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
  • A61K9/48—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
  • A61K9/14—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
  • A61K9/2072—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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

• the invention relates to the use of polymer mixtures for the production of coated dosage forms as well as to a dosage form with a polymeric mixing coating.
• neutral methacrylate copolymers that is to say methacrylate copolymers which consist predominantly of (at least 95%) (meth) acrylate monomers having neutral radicals, such as methyl methacrylate or ethyl acrylate, as coating agents and binders for dosage forms Delayed drug release has been known for a long time. Uses in mixtures with anionic dispersions are described, for. In EP-A 152 038, EP-A 208 213 or EP-A 617 972. WO 01/68767 describes the preparation of dispersions containing neutral methyl acrylate copolymers, using 1-10 wt .-% of a nonionic emulsifier with an HLB value of 15, 2 to 17.3.
• EP 0 152 038 A2 describes coated dosage forms with mixed coatings of water-soluble carboxyl-containing polymers and water-insoluble, film-forming polymers.
• the polymers may be present in ratios of 60:40 to 5:95.
• mixed coatings of polymers are described, which consist of an equal parts of ethyl acrylate and methacrylic acid and others may consist of polymers composed of ethyl acrylate and methyl methacrylate in the ratio of 2 to 1.
• EP 0 208 213 A1 is close in content to EP 0 152 038 A2, but additionally discloses the effect of high extensibility and elasticity of corresponding mixed coatings.
• EP 0 704 208 A2 describes coating and binding agents for intestinal juice-soluble drug casings. These are copolymers of 10 to 25% by weight of methacrylic acid, 40 to 70% by weight of methyl acrylate and 20 to 40% by weight of methyl methacrylate.
• WO 03/072087 describes a process for the preparation of a pharmaceutical form in which a copolymer is used, which is composed of
• the proportion of other polymers in the mixture can vary within a wide range and is between 1 and 99%, preferably between 10 and 90% by weight, particularly preferably between 25 and 85% by weight, based on the polymer mixture.
• polystyrene resin examples include polyvinylpyrrolidones, polyvinyl alcohols, anionic (meth) acrylate copolymers of methyl methacrylate and / or ethyl acrylate and methacrylic acid (EUDRAGIT ® L 100, EUDRAGIT ® S 100, EUDRAGIT ® L 100-55).
• Anionic (meth) acrylate copolymers of methyl methacrylate, methyl acrylate and methacrylic acid of the prior art see, for example, EP-A 0 704 207 or EP-A 0 704 208), carboxymethyl cellulose salts, hydroxypropyl cellulose (HPMC), neutral (meth) acrylate copolymers of methyl methacrylate and ethyl acrylate (dry substance of EUDRAGIT ® NE 30 D), copolymers of methyl methacrylate and butyl methacrylate (Plastoid ® B) or (meth) acrylate copolymers with quaternary ammonium groups (EUDRAGIT ® RL, EUDRAGIT ® RS).
• WO 2004/096185 describes a process for producing a coated drug form or a drug form in the form of a drug-containing matrix by reacting a copolymer, a pharmaceutically active substance, an optionally present core and / or pharmaceutically usual additives in a manner known per se by melting, injection molding, extrusion , Wet granulation, pouring, dipping, spreading, spraying or pressing into a coated dosage form and / or processed into a matrix containing active ingredient, using a copolymer which is composed of
• the glass transition temperature of the copolymer is 55 to 70 0 C.
• the proportion of other polymers in the mixture can vary within wide ranges and is between 5 and 95, preferably between 10 and 90 wt .-%, particularly preferably between 25 and 85 wt .-%.
• polystyrene resin examples include polyvinylpyrrolidones, polyvinyl alcohols, anionic (meth) acrylate copolymers of methyl methacrylate and / or ethyl acrylate and methacrylic acid (EUDRAGIT ® L 100, EUDRAGIT ® S 100, EUDRAGIT ® L 100-55).
• Anionic (meth) acrylate copolymers of methyl methacrylate, methyl acrylate and methacrylic acid of the prior art see, for example, EP-A 0 704 207 or EP-A 0 704 208), carboxymethyl cellulose salts, hydroxypropyl cellulose (HPMC), neutral (meth) acrylate copolymers of methyl methacrylate and ethyl acrylate (dry substance of EUDRAGIT ® NE 30 D), copolymers of methyl methacrylate and butyl methacrylate (Plastoid ® B) or (meth) acrylate copolymers with quaternary amino groups (EUDRAGIT ® RL, EUDRAGIT ® RS). Task and solution
• EP 0 152 038 A2 starts from dosage forms with coatings of polymers containing carboxyl groups.
• carboxyl group-containing polymers in particular methacrylic acid-containing (meth) acrylate copolymers, are resistant to gastric juices and at the same time, however, soluble in intestinal juice. Depending on the content of carboxyl groups, they dissolve at a specific pH. With a polymer of equal parts of ethyl acrylate and methacrylic acid coated dosage forms set the active ingredient z. B. from about pH 5.5 rapidly.
