% methacrylic acid (type EUDRAGIT® FS).
  • EUDRAGIT® FS is a copolymer of 25% by weight, methyl methacrylate, 65% by weight of methyl acrylate and 10% by weight of methacrylic acid.
  • EUDRAGIT® FS 30 D is a dispersion containing 30% by weight EUDRAGIT® FS.
  • This (meth) acrylate copolymer is suitable because of its good elongation at break especially for pressing pellets into tablets.
  • the copolymer is composed, in particular, of free-radically polymethylated units of
  • From 20 to 34 preferably from 25 to 33, particularly preferably from 28 to 32,% by weight of methacrylic acid or acrylic acid, preference is given to methacrylic acid,
  • the glass transition temperature of the copolymer (measurement without addition of plasticizer at a residual monomer content (REMO) of less than 100 ppm, heating rate 10 ° C. / min, nitrogen atmosphere) according to ISO 11357-2, point 3.3.3 (T mg ), at most 60, preferably 40 to 60, particularly preferably 45 to 55 0 C.
  • REMO residual monomer content
  • the copolymer preferably consists essentially or exclusively of the monomers methacrylic acid, methyl acrylate and ethyl acrylate in the abovementioned proportions.
  • glass temperature is meant in particular the midpoint temperature T mg according to ISO 11357-2, point 3.3.3.
  • the measurement takes place without added plasticizer, at residual monomer contents (REMO) of less than 100 ppm, at a heating rate of 10 ° C / min and under a nitrogen atmosphere.
  • REMO residual monomer contents
  • copolymers are obtained in a manner known per se by free-radical bulk, solution, bead or emulsion polymerization. They must be brought into the particle size range according to the invention before processing by suitable grinding, drying or spraying processes. This can be done by simply breaking extruded and cooled granule strands or hot stamping.
  • powders when mixed with other powders or liquids, the use of powders may be advantageous.
  • Suitable equipment for the preparation of the powder are familiar to the expert, for. B. air jet mills, pin mills, fan mills. If necessary, appropriate screening steps can be included.
  • a suitable mill for large industrial quantities, for example, is an opposed jet mill (Multi No. 4200), which is operated at about 6 bar overpressure.
  • copolymers are also suitable for the purposes of the invention.
  • copolymers see WO 2004/096185.
  • Copolymers of this type are particularly suitable for pressing pellets into tablets because of their good mechanical properties.
  • the above-mentioned copolymer is composed, in particular, of free-radically polymerized units of
  • From 20 to 33 preferably from 25 to 32, particularly preferably from 28 to 31,% by weight of methacrylic acid or acrylic acid, preference is given to methacrylic acid,
  • the monomer composition is selected so that the glass transition temperature of the copolymer 55 to 70 0 C, preferably 59 to 66, particularly preferably 60 to 65 0 C.
  • glass temperature is meant in particular the midpoint temperature T mg according to ISO 11357-2, point 3.3.3.
  • the measurement is carried out without addition of plasticizer, with residual monomer contents (REMO) of less than 100 ppm, at a heating rate of 10 ° C / min and under a nitrogen atmosphere.
  • REMO residual monomer contents
  • the copolymer is preferably substantially to exclusively, at 90, 95 or 99 to 100 wt .-%, of the monomers methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in the quantitative ranges given above.
  • copolymers are obtained in a manner known per se by free-radical substance, solution, bead or emulsion polymerization. They must be brought into the particle size range according to the invention before processing by suitable grinding, drying or spraying processes. This can be done by simply breaking extruded and cooled granule strands or hot stamping.
  • powders when mixed with other powders or liquids, the use of powders may be advantageous.
  • Suitable equipment for the preparation of the powder are familiar to the expert, for. B. air jet mills, pin mills, fan mills. If necessary, appropriate screening steps can be included.
  • a suitable mill for large industrial quantities, for example, is an opposed jet mill (Multi No. 4200), which is operated at about 6 bar overpressure.
  • the preparation of the anionic (meth) acrylate copolymers with proportions of anionic monomers of more than 5% by weight in the polymer can be carried out in a manner known per se by radical polymerization of the monomers (see, for example, EP 0 704 207 A2, EP 0 704 208 A2 WO 2003/072087, WO 2004/096185).
  • the copolymers can be prepared in a manner known per se by free-radical emulsion polymerization in an aqueous phase in the presence of preferably anionic emulsifiers, for example by the process described in DE-C 2,135,073.
