Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • 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

• copolymers based on amino group-containing polymers as matrix binders for the production of active ingredient-containing granules and dosage forms
• the present invention relates to matrix binders based on a cationic polymer, which is obtained by free-radical emulsion polymerization of a monomer mixture containing N, N-diethylaminoethyl methacrylate, for the production of active ingredient-containing granules and dosage forms from such granules.
• binder in pharmaceutical technology substances are referred to cause a juxtaposition of powder particles.
• binders which form the three-dimensional structure of moldings such as granules or tablets, one speaks of "matrix binders”.
• DE-AS 1090381 describes a process for coating drug forms with gastric soluble coating masses. These contain an acrylate copolymer of 20 to 80% of at least one amino ester of (meth) acrylic acid, for example the esters of acrylic acid and (meth) acrylic acid with ⁇ , ⁇ -dimethylaminoethanol, N, N-diethylaminoethanol,
• DE-AS 1219175 describes coating compositions based on copolymers containing N, N-dialkylaminoalkyl (meth) acrylamides in copolymerized form.
• Copolymers based on N, N-dialkylaminoalkyl (meth) acrylates are considered to be disadvantageous according to the teaching of this document, since the ester group is more likely to be saponified in the basic medium compared to the amide group.
• DE-OS 2135073 likewise describes coating compositions for dosage forms which comprise an aqueous polymer dispersion, the polymer being composed of 10 to 55% by weight of monomers having a carboxyl group and / or a monoalkyl or dialkylaminoalkyl ester group.
• a suitable monomer diethylaminoethyl methacrylate (DEAEMA) is mentioned in addition to a variety of others. Concrete emulsion polymers based on DEAEMA are not disclosed.
• DE-AS 2512238 teaches the use of a powder obtained by spray-drying a polymer dispersion for the preparation of coating solutions for these dosage forms for providing binders for pharmaceutical compositions with low residual monomer content.
• dispersions used for spray-drying reference is made to DE 1090381, DE 1219175 and DE 2135073.
• DE-OS 2838278 describes coatings for oral dosage forms for ruminants from a) at least one film-forming polymer having at least one basic amino group, For example, a copolymer of 40%, ⁇ -diethylaminoethyl methacrylate, but without specifying a method for its preparation.
• GB 1324087 describes coating compositions for oral ruminant dosage forms which comprise a) at least one N, N-dialkylaminoalkyl (meth) acrylate and b) at least one ethylenically unsaturated compound selected from vinylaromatics and their derivatives, vinyl esters, esters of ( Meth) acrylic acid and acrylonitrile in copolymerized form.
• Suitable monomers a) are ⁇ , ⁇ -dimethylaminoethyl methacrylate (DMAEMA) and tert-butylaminoethyl methacrylate (TBAEMA).
• comonomer b in particular methyl methacrylate is considered unsuitable, since it tends to form too brittle coatings.
• suitable polymerization processes substance, suspension, solution and emulsion polymerization are indicated.
• the copolymers of the embodiments were prepared by solution polymerization.
• DE 3426587 A1 describes a process for coating pharmaceutical forms by applying a film of a liquid, film-forming coating composition containing a dissolved polymer having pendant tertiary ammonium salt groups.
• inter alia copolymers based on N, N-dialkylaminoalkyl (meth) acrylates with aqueous inorganic or organic acids can be converted into aqueous ammonium salt solutions.
• DE 3049179 A1 is an additional application to DE 2512238 and relates to the use of a powder obtained by spray-drying according to the teaching of the latter document in the form of an aqueous suspension which additionally contains a softening agent for the production of coatings by thermogelation.
• EP 0058765 A2 describes coating compositions for dosage forms that are soluble or swellable in gastric juice and which contain as binder an emulsion polymer based on
• N, N-dialkylaminoalkyl (meth) acrylates wherein between the amino group and the (meth) acrylate group is a branched alkylene or aralkylene group having at least three arranged in a straight chain carbon atoms.
• WO 2005/055986 and WO 2005/056619 describe polymers with pH dependent swelling / dissolving behavior and their use in drug forms.
• WO 00/05307 is concerned with the provision of coating and binding agents for dosage forms which contain (meth) acrylate copolymers which have monomer residues with tertiary amino groups, wherein simple dry or aqueous further processing should be possible.
• this document teaches a process which comprises (a) a copolymer of C 1 -C 4 esters of (meth) acrylic acid and (meth) acrylate monomers having tertiary ammonium groups, (b) a plasticizer and (c) an emulsifier mixed with an HLB value of at least 14 and from which the coating or binder by melting, Casting, spreading or spraying manufactures, wherein the copolymer (a) is introduced in powder form with an average particle size of 1 to 40 ⁇ .
• the resulting processability is attributed to the provision of the copolymer (a) in powder form with an extremely small particle size.
• WO 02/067906 relates to coating and binding agents with improved water vapor permeability over those described in WO 00/05307.