• the polymer (I) is a (meth) acrylate copolymer containing 90 to 100 wt .-% radically polymerized units of 40 to 95 wt .-% of Ci- to C 4 - alkyl esters of acrylic or methacrylic acid and 5 bis 60 wt .-% units of (meth) acrylate monomers having an anionic group, and to 0 to 10 wt .-% of other vinylic polymerizable monomers, and
• the polymer (II) is a vinyl polymer other than the polymer (I) or a polysaccharide or a derivative of a polysaccharide containing 88 to 100% of neutral monomer units and up to 12% by weight of polymerized monomer units having ionic groups,
• a coated dosage form comprising a drug-containing core and a polymeric coating of the mixture of polymers (I) and (II)
• the glass transition temperature of the polymer (I) is not more than 70 ° C., and a drug release profile is obtained in which the active ingredient is released in a slower manner compared with a pharmaceutical form coated alone with the polymer (I), but starting at the same pH.
• the invention is based on the finding that the "pH-shift" effect described in EP 0 152 038 A2 for the polymer blends described therein does not occur with a selection of anionic or carboxyl-containing polymers whose glass transition temperature is not more than 70 ° C. In the case of these polymers, it is quite surprisingly found that the effect of changing the time course of the active ingredient release characteristic without altering the dissolution pH is dependent on the task.
• Copolymers of from 10 to 30% by weight, methyl methacrylate, from 50 to 70% by weight of methyl acrylate and from 5 to 15% by weight of methacrylic acid are known from EP 0 704 208 A2.
• Blends with other polymers corresponding to the type of polymer (II) described herein have evidently not previously been discussed.
• the invention is based on the finding that the pH-shift effect described in EP 0 152 038 A2 for the polymer mixtures described there does not occur in the case of a selection of anionic or carboxyl-containing polymers whose glass transition temperature is not more than 70 ° C. but the task-related effect of changing the time course of the drug release characteristics results without changing the dissolution pH.
• composition containing an active substance-containing core which is coated with a polymeric mixing coating, characterized in that the mixture coating comprises a mixture of 2 to 60% by weight of a polymer (I) with 40 to 95% by weight and one or more polymers ( II),
• the polymer (I) is a copolymer of 10 to 30% by weight, methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid
• the polymer (II) is a vinyl polymer other than the polymer (I) which is composed of 90 to 100% of neutral vinylically polymerized monomer units and may contain up to 10% by weight of vinylically polymerized ionic moiety monomer units.
• the mixture contains or consists essentially or preferably of 100% of 2 to 60, preferably 2 to 30% by weight of one or more polymers (I) and 40 to 98, preferably 70 to 98% by weight of one or more Polymers (II). Almost all transitions between the release profiles of the polymers (I) and (II) can be adjusted in this range, so that a new alternative is available to the person skilled in the art when formulating drug forms.
• a preferred mixture contains or consists essentially or preferably to 100% of 2 to 15 wt .-% of one or more polymers (I) with 85 to 98 wt .-% of one or more polymers (II).
• the undesirably strong retarding release characteristic of the polymer (II) is controlled in a range which is responsible for a long-lasting, approximately constant release of a variety of drugs in the various intestinal sections from a therapeutic point of view is desirable.
• the active ingredient is released in the release test according to USP (USP 28-NF23) in less than 50% in 60 minutes.
• the active ingredient is released at more than 10% in the release test according to USP in 60 minutes at the pH at which the polymer (I) begins to dissolve.
• the degree of release is always influenced by the layer thickness of the coating. This can be increased or decreased at a given mixing ratio to control the release in the desired range.
• 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 (100 Upm, 37 0 C) are determined with the following modification:
• the coated pellets were first tested for 120 min in artificial gastric juice (USP) at pH 1, 2 for gastric juice resistance, then buffered with phosphate buffer to pH 7.5, which is an artificial intestinal milieu
• the active compound concentration in the test medium can be determined, for example, photometrically, depending on the active ingredient.
• the glass transition temperature of the polymer (I) is not more than 70 ° C., preferably 45 to 68 ° 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 polymers (I) are (meth) acrylate copolymers containing or consisting of 90 to 100, preferably 95 to 100, particularly preferably 100 wt .-% of 40 to 95, preferably 66 to 95 wt .-% radical polymerized units of C to C 4 alkyl esters of acrylic or methacrylic acid and 5 to 60, preferably 5 to 34 wt .-% units of (meth) acrylate monomers having an anionic group.
• 0 to 10 wt .-% residues of other vinylic polymerizable monomers in the polymer (I) may be included.
• C 1 to 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.