  • the copolymer can be prepared by conventional free-radical polymerization processes continuously or batchwise in the presence of free-radical initiators and, if appropriate, regulators for adjusting the molecular weight in bulk, in solution, by means of bead polymerisation or in emulsion.
  • the average molecular weight M w (weight average, determined, for example, by measuring the solution viscosity) can be determined by e.g. B. in the range of 80,000 to 1,000,000 (g / mol) are.
  • the emulsion polymerization in the aqueous phase in the presence of water-soluble initiators and (preferably anionic) emulsifiers.
  • the copolymer can be obtained in solid form by crushing, extrusion, granulation or hot peeling.
  • Corresponding (meth) acrylate copolymers are, for. B. from EP-A 181 515 or DE-PS 1 617 751 known. It is independent of the pH-soluble or swellable polymers that are suitable for ArzneiffenMaurüberz ⁇ gen.
  • the substance polymerization is to be mentioned in the presence of a radical-forming initiator dissolved in the monomer mixture.
  • the polymer can also be prepared by solution or precipitation polymerization. The polymer can be obtained in this way in the form of a fine powder, which in the Subtanzpolymerisation by grinding, in solution and precipitation polymerization z. B. can be reached by spray drying.
  • the (meth) acrylate copolymer is composed of 85 to 98 wt .-% radically polymerized d- to C 4 -alkyl esters of acrylic or methacrylic acid and 15 to 2 wt .-% (meth) acrylate monomers with a quaternary ammonium group in the alkyl radical together.
  • Preferred C 1 to C 4 alkyl esters of acrylic or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and methyl methacrylate.
  • (meth) acrylate monomer having quaternary ammonium groups 2-trimethylammoniumethyl methacrylate chlohd is particularly preferred.
  • a corresponding copolymer, for. B. from 50 to 70 wt .-% methyl methacrylate, 20 to 40 wt .-% ethyl acrylate and 7- 2 wt .-% 2-Thmethylammoniumethylmethacrylat-Chlohd be constructed.
  • a concrete suitable copolymer contains 65 wt .-% methyl methacrylate, 30 wt .-% ethyl acrylate and 5 wt .-% 2-Thmethylannnnoniunnethylnnethacrylat Chlohd be constructed (EUDRAGIT® RS).
  • Another suitable (meth) acrylate copolymer may, for. B. from 85 to less than 93 wt .-% C1 to C4 alkyl esters of acrylic or methacrylic acid and more than 7 to 15 wt .-% of (meth) acrylate monomers with a quaternary ammonium group in the alkyl radical.
  • Such (meth) acrylate monomers are commercially available and have long been used for retarding coatings.
  • a concrete suitable copolymer contains z. B. 60 wt .-% methyl methacrylate, 30 wt .-% ethyl acrylate and 10 wt .-% 2-Thmethylammoniumethlymethacrylat-Chlohd (EUDRAGIT® RL).
  • the invention relates to oral sustained-release dosage forms. These are sustained-release type, sustained-release type, repeated-action or layered-time-type, or delayed-release type, for oral Recording are provided.
  • the drug release should usually be controlled over a longer period, so long-lasting blood levels of the drug in the therapeutically optimal range can be effected.
  • the oarle sustained-release pharmaceutical form contains an active substance which is embedded in a matrix of a gastric juice-insoluble (meth) acrylate copolymer, and optionally further pharmaceutical auxiliaries.
  • the proportions of active substance, gas solvent-insoluble (meth) acrylate copolymers, and the optional pharmaceutical excipients contained add up to 100 wt .-%.
  • the dosage form contains a drug-containing matrix which may contain from 5 to 80, preferably from 10 to 30,% by weight of the enteric-insoluble (meth) acrylate copolymer.
  • the pharmaceutical form contains a drug-containing matrix which may contain an active ingredient content of 0.01 to 95, preferably from 20 to 60 wt .-%.
  • the pharmaceutical form or the active ingredient-containing matrix can have a proportion of pharmaceutical excipients of up to 94.99% by weight.
  • the dosage form can be present as a pellet. Better results are achieved with matrix tablets, so that the shape is preferred.
  • pellets By pellets is meant a particularly round or spherical form of granules which includes an active ingredient. Pellets usually have good flow properties. The mean particle size can be z. B. in the range of 50 - 2000 microns. They are preferably filled into capsules or sachets or compressed after admixing other excipients to disintegrating tablets.