• the preparation of the coating and binding agents is carried out using a mixture which comprises (a) a copolymer of C 1 -C 4 esters of (meth) acrylic acid and further (meth) acrylate monomers having functional tertiary ammonium groups in powder form with an average particle size from 1 to 40 ⁇ , (b) an emulator having an HLB value of at least 14 and (c) contains a Ci2-Ci8 monocarboxylic acid or a Ci2-Ci 8 -Hydroxylitati.
• WO 2004/019918 describes coating compositions and binders which, with regard to their composition, correspond to those described in WO 00/05307 and WO 02/067906.
• a type C methacrylic acid copolymer is to be used as disintegrant.
• the methacrylic acid copolymer type C is a gastric juice-resistant polymer, which is not soluble in the acidic pH range, in the pH range of 7, as it is in the oral cavity, but is water-soluble.
• the tablets have, in addition to a low breaking strength ( ⁇ 20N), a high friability (> 7%) and contain a high proportion in the range of 15% by weight of a coarse-grained disintegrant. Consequently, they have a low mechanical strength and produce an unpleasant, sandy mouthfeel due to the high proportion of coarse disintegrant.
• the matrix components based on sugar alcohols, disintegrants and insoluble polymers are generally known for pharmaceutical applications from WO 2007/071581.
• WO 2009/016258 discloses the preparation of the aqueous polymer dispersions of cationic polymers based on ⁇ , ⁇ -diethylaminoethyl methacrylate, as used in accordance with the invention, and their use for coating medicaments. It is further stated in general that the polymers coating and binding agents are suitable, wherein only the use as film formers in coating compositions is described concretely. The use as a matrix binder for the production of granules is not mentioned.
• the present invention is based on the object to find improved matrix binders, which lead to a strong granulation effect, a reduced fines content of the granules and too little abrasion-sensitive granules. Dosage forms produced therefrom by compression should have a high strength even at low pressure and quickly disintegrate. Accordingly, the use of copolymers containing
• At least one free-radically polymerizable compound selected from esters of ⁇ , ⁇ -ethylenically unsaturated mono- and dicarboxylic acids with C 1 -C 6 -alkanols, as matrix binders for the preparation of active ingredient-containing granules.
• the active ingredient-containing granules are pharmaceutical granules.
• the matrix binders may still contain: ii) as component B, one or more antioxidants,
• component C one or more plasticizers, and as components D physiologically acceptable acids,
• the matrix binders are used as wet binders.
• the moist binder formulations are particularly preferably used in the form of aqueous polymer dispersions.
• the binder preparations Based on the total weight of the preparation, the binder preparations,
• Preferred binder formulations contain, based on the total weight of the preparation,
• Particularly preferred binder formulations contain, based on the total weight of the preparation,
• binder preparations comprising, based on the total weight of the preparation,
• component a) is preferably used in an amount of from 25 to 65% by weight, more preferably from 30 to 60% by weight, in particular from 38 to 48% by weight, especially from 43 to 47% by weight .-%, based on the total weight of the monomers used for the polymerization, used.
• Component b) is selected from esters of alpha, beta-ethylenically unsaturated mono- and dicarboxylic acids with C 1 -C 6 -alkanols. Suitable compounds b) are methyl (meth) acrylate, methyl methacrylate,
• component b methyl methacrylate or a monomer mixture containing methyl methacrylate.
• component b) is preferably used in an amount of 35 to 75% by weight, more preferably 40 to 70% by weight, in particular 52 to 62% by weight, especially 53 to 57% by weight. %, based on the total weight of the monomers used for the polymerization used.
• the monomer mixtures M) used to prepare the polymer dispersions may additionally contain at least one further monomer c).
• the additional monomers c) are preferably selected from esters of alpha, beta-ethylenically unsaturated mono- and dicarboxylic acid.
• carboxylic acids with C 3 -C 30 -alkanols and C 2 -C 30 -alkanediols amides of ⁇ , ⁇ -ethylenically unsaturated mono- and dicarboxylic acids with C 2 -C 30 -aminoalcohols which have a primary or secondary amino group, primary amides of ⁇ , ⁇ -ethylenically unsaturated mono- carboxylic acids and their N-alkyl and ⁇ , ⁇ -dialkyl derivatives, N-vinyllactams, open-chain N-vinylamide compounds, esters of vinyl alcohol and allyl alcohol with C1-C30-
• Monocarboxylic acids Monocarboxylic acids, vinyl ethers, vinyl aromatics, vinyl halides, vinylidene halides, C 2 -C 6 monoolefins, unsaturated nitriles, non-aromatic hydrocarbons having at least two conjugated double bonds and mixtures thereof.