• the abovementioned proportions of the C 1 - to C 4 -alkyl esters of acrylic or methacrylic acid and of the (meth) acrylate monomers having an anionic group add up to 100% by weight.
• Most commercially available polymers (I) contain no residues of other monomer types.
• further vinylic copolymerizable monomers such as.
• hydroxyethyl methacrylate or hydroxyethyl acrylate butyl acrylate vinyl pyrrolidone, vinyl malonic acid, styrene, vinyl alcohol, vinyl acetate and / or derivatives thereof may be included.
• no further vinylically copolymerizable monomers are contained.
• the glass transition temperature of the polymer (I) is not more than 70, preferably 40 to 70, particularly preferably 45 to 65, in particular 45 to 55 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 polymer (I) is generally an emulsion polymer and is preferably produced and used in the form of a 10 to 50% strength by weight, in particular 20 to 40% strength, aqueous dispersion. As a commercial form, a solids content of 30 wt .-% is preferred. For processing, a partial neutralization of the methacrylic acid units is dispensable; However, it is possible, for example, to an extent of up to 5 or 10 mol%, if stabilization or thickening of the coating agent dispersion should be desired.
• the weight-average latex particle size (radius) is generally 40 to 100 nm, preferably 50 to 70 nm, which ensures a processing-technically favorable viscosity below 1000 mPa ⁇ s. The particle size may be determined by laser diffraction, e.g. B. with the Mastersizer 2000 (Malvern) can be determined.
• the anionic copolymer may, for. B. gradually in a final concentration of 1 to 40 wt .-% are stirred into water and thereby partially or completely neutralized by addition of a basic substance such. As NaOH, KOH, ammonium hydroxide or organic bases such as. B. triethanolamine. It is also possible to use a powder of the copolymer, the already in its preparation for the purpose of (partial) neutralization of a base z. B.
• the pH of the solution is usually over 4, z. B. in the range of 4 to about 7. You can also z. B. mixtures of batches of fully or partially neutralized dispersions with non-neutralized dispersions and process in the manner described, ie use the mixture for coatings or first freeze-drying or spray-drying to a powder.
• the dispersion may, for. B. also be spray-dried or freeze-dried in a conventional manner and provided in the form of a redispersible powder (see, for example, EP-A 0262 326).
• Alternative methods are freeze-drying or coagulation and squeezing off the water in an extruder with subsequent granulation (see, for example, EP-A 0 683 028).
• copolymer dispersions of spray-dried or freeze-dried and redispersed powders have increased shear stability. This is particularly advantageous when spraying. This advantage is particularly pronounced when the copolymer contained in the dispersion is present in partially neutralized form (based on the acid groups contained in the copolymer) to 2 to 10, preferably to 5 to 7 mol%. For this purpose, partial neutralization by means of is preferred Addition of NaOH.
• An anionic emulsifier is preferably contained in an amount of from 0.1 to 2% by weight. Particular preference is given to sodium lauryl sulfate as emulsifier.
• Suitable polymers (I) are (meth) acrylate copolymers consisting of 10 to 30% by weight, methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid (Type EUDRAGIT® FS).
• the pH of the start of the specific release of active ingredient in intestinal juice or artificial intestinal juice can be given as pH 7.0.
• the glass transition temperature of this polymer (I) is preferably 45 to 55 ° C.
• 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.
• the glass transition temperature Tm g according to ISO 11357-2, point 3.3.3 is about 48 0 C.
• polymers (I) are copolymers known from WO 03/072087
• this (meth) acrylate copolymer is particularly suitable for pressing pellets into tablets.
• the above-mentioned copolymer is composed, in particular, of free-radically polymerized 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.
• small amounts ranging from 0 to 10, z. B. 1 to 5 wt .-% of further vinylic copolymerizable monomers, such as.
• methyl methacrylate, butyl methacrylate, butyl acrylate or hydroxyethyl methacrylate may be included.
• 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
• 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 is the Example: an opposed jet mill (Multi No. 4200), which is operated with approx. 6 bar overpressure.
• the proportions of monomers are selected so that the glass transition temperature of the copolymer (glass transition temperature) according to ISO 11357-2, subsection 3.3.3 (midpoint temperature T m), is 55 to 70 0 C.
• 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.
• 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.
• the polymer (II) is a vinyl polymer other than the polymer (I) or a polysaccharide or a derivative of a polysaccharide composed of 80 to 100% of neutral monomer units and containing up to 12% by weight of ionic moiety monomer units.
• the polymer (II) may be a vinyl polymer containing from 88 to 100% of neutral vinylically polymerized monomer units and up to 12% by weight of vinylically polymerized ionic moiety monomer units.