  • Blends for pellet pellets are prepared by mixing the pellets with suitable binding agents for tableting, adding disintegrants if necessary, and adding lubricants if necessary. The mixing can take place in suitable machines. Unsuitable are mixers that cause damage to the pellets, eg. B. plowshare mixer. To achieve suitable short disintegration times, a special order of addition of the excipients to the pellets may be required. By premixing with the pellets with the lubricant or mold release agent magnesium stearate their surface can be hydrophobized and thus sticking can be avoided.
  • Under a matrix tablet is a compressed tablet with a porous Gerüst stated. Understood matrix structure that releases the active ingredient by solution and diffusion processes while largely maintaining the tablet form, in contrast to disintegrating tablets, controlled or retarded.
  • Typical binders for matrix tablets are e.g. As calcium phosphates, Ludipress ® , lactose or other suitable sugars or calcium sulfates. Preference is given to substances having a low bulk density.
  • Disintegrating agent such as. As crosslinked polyvinylpyrrolidone, optionally in small quantities, for. B. from 0 to 5 wt .-% may be included. Preferably, no disintegrating agents are included or only in such small amount, z. B. to 5 wt .-%, so that they do not contribute to the disintegration of the tablet but only to loosen up the matrix structure.
  • disintegrating agent such as. As crosslinked polyvinylpyrrolidone, optionally in small quantities, for. B. from 0 to 5 wt .-% may be included.
  • no disintegrating agents are included or only in such small amount, z. B. to 5 wt .-%, so that they do not contribute to the disintegration of the tablet but only to loosen up the matrix structure.
  • the use of disintegrant can be omitted.
  • Typical lubricants and mold release agents are magnesium stearates or other suitable salts of fatty acids or substances listed in the literature for this purpose (e.g., lauric acid, calcium stearate, talc, etc.).
  • suitable machinery e.g., tablet press with external lubrication
  • suitable formulations the use of a lubricant and mold release agent in the blend may be eliminated.
  • the mixture may optionally be accompanied by a flow improver (eg highly disperse silicic acid derivatives, talc, etc.).
  • a flow improver eg highly disperse silicic acid derivatives, talc, etc.
  • the tableting can be carried out on conventional tablet presses, eccentric or rotary tablet presses, with pressing forces in the range of 5 to 40 kN, preferably 10 - 20 kN.
  • the tablet presses can be equipped with systems for external lubrication. If necessary, special systems for filling the matrix are used, which avoid the filling of matrices by means of agitator blades. drugs
  • the invention is suitable in principle for all types of active ingredients. However, the effect according to the invention occurs all the more, the lower the ethanol solubility of the active ingredient itself is. Also preferred are agents in which the abuse or side effect potential is particularly high or critical for the patient.
  • agents in which the abuse or side effect potential is particularly high or critical for the patient are z. B. the classes of analgesics, z. As diclofenac or opioids, psychotropic agents, eg. B. antidepressants such. As amitryptiline, or other effective in the central nervous system substances.
  • substances in which the therapeutic range is particularly narrow, z. B. herz becamee substances such.
  • Typical pharmaceutical excipients are, in particular, fillers, binders, lubricants, flow regulators, lubricants, mold release agents, disintegrants, humectants, counter-disintegrants and plasticizers.
  • Crosslinked hydrogel formers as described in WO 2006/094083, in particular xanthan gum and locust bean gum. In these natural-based substances, excessive fluctuations in product properties are often found which make them unsuitable for the purposes of the invention.
  • Hydroxypropyl cellulose, hydroxypropylmethyl cellulose or hydroxyethyl cellulose, according to US 2005/0163856 A1, may optionally also be excluded since their degree of hydration may lead to interactions with food components (food effects).
  • the measurement of the percentage released amount of active ingredient is carried out by On-Iine UV-Vis spectroscopy at a suitable wavelength for the respective drug.
  • the sample is prepared by melt extrusion on a twin-screw extruder with separate solids supply at a maximum temperature of 170 0 C.
  • 50% theophylline (melting point 270-274 0 C) is embedded unmelted in the polymer matrix consisting of 50% EUDRAGIT ® RS PO.
  • the melt is processed on a Leistritz Micro Pelletizer to form spherically shaped, rounded micro pellets at a discharge temperature of about 150 0 C.
  • the speed of the pelletizer running with a knife was 2500 / min.