• Suitable additional monomers c) are esters of alpha, beta-ethylenically unsaturated mono- and dicarboxylic acids with C 9 -C 30 -alkanols, such as n-nonyl (meth) acrylate, n-decyl (meth) acrylate, n-undecyl (meth) acrylate, tridecyl (meth) acrylate,
• Suitable additional monomers c) are furthermore esters of alpha, beta-ethylenically unsaturated mono- and dicarboxylic acids with C 2 -C 3 -alkanediols, such as 2-hydroxyethyl acrylate,
• Suitable additional monomers c) are also primary amides of alpha, beta-ethylenically unsaturated monocarboxylic acids and their N-alkyl and ⁇ , ⁇ -dialkyl derivatives, such as
• N-palmitoleinyl (meth) acrylamide N-oleyl (meth) acrylamide, N-linolyl (meth) acrylamide,
• N-linolenyl (meth) acrylamide N-stearyl (meth) acrylamide, N-lauryl (meth) acrylamide,
• Morpholinyl (meth) acrylamide As additional monomers c) are also suitable N-vinyl lactams and derivatives thereof, the z. B. one or more Ci-C ß- alkyl substituents, such as methyl, ethyl, n-propyl,
• Isopropyl, n-butyl, sec-butyl, tert-butyl, etc., may have. These include z. B.
• N-vinylpyrrolidone N-vinylpiperidone, N-vinylcaprolactam
• N-vinyl-5-methyl-2-pyrrolidone N-vinyl-5-ethyl-2-pyrrolidone
• N-vinyl-6-methyl-2-piperidone N- Vinyl-6-ethyl-2-piperidone
• N-vinyl-7-methyl-2-caprolactam N-vinyl-7-ethyl-2-caprolactam etc.
• Preference is given to using N-vinylpyrrolidone and N-vinylcaprolactam.
• Suitable open-chain N-vinylamide compounds as monomers c) are, for example, N-vinylformamide, N-vinyl-N-methylformamide, N-vinylacetamide, N-vinyl-N-methylacetamide, N-vinyl-N-ethylacetamide, N-vinylpropionamide, N-vinyl N-methylpropionamide and N-vinylbutyramide.
• Suitable additional monomers c) are also vinyl acetate, vinyl propionate, vinyl butyrate and mixtures thereof.
• Suitable additional monomers c) are also ethylene, propylene, isobutylene, butadiene, styrene, alpha-methylstyrene, acrylonitrile, methacrylonitrile, vinyl chloride, vinylidene chloride, vinyl fluoride, vinylidene fluoride and mixtures thereof.
• the component c) is preferably used in an amount of 0 to 80 wt .-%, based on the total weight of the monomers used for the polymerization.
• a specific embodiment relates to polymer dispersions Pd) which contain no additional monomer c) in copolymerized form.
• the component c) is preferably used in an amount of 0.1 to 70 wt .-%, more preferably 1 to 60 wt .-%, in particular 5 to 50 wt .-%, based on the total weight of the polymerization used Monomers used.
• the monomer mixtures M) used to prepare the polymer dispersions may contain, in addition to compound a), at least one further, different compound d) thereof polymerized in copolymerizable form with a free-radically polymerizable alpha, beta-ethylenically unsaturated double bond and at least one cationogenic and / or cationic group.
• the cationogenic or cationic groups of component d) are preferably nitrogen-containing groups, such as primary, secondary and tertiary amino groups, and quaternary ammonium groups.
• the nitrogen-containing groups are tertiary amino groups or quaternary ammonium groups.
• Charged cationic groups can be prepared from the amine nitrogens either by protonation, e.g.
• alkylating agents such as Ci-C4-alkyl halides or sulfates produce.
• alkylating agents are ethyl chloride, ethyl bromide, methyl chloride, methyl bromide, dimethyl sulfate and diethyl sulfate.
• Suitable compounds d) are, for.
• DEAEMA different esters of alpha, beta-ethylenically unsaturated mono- and dicarboxylic acids with amino alcohols.
• Preferred amino alcohols are C 2 -C 12 -amino alcohols which are mono- or dialkylated on the amine nitrogen by C 1 -C 4.
• acid component of these esters are z.
• Acrylic acid, methacrylic acid and mixtures thereof are preferably used as the acid component of these esters.
• Suitable additional compounds d) are N, N-dimethylaminomethyl (meth) acrylate, N, N-dimethylaminoethyl (meth) acrylate, N, N-diethylaminoethyl acrylate,
• N, N-dimethylaminocyclohexyl (meth) acrylate N, N-dimethylaminocyclohexyl (meth) acrylate.
• Suitable monomers d) are furthermore the amides of the abovementioned alpha, beta-ethylenically unsaturated mono- and dicarboxylic acids with diamines which have at least one primary or secondary amino group.
• diamines having a tertiary and a primary or secondary amino group.
• Suitable monomers d) are also ⁇ , ⁇ -diallylamines and N, N-diallyl-N-alkylamines and their acid addition salts and quaternization products.