• the polymer (N) may be a copolymer of methyl methacrylate and ethyl acrylate, a copolymer of methyl methacrylate and ethyl acrylate and methacrylic acid, a copolymer of methyl methacrylate, ethyl acrylate and trimethyl ammonium ethyl methacrylate, a polyvinyl pyrolidone (PVP), polyvinyl alcohols, polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat® IR), polyvinyl acetate (PVAc, Kollicoat® SR), vinyl acetate-vinylpyrolidone copolymer (Kollidon® VA64), vinyl acetate: crotonic acid copolymer 9: 1 (VAC: CRA, Kollicoat® VAC),
• the polymer (II) may be a polysaccharide or the derivative of a polysaccharide containing 88 to 100% of neutral monomer units and up to 12% by weight of polymerized monomer units having ionic groups.
• the polymer (II) may be: starch and its derivatives, hydroxyethylcellulose (HEC, Klucel®, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC, Pharmacoat®, Methocel®, Sepifilm®, Viscontran®, Opadry®), hydroxymethylcellulose (HEMC) , ethylcellulose (EC, Ethocel ®, Aquacoat ®, Surelease ®), methylcellulose (MC, Viscontran®, Tylopur®, Methocel®), Celluloseester, cellulose glycolate or a mixture of said polymers.
• HEC hydroxyethylcellulose
• HPC hydroxypropylcellulose
• HPMC hydroxypropylmethylcellulose
• HEMC e
• the polymer (II) may be a (meth) acrylate copolymer other than the polymer (I) containing 88 to 100% of neutral monomer units and up to 12% by weight of polymerized monomer units having ionic groups.
• the polymer (II) may particularly preferably be a copolymer of 20 to 40% by weight of ethyl acrylate and 60 to 80% by weight of methyl methacrylate (type EUDRAGIT® NE).
• polymer (II) is a copolymer of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate (EUDRAGIT® NE).
• the polymer (II) may further comprise from 88 to 98 wt .-% of radically polymerized Cr to C 4 alkyl esters of acrylic or methacrylic acid and 12 to 2 wt .-% of (meth) acrylate monomers having a quaternary amino group in the alkyl radical put together.
• Preferred Cr 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 amino groups 2-trimethylammoniumethyl methacrylate chloride is particularly preferred.
• the polymer (II) may be a copolymer of 50-70% by weight of methyl methacrylate, 20-40% by weight of ethyl acrylate and 12-2% by weight of trimethylammoniumethyl methacrylate chloride (type EUDRAGIT® RS / RL).
• a concretely suitable copolymer contains 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammoniumethyl methacrylate chloride (EUDRAGIT® RS).
• a concretely suitable copolymer contains 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammoniumethyl methacrylate chloride (EUDRAGIT® RL).
• Active substance-containing pellets can be prepared by applying active ingredient by means of a layering process.
• active substance is shared with homogenized further excipients (release agent, if necessary, plasticizer) and dissolved or suspended in a binder.
• the liquid can be applied to placebopellets or other suitable carrier materials, the solvent or suspending agent being evaporated (Literature: International Journal of Pharmaceutics 143, p. 13-23).
• a drying step can follow.
• the active ingredient can be applied in several layers.
• active ingredients eg. As acetylsalicylic acid, are commercially available in the form of active ingredient crystals and can be used in this form instead of pellets containing active ingredient.
• Film coatings on active ingredient-containing pellets are usually applied in fluidized bed apparatus. Formulation examples are mentioned in this application. Film formers are usually mixed with plasticizers and release agents by a suitable method. Here, the film formers may be present as a solution or suspension. The auxiliaries for film formation may also be dissolved or suspended. Organic or aqueous solvents or dispersants may be used. Stabilizers may additionally be used to stabilize the dispersion (example: Tween 80 or other suitable emulsifiers or stabilizers).
• release agents are glycerol monostearate or other suitable fatty acid derivatives, silicic acid derivatives or talc.
• plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, as well as other substances mentioned in the literature.
• a separating layer may be applied between the active substance-containing layer and the copolymer layer according to the invention, which serves to separate the active ingredient and the coating material for the purpose of preventing interactions.
• This layer can consist of inert film formers (for example HPMC, HPC or (meth) acrylic acid copolymers) or, for example, talc or other suitable pharmaceutical substances. Likewise, combinations of film formers and talcum or similar substances can be used.
• Mixtures for the production of coated particle tablets are prepared by mixing the pellets with suitable binders for tabletting, if necessary adding disintegrants and, if necessary, adding lubricants.
• the mixing can take place in suitable machines. Unsuitable are mixers that cause damage to the coated particles, eg. B. plowshare mixer. To achieve suitable short disintegration times, a special order of addition of the excipients to the coated particles may be required.
• suitable mixtures usually contain 3 to 15% by weight of a disintegrating agent, for. B. Kollidon CL and z. B. 0.1 to 1 wt .-% of a lubricant and mold release agent such as magnesium stearate.
• the binder content is determined by the required proportion of coated particles.
• Typical binders are z.