  • the produced particles are more than 90% in the particle size range of 800 - 1000 microns.
  • 700 g of diltiazem HCl and 1300 g of calcium hydrogen phosphate are mixed in the fluidized bed apparatus and preheated.
  • the fluidized bed apparatus used is a Glatt WSG 2 (top spray mode) with 1.2 mm nozzle diameter and 2 bar spray pressure.
  • the granules are mixed with 0.5% (m / m) magnesium stearate for 10 min in the Erweka biconical mixer.
  • the tabletting is carried out on an instrumented Korsch EK 0 eccentric press (12 mm punch, radius of curvature 20) into tablets with 500 mg mass and an active substance content of 175 mg. The tablets do not disintegrate in the release media.
  • the above formulation remains in acidic medium and in buffered medium after 6 hours at all EtOH concentrations below the required 20% value for the acceleration or deceleration of drug release compared to the medium without EtOH.
  • the formulation is therefore particularly suitable for reducing the influence of EtOH on drug release.
  • the granules are mixed with 0.5% (m / m) magnesium stearate for 1 min.
  • the tabletting is carried out on a rotary press (Shanghai Tianxiang Pharmaceutical Co., Ltd.) (8 mm stamp) into tablets with 250 mg mass and an active substance content of 100 mg and a breaking strength of 15 kg / cm 2 .
  • the above formulation remains in acidic medium and in buffered medium after 6 hours at an EtOH concentration of 5% below the required 20% value for the acceleration or deceleration of drug release in comparison to the medium without EtOH.
  • the formulation is therefore suitable for assessing the effect of low EtOH ethanol-containing beverages, e.g. As beer, to reduce the drug release.
  • diltiazem HCl and 650 g of calcium hydrogen phosphate are mixed in the fluidized bed apparatus and preheated.
  • the fluidized bed apparatus used is a Glatt GPCG 1.1 (top spray mode) with 1.2 mm nozzle diameter and 2 bar spray pressure.
  • the granules are mixed with 0.5% (m / m) magnesium stearate for 10 min in the Erweka biconical mixer. Tableting is carried out on an instrumented Korsch EK 0 eccentric press (11 mm punch, radius of curvature 8.5) into tablets with 500 mg mass and an active substance content of 175 mg. The tablets do not disintegrate in the release media.
  • the above formulation remains in acidic medium and in buffered medium after 6 hours at all EtOH concentrations below the required 20% value for the acceleration or deceleration of drug release compared to the medium without EtOH.
  • the formulation is therefore particularly suitable for reducing the influence of EtOH on drug release.
  • 700 g of diltiazem HCl and 1300 g of calcium hydrogen phosphate are mixed in the fluidized bed apparatus and preheated.
  • the fluidized bed apparatus used is a Glatt WSG 2 (top spray mode) with 1.2 mm nozzle diameter and 2 bar spray pressure.
  • the granules are mixed with 0.5% (m / m) magnesium stearate for 10 min in the Erweka biconical mixer.
  • the tabletting is carried out on an instrumented Korsch EK 0 eccentric press (12 mm punch, radius of curvature 20) into tablets with 500 mg mass and an active substance content of 175 mg. The tablets do not disintegrate in the release media.
  • the above formulation remains in acidic medium and in buffered medium after 6 hours at all EtOH concentrations below the required 20% value for the acceleration or deceleration of drug release compared to the medium without EtOH.
  • the formulation is therefore, it is therefore particularly suitable for reducing the influence of EtOH on drug release.

Abstract

L'invention concerne l'utilisation de copolymères de (méth)acrylate insolubles dans le suc gastrique dans des formes orales de médicaments à délivrance retardée en tant que partie constitutive de la matrice contenant la substance active dans le but de réduire les effets d'accélération ou de ralentissement de la délivrance de la substance active provoqués par l'éthanol en conditions in vitro.
PCT/EP2007/058100 2006-10-26 2007-08-06 Utilisation de copolymères de (méth)acrylate dans des formes de médicaments à délivrance retardée pour diminuer les effets de l'éthanol sur la libération de la subtance active WO2008049657A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE200610051020 DE102006051020A1 (de) 2006-10-26 2006-10-26 Verwendung von (Meth)acrylat-Copolymeren in Retard-Arzneiformen zur Verringerung des Einflusses von Ethanol auf die Wirkstofffreisetzung
DE102006051020.8 2006-10-26

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