• Alkyl is preferably C 1 -C 24 -alkyl. Preference is given to N, N-diallyl-N-methylamine and N, N-diallyl-N, N-dimethylammonium compounds, such as. As the chlorides and bromides.
• Suitable monomers d) are also vinyl- and allyl-substituted nitrogen heterocycles, such as N-vinylimidazole, N-vinyl-2-methylimidazole, vinyl- and allyl-substituted heteroaromatic compounds, such as 2- and 4-vinylpyridine, 2- and 4-allylpyridine, and the salts from that.
• the monomer d), if present, is preferably used in an amount such that the sum of the amounts of the monomers a) and the monomers d) is in a range from 25 to 65% by weight, especially preferably 30 to 60 wt .-%, based on the total weight of the monomers used for the polymerization, is located.
• component d) is preferably used in an amount of from 0 to 50% by weight, based on the total weight of the monomers used for the polymerization.
• polymer dispersions Pd) according to the invention and used according to the invention, based on DEAEMA (component a), have a particularly good property profile.
• This property profile can usually be achieved without the use of further monomers with cationogenic / cationic groups.
• a specific embodiment therefore relates to polymer dispersions Pd) which contain no additional monomer d) in copolymerized form.
• component d) is preferably used in an amount of 0.1 to 40% by weight, particularly preferably 1 to 30% by weight, in particular 2 to 25% by weight, based on the total weight of the polymerization used Monomers used.
• a monomer mixture M) which consists of
• the polymers contained in the dispersions according to the invention preferably have a mean molecular weight M w in the range determined by means of gel permeation chromatography from 30,000 to 500,000, particularly preferably 60,000 to 140,000, in particular 80,000 to 120,000 g / mol.
• the polymers present in the novel dispersions Pd) preferably have a K value (determined according to Fikentscher on a 1% strength solution in N-methylpyrrolidone (NMP)) in the range from 40 to 60.
• the glass transition temperature TG (determined by means of DSC) is preferably in a range from 40 to 70.degree. C., particularly preferably from 52 to 62.degree.
• the polymers contained in the dispersions used according to the invention are essentially random copolymers.
• the average particle diameter of the polymer particles contained in the polymer dispersion is preferably in a range from 70 to 200 nm, more preferably from 80 to 150 nm, in particular from 90 to 120 nm.
• the particle size distribution is preferably substantially unimodal.
• the LD value of the dispersions used according to the invention is preferably at least 70%, more preferably at least 80%.
• the determination of the light transmission is z. In Dieter Distler, Aqueous Polymer Dispersions, Wiley-VCH (1999), p. 40.
• the solids content of the dispersions used according to the invention is according to
• Preparation preferably 10 to 50 wt .-%, particularly preferably 20 to 40 wt .-%.
• inventive composition preferably 10 to 50 wt .-%, particularly preferably 20 to 40 wt .-%.
• Dispersions preferably before and after ultrafiltration solids contents that are in these areas.
• a dilute polymer dispersion it is also possible to subject a dilute polymer dispersion to concentration by ultrafiltration.
• the dispersions used according to the invention as matrix binders for granules have z. B. even at a solids content of 30 wt .-% extremely low viscosities of preferably less than 50 mPas, more preferably less than 25 mPas and in particular less than 10 mPas (values determined by Brookfield viscometer at 20 ° C and 100 s 1 ). Such low viscosities are of particular importance for many applications.
• the charge of the polymers contained in the dispersions used according to the invention is dependent on the pH of the dispersion.
• the isoelectric point is preferably in a pH range of about 7.5 to 8.5.
• the finished dispersion preferably has a pH in the range from 8 to 10, particularly preferably from 8.5 to 9.5 (at a solids content of 30% by weight). It is advantageous that the pH of the finished dispersion is chosen higher (more alkaline) than its isoelectric point, as long as a dissolution or swelling of the In the dispersion contained polymer particles is not desired.
• the dispersions according to the invention are therefore preferably basic dispersions.
• the polymer dispersions according to the invention are distinguished by their pH-dependent
• Solubility An adjustment of the pH range in which the dispersion dissolves on acidification, is successful for.
• polymer dispersions Pd) according to the invention at a pH of at most 6.8, more preferably at a pH of at most 6.0.
• polymer dispersions which contain a polymer which contains from 43 to 47% by weight, based on the total weight of the monomers used for the polymerization, of ⁇ , ⁇ -diethylaminoethyl methacrylate a), and
• the coating compositions according to the invention may contain, in addition to the polymer, one or more antioxidants or a combination of antioxidants (indicated by "/".)
• one or more antioxidants or a combination of antioxidants indicated by "/”.