• Cellactose ® microcrystalline cellulose, calcium phosphates, Ludipress ® , lactose or other suitable sugars, calcium sulfates or starch derivatives. Preference is given to substances having a low bulk density.
• disintegrants are crosslinked starch or cellulose derivatives, as well as crosslinked polyvinylpyrrolidone. Likewise, cellulose derivatives are suitable. By selecting a suitable binder, 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.
• a mixture of one or more polymer (I) and one or more polymer (II) is prepared.
• the mixture of aqueous dispersions of one or more of the polymer (I) and one or more of the polymer (II) is prepared.
• a polymer (I) and a polymer (II) will be used in each case.
• the mixture contains 2 to 60, preferably 10 to 55 wt .-% of a polymer (I) with 40 to 98, preferably 45 to 90 wt .-% of one or more polymers (II), wherein the proportions to 100 wt. % complete.
• pharmaceutically customary excipients are added, which may be separately dissolved or dispersed.
• the invention further relates to a pharmaceutical form with a selected polymer (I) which does not appear from EP 0 152 038 A2.
• the polymer (II) contained in the dosage form is identical to the polymers (II) used according to the invention described herein.
• the invention relates to a dosage form containing an active ingredient-containing core which is coated with a polymeric blend coating, characterized in that the blend coating comprises a mixture of 2 to 60 wt .-% of a polymer (I) with 40 to 95 wt .-% and one or more polymers (II),
• the polymer (I) is a copolymer of 10 to 30% by weight, methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid, and
• the polymer (II) is a vinyl polymer other than the polymer (I) or a polysaccharide or a derivative of a polysaccharide which is comprised of 88 to 100% of neutral monomer units and may contain up to 12% by weight of monomer units having ionic groups.
• Suitable polymers (I) for the dosage form according to the invention are known from EP 0 704 208 A2.
• Polymers (I) are (meth) acrylate copolymers consisting of 10 to 30% by weight, methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid (type EUDRAGIT® FS).
• the pH of the start of the specific release of active ingredient in intestinal juice or artificial intestinal juice can be given as pH 7.0.
• the glass transition temperature of this polymer (I) is preferably 45 to 55 ° C.
• 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.
• the glass transition temperature 7 mg according to ISO 11357-2, point 3.3.3 is about 48 0 C.
• Carriers for the coatings are capsules, tablets, granules, pellets, crystals of regular or irregular shape.
• the size of granules, pellets or crystals is between 0.01 and 2.5 mm, that of tablets between 2.5 and 30.0 mm.
• Capsule consist of gelatin, starch or cellulose derivatives.
• binders such as cellulose and their derivatives, polyvinylpyrrolidone (PVP), humectants, disintegrants, lubricants, disintegrants, (meth) acrylates, starch and its derivatives, sugar solubilizers or others.
• Active substance-containing pellets can, for. B. be prepared by applying active ingredient by means of a Layeringreaes.
• active ingredient is homogenized together with other excipients (release agent, if necessary plasticizer) and dissolved or suspended in a binder.
• the liquid can be applied to placebopellets or other suitable carrier materials, the solvent or suspending agent being evaporated (Literature: International Journal of Pharmaceutics 143, pp. 13-23).
• a drying step can follow.
• the active ingredient can be applied in several layers.
• active ingredients eg. As acetylsalicylic acid, are commercially available in the form of active ingredient crystals and can be used in this form instead of pellets containing active ingredient.
• a mixture of the polymer (I) and the polymer (II) is prepared. These are z. B. two dispersions proportionately mixed.
• Film coatings on active ingredient-containing pellets are usually applied in fluidized bed apparatus. Formulation examples are mentioned in this application. Film formers are usually mixed with plasticizers and release agents by a suitable method. Here, the film formers may be present as a solution or suspension. The auxiliaries for film formation may also be dissolved or suspended. Organic or aqueous solvents or dispersants may be used. Stabilizers may additionally be used to stabilize the dispersion (example: Tween 80 or other suitable emulsifiers or stabilizers).
• release agents are glycerol monostearate or other suitable fatty acid derivatives, silicic acid derivatives or talc.
• plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, as well as other substances mentioned in the literature.
• a separating layer may be applied between the active substance-containing layer and the coating layer according to the invention, which serves to separate the active ingredient and the coating material for the purpose of preventing interactions.
• This layer can be made from inert film formers (e.g., HPMC, HPC, or (meth) acrylic acid copolymers) or e.g. Talc or other suitable pharmaceutical substances. Likewise, combinations of film formers and talcum or similar substances can be used.
• the polymer coating may preferably z. B. 2 to 20 wt .-% in terms of the weight of the active ingredient-containing core.
• the degree of release is always influenced by the layer thickness of the coating. This can be increased or decreased at a given mixing ratio to control the release in the desired range.