• the following agents, listed combinations or further combinations are particularly suitable for improving the release stability as antioxidants:
• N-acetylcysteine allantoin, arginine, arginine / butylhydroxytoluene, arginine / N-acetylcysteine, ascorbyl palmitate, aspartic acid, biotin, butylhydroxyanisole,
• Oleic acid simethicone, butylhydroxytoluene, sodium hydrogensulfite, tocopherol, sodium dihydrogen citrate, sodium hypochlorite, sodium hypophosphite, disodium hydrogenphosphate, tocopherol, tocopherol acetate, arginine,
• Preferred antioxidants are phenolic-type compounds.
• Preferred phenolic compounds are, for example, butylhydroxytoluene or butylhydroxyanisole, as they completely prevent both the dissolution retardation and yellowing.
• Further suitable products are: catechol, gallic acid or its esters, tocopherol, caffeic acid, hydroquinone monomethyl ether (MEHQ), nordihydroguaiaretic acid, resveratrol.
• antioxidants are thiol compounds, such as N-acetylcysteine, cysteamine, thioglycolic acid. Also preferred are basic amino acids such as arginine and lysine.
• Preferred antioxidants are also alkali metal carbonates or alkali bicarbonates, in particular the sodium salts, preferably sodium carbonate. Also preferred are combinations with EDTA, in particular Na-EDTA or with citric acid.
• N-acetylcysteine arginine, lysine, butylhydroxytoluene, butylhydroxytoluene / Na EDTA, as well as sodium carbonate or combinations thereof. All of these compounds or classes of compounds can also be used in combination.
• the antioxidants can be used in amounts of from 0.01 to 30, preferably from 0.1 to 20, particularly preferably from 0.5 to 12,% by weight, based on the total amount of the solids content of the wet-tie binder preparation.
• the wet binders according to the invention may contain as component C plasticizers, preferably lipophilic plasticizers.
• plasticizers are tributyl citrate, acetyltributyl citrate, triacetin, triethyl citrate, acetyl triethyl citrate, diethyl sebacate and dibutyl sebacate.
• the plasticizers may be used in amounts of 1 to 30, preferably 2 to 25, particularly preferably 5 to 20 wt .-%, based on the total amount of the solids content of the wet binder formulation.
• the moist binders for pharmaceutical dosage forms used according to the invention may additionally contain as components D at least one physiologically acceptable acid. This acid results in partial to complete salt formation with the basic polymer. Complete salt formation forms a polymer solution.
• Physiologically acceptable are the acids which are known to be usable in the field of pharmacy, food technology and related fields, in particular those in relevant pharmacopoeias (eg Ph. Eur., USP, JP), Foddzumikslisten and the books Fiedler, HP Lexicon der Hilfsstoffe für Pharmazie , Cosmetics and adjacent areas, 4th ed., Aulendorf: ECV Editio-Cantor-Verlag, 1996 and PH Steel and CG Steel, Handbook of Pharmaceutical Salts, published by Helvetica Chimica Acta, 2002.
• Suitable acids are, for. B: hydrochloric acid, sulfuric acid, phosphoric acid; Carbonic acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, maleic acid, fumaric acid, malonic acid, malic acid, succinic acid, citric acid, tartaric acid, lactic acid, benzoic acid, adipic acid, glycolic acid, propionic acid, salicylic acid, mandelic acid, glutamic acid, aspartic acid.
• the acids can be used in amounts of from 1 to 50% by weight, preferably from 2 to 35% by weight, in particular from 5 to 25% by weight, based on the total weight of the solids content of the wet binder preparation.
• aqueous dispersions containing only component A are used as wet binder preparations.
• aqueous dispersions are used as wet-binder formulations which, in addition to component A), additionally comprise a component B) (method n).
• the wet-binder formulations comprise a combination of components A) and C) (method III).
• the aqueous dispersions contain a combination of components A) and D), wherein depending on the degree of neutralization, the aqueous dispersion is converted into an aqueous solution (method IV).
• Another embodiment relates to a combination of components A), C) and D) (method V). Another embodiment relates to a combination of components A), B) and C) (Method VI).
• Another embodiment relates to a combination of components A), B) and D) (method VII).
• the invention also relates to an embodiment in which the wet binders contain a combination of components A), B), C) and D) (Method VIII).
• the quantities of component A are based on the total weight of the wet binder.
• the quantities of components B), C) and D) relate to the total solids content of the wet binder.
• the quantitative ranges can be freely combined in the various embodiments, depending on which property profile is to be set for the granules and the tablets obtainable therefrom.
• the variation of grain size components B the release stability can be adjusted.
• the mechanical properties and / or the release profile can be adjusted.
• the preparations contain 2 to 35% by weight.
• Component D based on component A), wherein the proportion of component A) based on the total weight of the dispersion is 2 to 40 wt .-%.
• the preparations contain 2 to 25 wt .-% of component C), based on component A), wherein the proportion of component A) based on the total weight of the dispersion is 2 to 40 wt .-%.
• the preparations contain 0.1 to 20 wt .-% of component B), based on component A), wherein the proportion of component A) based on the total weight of the dispersion is 2 to 40 wt .-%.
• the preparations contain 2 to 25 wt .-% of component C) and 2 to 35 wt .-% of component D), based on component A), wherein the proportion of component A) based on the total weight of the dispersion to 40 wt .-% is.
• the preparations contain 2 to 55 wt .-% of component D), based on component A), wherein the proportion of component A) based on the total weight of the dispersion is 5 to 30 wt .-%.
• the preparations contain 5 to 20 wt .-% of component C), based on component A), wherein the proportion of component A) based on the total weight of the dispersion is 5 to 30 wt .-%.
• the preparations contain 0.5 to 20 wt .-% of component B), based on component A), wherein the proportion of component A) based on the total weight of the dispersion is 5 to 30 wt .-%.
• the preparations contain 5 to 20 wt .-% of component C) and 5 to 25 wt .-% of component D), based on component A), wherein the proportion of component A) based on the total weight of Dispersion 5 to 30 wt .-% is.
• the amounts of components A, B, C, D and dispersant and / or solvent add up to 100% by weight.
• Dispersants are water or mixtures of water and a water-miscible organic solvent.
• the preparation of the moist binder formulations is carried out according to an embodiment of the invention starting from an aqueous dispersion of component A.
• incorporation of the components B - D into the aqueous polymer dispersion can generally be effected by stirring or intimate mixing. Both with solid and with liquid components B - D, these can also be dissolved in water or diluted with water before addition to the polymer dispersion.
• the polymers described (components A) are used as a solution in a purely organic solvent.
• the solid polymers are dissolved in a suitable solvent, e.g. Dissolved ethanol, isopropanol, methanol, acetone, methylene chloride, ethyl acetate, tetrahydrofuran, dioxane.
• the preparation of an organic-aqueous solution can also by addition of a water-miscible solvent such.
• a water-miscible solvent such as B ethanol, isopropanol, methanol, acetone, tetrahydrofuran, dioxane to a polymer dispersion.
• a ratio of solvent to polymer dispersion of greater than 1: 1 to 25: 1 is required for complete dissolution.
• This organic or organic-aqueous solution can be used as a purely aqueous preparation for wet granulation.
• the wet binder formulations preferably do not contain additional organic solvents.
• the binders are used for the production of pharmaceutical dosage forms, in particular pharmaceutical granules and tablets obtained by compression of such granules.
• the moisture binder effectiveness can surprisingly be increased considerably if the basic polymers are neutralized or partially neutralized and / or mixed with plasticizers.
• the wet binders provide abrasion-resistant, stable granules with little fines, which therefore do not dust much.
• the tablets made from these granules are very hard, little susceptible to abrasion and disintegrate very quickly.
• the polymers of the invention ideally meet the requirements of a highly effective wet binder.
• the preparation of the wet binding agent can, for. B. by stirring and intimately mixing a polymer dispersion according to the invention with at least one excipient.
• the moist binder according to the invention can be used in aqueous dispersion or completely neutralized as a solution by means of casting, dropwise addition or spraying.
• the moistened mass is dried after addition of the binder preparation. In the case of fluidized bed granulation, the spraying and the drying takes place in parallel.
• the moisturizing binders according to the invention are suitable for dosage forms in principle of any active pharmaceutical ingredients which can preferably be administered in isolated or protected form, such as antidepressants, beta-blockers, antidiabetics, analgesics, antiphlogistics, antirheumatics, antihypotonics, antihypertensives, psychotropic drugs, tranquilizers, antiemetics, muscle relaxants, glucocorticoids, Agents for the treatment of ulcerative colitis or Crohn's disease, antiallergic agents, antibiotics, anticonvulsants, anticoagulants, antifungals, antitussives, arteriosclerotic agents, diuretics, enzymes, enzyme inhibitors, gout, hormones and their inhibitors, cardiac glycosides, immunotherapeutics and cytokines, laxatives, lipid-lowering agents, gastrointestinal , Migraine remedies, mineral preparations, otologics, Parkinson's drugs, thyroid therapeutics, spasmolytics, antiplatelet agents, vitamins,
• Suitable active ingredients are: acarbose, non-steroidal anti-inflammatory drugs, cardiac glycosides, acetylsalicylic acid, antivirals, aclubicin, acyclovir, cisplatin, actinomycin, ⁇ - and ⁇ -sympathomimetics, allopurinol, alosetron, alprostadil, prostaglandins, amantadine, ambroxol, amlodipine, methotrexate, 5-aminosalicylic acid , Amitriptyline, amoxicillin, anastrozole, atenolol, a-torvastatin, azathioprine, balsalazide, beclomethasone, betahistine, bezafibrate, bicalutamide, diazepam and diazepam derivatives, budesonide, bufexamac, buprenorphine, methadone, calcium salts, potassium salts,
• vitamin D derivatives of vitamin D, colestyramine, cromolyn sodium, coumarin and coumarin derivatives, cysteine, cytarabine, cyclophosphamide, ciclosporin, cyproterone, cytarabine, dapiprazole, desogestrel, desonide, dihydralazine, diltiazem, ergot alkaloids, dimenhydrinate, dimethyl sulfoxide, dimethicone, dipyridol, domperidone and domperidone derivatives, donepzil, dopamine, doxazosin, doxorubicin, dodylamine, dapiprazole, benzodiazepines, diclofenac, glycoside antibiotics, desipramine, econazole, ACE inhibitors, enalapril, ephedrine, epinephrine, epoetin and epo
• the active compounds can also be used in the form of their pharmaceutically acceptable salts or derivatives, and in the case of chiral active compounds, both optically active isomers and racemates or mixtures of diastereoisomers can be used.