• topcoat of a further, preferably water-soluble, polymers and excipients, for.
• pigments and / or release agents which ensures further functions, such as coloring or prevention of sticking.
• the coated dosage form is preferably in the form of pellets which are contained in a multiparticulate dosage form, in particular in pellet-containing tablets, minitablets, capsules, sachets or dry juices.
• the invention is particularly suitable for the production of multiparticulate drug forms, since the mixture according to the invention withstands the high pressures during the compression of the pellets with the filler.
• the coated dosage form is preferably in the form of pellets which are contained in a multiparticulate dosage form, in particular in pellet-containing tablets, minitablets, capsules, sachets or dry juices.
• the production of multiparticulate drug forms by compressing a pharmaceutically conventional binder with active ingredient-containing particles is z. Beckert et al. (1996), “Compression of enteric-coated pellets to disintegrating tablets", International Journal of Pharmaceutics 143, pp. 13-23, and described in detail in WO 96/01624.
• Active substance-containing pellets can be prepared by applying active ingredient by means of a layering process.
• active ingredient is homogenized together with other excipients (release agent, if appropriate plasticizer) and dissolved or suspended in a binder.
• the liquid can be applied to placebopellets or other suitable carrier materials, the solvent or suspending agent being evaporated (Literature: International Journal of Pharmaceutics 143, pp. 13-23).
• a drying step can follow.
• the active ingredient can be applied in several layers.
• active ingredients eg. As acetylsalicylic acid, are commercially available in the form of active ingredient crystals and can be used in this form instead of pellets containing active ingredient.
• Film coatings on active ingredient-containing pellets are usually applied in fluidized bed apparatus. Formulation examples are mentioned in this application. Film formers are usually mixed with plasticizers and release agents by a suitable method. Here, the film formers may be present as a solution or suspension. The auxiliaries for film formation may also be dissolved or suspended. Organic or aqueous solvents or dispersants may be used. To stabilize the dispersion In addition, stabilizers can be used (example: Tween 80 or other suitable emulsifiers or stabilizers).
• release agents are glycerol monostearate or other suitable fatty acid derivatives, silicic acid derivatives or talc.
• plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, as well as other substances mentioned in the literature.
• Mixtures for the production of coated particle tablets are prepared by mixing the pellets with suitable binders for tabletting, if necessary adding disintegrants and, if necessary, adding lubricants.
• the mixing can take place in suitable machines. Unsuitable are mixers that cause damage to the coated particles, eg. B. plowshare mixer. To achieve suitable short disintegration times, a special order of addition of the excipients to the coated particles may be required.
• suitable mixtures usually contain 3 to 15% by weight of a disintegrating agent, for. B. Kollidon CL and z. B. 0.1 to 1 wt .-% of a lubricant and mold release agent such as magnesium stearate.
• a disintegrating agent for. B. Kollidon CL and z. B. 0.1 to 1 wt .-% of a lubricant and mold release agent such as magnesium stearate.
• the binder content is determined by the required proportion of coated particles.
• Typical binders are z. As Cellactose ® , microcrystalline cellulose, calcium phosphates, Ludipress ® , lactose or other suitable sugars, calcium sulfates or starch derivatives. Preference is given to substances having a low bulk density.
• Typical disintegrants are crosslinked starch or cellulose derivatives, as well as crosslinked polyvinylpyrrolidone. Likewise, cellulose derivatives are suitable. By selecting a suitable binder, 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 mixture 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.
• an active substance release profile is obtained in which the active substance is coated in comparison to one coated alone with the polymer (I) Dosage form, however, is released at the same pH but slows down.
• an active substance release profile is obtained in which the active ingredient is released more rapidly in comparison to a pharmaceutical form coated alone with the polymer (II), starting at the same pH value.
• Preferred dosage forms are those in which the active ingredient at a pH at which the polymer (I) begins to dissolve in the release test according to USP (USP 28-NF23) to less than 50%, preferably less than 25%, in 60 minutes. , particularly preferably liberated to 10 to 50%.
• the release test z The release test z.
• the test conditions are, in particular: paddle method, 100 revolutions per minute, 37 ° C., pH 1, 2, for example according to USP (USP 28-NF23, method B, modified test for enteric coated products) with 0.1 N HCl, pH 7.5 by adding 0.2 M phosphate buffer and adjusting with 2N NaOH See also USP 27-NF22 Supplement 1, Method "Delayed Release” Monograph ⁇ 724> Drug Release.
• pharmaceutically customary auxiliaries are preferably added during the preparation of the granules or powders.
• the aggregates can also be added to the coating and binder during processing.
• all substances used must be toxicologically safe and in particular be used in medicaments without risk to patients.
• Amounts used and the usual additives in drug coatings or coatings are familiar to the expert.
• Usual additives can z.
• They are added to the polymer formulations prior to processing and can affect the permeability of the coatings, which may optionally be used as an additional control parameter.
• Release agents usually have lipophilic properties and are usually added to the spray suspensions. They prevent agglomeration of the cores during the filming. Preference is given to using talc, Mg or Ca stearate, ground silicic acid, kaolin or nonionic emulsifiers having an HLB value between 3 and 8. Usual amounts of release agent in the coating and binding agents according to the invention are between 0.5 to 100 wt .-% based on the dry weight of the dispersion. pigments:
• Pigments which are incompatible with the coating agent are in particular those pigments which, when added directly to the (meth) acrylate copolymer dispersion, e.g. B. by stirring, in the usual application of z. B. 20 to 400 wt .-% based on the dry weight of the (meth) acrylate copolymer for destabilizing the dispersion, coagulation, lead to segregation phenomena or similar undesirable effects.
• the pigments to be used are of course non-toxic and suitable for pharmaceutical purposes. See z. Also: German Research Foundation, Dyestuffs for Food, Harald Boldt Verlag KG, Boppard (1978); German Food Review 74, No. 4, p. 156 (1978); Pharmaceutical Dye Ordinance AmFarbV of 25.08.1980.
• incompatible pigments can, for. B. alumina pigments.
• Incompatible pigments are z. B. yellow-orange, cochineal red, color pigments based on aluminum oxide or azo dyes, sulfonic acid dyes, yellow-orange S (E110, CI 15985, FD & C Yellow 6), indigo carmine (E132, CI 73015, FD & C Blue 2), tartrazine (E 102, Cl 19140, FD & C Yellow 5), Ponceau 4R (E 125, CI 16255, FD & C Cochineal Red A), quinoline singleb (E 104, CI 47005, FD & C Yellow 10), erythrosine (E127, CI 45430, FD & C Red 3).
• E numbers of the pigments refer to an EU numbering. See also "Deutsche Klastician, Dyestuffs for Food, Harald Boldt Verlag KG, Boppard (1978); German Food Review 74, No. 4, p. 156 (1978); Pharmaceutical Dye Ordinance AmFarbV of 25.08.1980.
• the FD & C numbers refer to approval by the US Food and Drug Administration (FDA) in Food, Drugs and Cosmetics: US Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors: Code of Federal Regulations - Title 21 Color Additive Regulations Part 82, Listing of Certified Provisionally Listed Colors and Specifications (CFR 21 Part 82).
• additives may also be plasticizers. Usual amounts are between 0 and 50, preferably 5 to 20 wt .-%.
• plasticizers can influence the functionality of the polymer layer. Plasticizers achieve by physical interaction with the polymer, a lowering of the glass transition temperature and promote, depending on the amount added to the film. Suitable substances generally have a molecular weight between 100 and 20,000 and contain one or more hydrophilic groups in the molecule, eg. B. hydroxyl, ester or amino groups.
• plasticizers examples include citric acid alkyl esters, glycerol esters, alkyl phthalates, sebacic acid alkyl esters, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate and polyethylene glycols 200 to 12,000.
• Preferred plasticizers are triethyl citrate (TEC), acetyl triethyl citrate (ATEC) and dibutyl sebacate (DBS).
• TEC triethyl citrate
• ATC acetyl triethyl citrate
• DBS dibutyl sebacate
• Citric acid and sebacic acid esters are preferably used.
• plasticizer to the formulation can be carried out in a known manner, directly, in aqueous solution or after thermal pretreatment of the mixture. Also, mixtures of plasticizers can be used.
• the medicaments used in the context of the invention are intended to be used on or in the human or animal body
• the formulation according to the invention is suitable for administration of any desired pharmaceutical active ingredients or biologically active substances.