• the compositions according to the invention may also contain two or more active pharmaceutical ingredients.
• the granules can be packaged in capsules, sachets or bulk packs such as glass or plastic powder bottles. Frequently, the granules are then pressed into tablets. Depending on the type, the tablets can release the active ingredient quickly or with a delay and they can also be further processed into film-coated tablets.
• the insolubility of the polymers in saliva often conceals the bitterness and bad taste of drugs. This means that a taste-masking effect can be achieved by granulation. Nevertheless, there is a very rapid release of the drug from the dosage form in the stomach.
• the use of the polymers according to the invention in granulation therefore has several advantages: stable granules and stable tablets, good flowability, good taste masking, rapid release of active substance in the stomach.
• the polymers according to the invention can process medicaments which are sparingly soluble in water to form rapidly releasing dosage forms.
• Drugs which are sparingly soluble in water are those which require at least 100 parts of water in order to dissolve a part of the drug. This also includes practically insoluble drugs requiring at least 10,000 parts of water to dissolve a portion of drug.
• the granules can also be mixed with other customary pharmaceutical excipients.
• fillers plasticizers, solubilizers, binders, silicates and explosives and adsorbents, lubricants, flow agents, dyes, stabilizers such as antioxidants, wetting agents, preservatives, mold release agents, flavors or sweeteners, preferably around fillers, disintegrants and lubricants.
• fillers e.g. inorganic fillers such as oxides of magnesium, aluminum, silicon, titanium or calcium carbonate, calcium or magnesium phosphates or organic fillers such as lactose, sucrose, sorbitol, mannitol may be added.
• inorganic fillers such as oxides of magnesium, aluminum, silicon, titanium or calcium carbonate, calcium or magnesium phosphates or organic fillers such as lactose, sucrose, sorbitol, mannitol may be added.
• Suitable plasticizers are, for example, triacetin, triethyl citrate, glycerol monostearate, low molecular weight polyethylene glycols or poloxamers.
• Suitable additional solubility mediators are surface-active substances having an HLB value (hydrophilic lipophilic balance) greater than 11, for example ethoxylated hydrogenated castor oil (Cremophor® RH 40), castor oil ethoxylated with 35 ethylene oxide units (Cremophor eL), polysorbate 80, poloxamers or sodium lauryl sulfate.
• HLB value hydrophilic lipophilic balance
• stearates of aluminum, calcium, magnesium and tin, as well as magnesium silicate, free fatty acids such as stearic acid, poloxamers, Natriumstearylfu- marat and the like can be used.
• flow agents for example, talc or colloidal silica can be used.
• Suitable binders are, for example, microcrystalline cellulose.
• Crosslinking polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, L-HPC or cross-linked sodium carboxymethyl starch can be used as disintegrants.
• Stabilizers may be ascorbic acid or tocopherol.
• Dyes are e.g. Iron oxides, titanium dioxide, triphenylmethane dyes, azo dyes, quinoline dyes, indigotine dyes, carotenoids to color the dosage forms, opacifying agents such as titanium dioxide or talc to reduce the light transmission and to save dyes.
• RRSB particle size distribution according to Rosin, Rammler, Sperling and Bennett; the average particle size corresponds to the particle size at a sieve residue of 36.8% (Ingfried Zimmermann, Pharmaceutical Technology, Springer Verlag, 1998, 276-278).
• Friability and breaking strength were determined according to the European Pharmacopoeia 7.0 Volume 1.
• Granulac® 230 lactose, fine powder
• Kollidon® CL cross-linked polyvinylpyrrolidone (crospovidone), average particle size 120 ⁇
• Kollidon® 30 polyvinylpyrrolidone with K value 30 (corresponding to 1% strength by weight in water)
• the polymers are prepared analogously to Example 1 of WO 2009/016258.
• Polymer B methyl methacrylate / diethylaminoethyl methacrylate, wt. Ratio 55:45,
• Polymer C methyl methacrylate / diethylaminoethyl methacrylate, weight ratio 53:47
• the polymers were used as 30 wt .-% aqueous dispersions having a pH of 9 +/- 0.3.