• These pharmaceutically active substances may belong to one or more classes of drugs, such as ACE inhibitors, adrenergics, adrenocorticosteroids, acne therapeutics, aldose reductase inhibitors, aldosterone antagonists, alpha-glucosidase inhibitors, alpha 1 antagonists, anti-alcoholic agents, amino acids, amoebicides, anabolic steroids , Anesthetics, anesthetics, anesthetics (non-inhalative), anesthetics (local), analgesics, androgens, anginatherapeutics, antagonists, antiallergic drugs, antiallergic drugs such as PDE inhibitors, antiallergic drugs for asthma treatment, other antiallergic drugs (eg leukotriene antagonists, antianemics, antiandrogens, antianxiolytics, Antiarthritics, antiarrhythmics, antherosclerotic agents, antibiotics, anticholinergics, anticonvulsants, antidepressants,
• Suitable active substances are acarbose, acetylsalicylic acid, abacavir, aceclofenac, aclarubicin, acyclovir, actinomycin, adalimumab, adefovir, adefovir dipivoxil, adenosylmethionine, epinephrine and adrenaline derivatives, agalsidase alpha, agalsidase beta, alemtuzumab, almotriptan, alphacept, allopurinol, almotriptan, alosetron, alprostadil, Amantadine, Ambroxol, Amisulpride, amlodipine, amoxicillin, 5-aminosalicylic acid, amitriptyline, amlodipine, amoxicillin, amprenavir, anagrelide, anakinra, anastrozole, androgen and androgen derivative
• Ketoconazole Ketoprofen, Ketotifen, Lacidipine, Lamotrigine, Lansoprazole, Laronidase, Latanoprost, Leflunomide, Leminoprazole, Lepirudin, Lercanidipine, Leteprinim, Letrozole, Levacetylmethadol, Levetiracetam, Levocetirizine, Levodopa, Levodrpropicin, Levofloxacin, Levomethadone, Licofelone, Linezolid , Lipinavir, lipoic acid and lipoic acid derivatives, lisinopril, lisuride, lofepramine, lodoxamide, lomefloxacin, lomustine, loperamide, lopinavir, loratadine, lornoxicam, losartan, lumefantrine, lutropines, magnesium salts, macrolide
• Growth Factors Tiagabine, Tiapride, Tibolone, Ticlopidine, Tilidine, Timolol, Tinidazole, Tioconazole, Tioguanine, Tiotropium, Tioxolone, Tirazetam, Tiropramide, Trofiban, Tizanidine, Tolazoline, Tolbutamide, Tolcapone, Tolnaftate, Tolperisone, Tolterodine, Topiramate, Topotecan, Torasemide, Tramadol, tramazoline, trandolapril, tranylcypromine, trapidil, trastuzumab, travoprost, trazodone, trepostinil, triamcinolone and triamcinolone derivatives, triamterene, trifluperidol, trifluridine, trimetazidine, trimethoprim, trimipramine, tripeienamine, triprolidine, trifosf
• Preferred active ingredient groups are analgesics, antibiotics, antidiabetic agents, antibodies, peptides, proteins, chemotherapeutic agents, corticoids / corticosteroids anti-inflammatory agents, enzyme preparations hormones and their inhibitors, parathyroid hormones digestive agents, laxatives, vitamins, cytostatics as well as active ingredients of other groups, which are beneficial for lower kinetic reasons Intestinal sections are applied.
• Examples of particularly preferred active ingredients are mesalazine, sulfasalazine, bethamethasone 21-dihydrogenophosphate, hydrocortisone 21-acetate, cromoglicic acid, dexamethasone, olsalazine-Na, budesonide, prednisone bismunitrate, karaya gum, methylprednisolone 21-hydrogensuccinate myhrre, coffee charcoal, chamomile extract, preparations of Human placenta
• balsalazide adalimumab, alemtuzumab, basiliximab, daclizumab, ibritumomab, ifliximab, cetuximab, palivizumab, rituximab, trastuzumab, other orally administered peptides (eg RDP 58), Interleukin 6, interleukin 12, llodecakin (interleukin 10), nicotine tartrate, 5-ASA conjugates (CPR 2015), monoclonal antibody to interleukin 12, diethyldihydroxy homospermine (DEHOHO), diethyl homospermine (DEHOP), cholecystokinin (CCK) antagonist (CR 1795), 15 Amino acid fragment of a 40 kd peptide from gastric juice (BPC 15), glucocorticoid analogue (CBP 1011
• Nozzle Three-fluid nozzle, nozzle diameter: 0.8 mm
• Theophylline pellets (particle diameter: 0.8-1.2 mm) Active substance content: approx. 93% Application size: 200 or 800g
• Spray rate at 200g batch size: approx. 12 g / min / kg at 800g batch size: approx. 5 g / min / kg
• Eudragit® NE 30 D (NE30 D): ethyl acrylate methyl methacrylate copolymer
• Kollicoat® SR 30 D polyvinyl acetate
• DI water and Polysorbate 80 are heated to 75 ° C with gentle stirring.
• the glycerol monostearate is added and homogenized with vigorous stirring for about 30 minutes.
• the polymer dispersions and the plasticizer are added. If necessary, coagulation during mixing of the dispersions by prior adjustment of the pH values is avoided.
• the release test is performed according to USP 28-NF23, General Chapter ⁇ 711>, Dissolution, Apparatus 2 (Paddle), Method ⁇ 724>"Delayed Release (Enteric Coated) Articles-General General Drug Release Standard", Method B (100 rpm, 37 0 C) with the following modification:
• the coated pellets were first tested for 120 min in artificial gastric juice (USP) at pH 1, 2 for gastric juice resistance, then buffered with phosphate buffer to pH 7.5, which corresponds to an artificial intestinal milieu in the test medium was determined photometrically.
• USP artificial gastric juice
• the results are summarized in Tables 1 to 3.
• the figures 6, 10 and 15% respectively indicate the dry weight of the coating in relation to the core weight.

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