• the mean particle size of the primary dispersion was 1 10 nm.
• 150 g of the aqueous dispersion of the cationic polymer A were mixed with 150 g of water.
• 150 g of the aqueous dispersion were diluted with 56.5 g of water and then admixed with 97 ml of a 1 N HCl solution.
• the 97 ml of the 1 N HCI solution contained 3.5 g of HCl.
• plasticizer 6.75 g of plasticizer were diluted with 150 g of water and then added slowly to 150 g of the 30% dispersion.
• Calcium hydrogen phosphate and Granulac 230 were weighed into a Diosna stirred tank. This mixture was mixed for 1 min in the Diosna mixer (400 rpm stirrer / 2200 rpm chopper). 85 g of the 15.0% binder solution were added by means of a syringe within 45 s with constant stirring in the stirred tank (400 rpm stirrer / 2200 rpm chopper). After addition of the binder solution to the mixture, a mixing time of 3 minutes followed. Thereafter, the moistened mass was passed through a sieve of mesh size 0.8 mm and dried the moist granules for at least 12 hours in air at 25 ° C on trays. Subsequently, the dry granules were again passed through a sieve of mesh size 0.8 mm.
• Magnesium stearate 0.5% The disintegrant and lubricant were passed through a sieve of 0.8mm mesh size and then to the granules. The entire mass was filled into a glass bottle, sealed and mixed for 5 minutes in the Turbula mixer.
• the tabletting mixture was pressed at 10 kN on an eccentric press (Korsch, XP 1) into bilayer tablets with a diameter of 10 mm.
• the tablet weight was 500 mg.
• the friability of the granules was determined by means of an air jet sieve LPS 200 MC from Rhewum. Here, first of all, a screening of the fine fraction ⁇ 125 ⁇ m takes place at a low air throughput of 20 m / h and a sieving time of 1 min. Subsequently, the residue was weighed and treated with an air flow of 75 m / h for 3 min (heavy duty). The remaining residue was weighed again. The difference results in the friability, which was expressed as a percentage of the residue after screening of the fine fraction.
• the disintegrant and lubricant were passed through a sieve of 0.8mm mesh size and then to the granules. The entire mass was filled into a glass bottle, sealed and mixed for 5 min in a Turbula mixer.
• the tabletting mixture was pressed on an eccentric press (Korsch, XP 1) with 18 kN to biplane tablets with a diameter of 10 mm.
• the tablet weight was 500 mg. 2.1 Kollidon 2.2. Kationi2.3. Kationi2.4. Kationi30 / Comparison of Nice Polyes Polymer B mer B neutral B with triacetin
• plasticizer 11.25 g of plasticizer were diluted with 500 g of water and then slowly added to 250 g of the 30% dispersion.
• Vitamin C was weighed into the granulation container of the Glatt WSG GPC G3 (as powder with grain size 45 ⁇ ) and heated for 5 min. The volume flow was 87 m 3 / h and the temperature of the supply air 55 ° C. 600 g of the 10.0% binder solution were sprayed on the vitamin C within 30 min. After spraying, the granules were treated at a supply air temperature. temperature of 55 ° C for 5 min dried. Subsequently, the dry granules were again passed through a sieve of mesh size 0.8 mm.
• the disintegrant and lubricant were passed through a sieve of 0.8mm mesh size and then to the granules. The entire mass was filled into a glass bottle, sealed and mixed for 5 min in a Turbula mixer.
• the tabletting mixture was pressed on an eccentric press (Korsch, XP 1) with 18 kN to biplane tablets with a diameter of 10 mm.
• the tablet weight was 300 mg.
• Fines content ⁇ 125 ⁇ 53.0 57.6 38.3 42.7
• Granulation of paracetamol in the fluidized bed by means of an organic-aqueous polymer solution by means of an organic-aqueous polymer solution.
• Paracetamol was weighed into the granulation container of the Glatt WSG GPC G3 and heated for 5 min. The volume flow was 87m 3 / h and the temperature of the supply air 40 ° C. 1200 g of the 10.0% binder solution were sprayed onto the paracetamol within 30 min. After spraying, the granules were dried at a supply air temperature of 40 ° C for 5 min. Subsequently, the dry granules were again passed through a sieve of mesh size 0.8 mm. Subsequently, a tabletting mixture was produced from the granules.
• Kollidon CL microcrystalline cellulose and polyethylene glycol were passed through a sieve of mesh size 0.8 mm and then to granules. The entire mass is filled into a glass bottle, closed and mixed for 5 min in the Turbula mixer.
• the Tablettiermischung was pressed on an eccentric press (Korsch, XP 1) with 25 kN to biplane tablets with a diameter of 12 mm.
• the tablet weight was 625 mg.
• the tablets had no bitter taste.

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• 2011
  • 2011-08-30 WO PCT/EP2011/064853 patent/WO2012031934A1/de active Application Filing
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