EP1534247A1

EP1534247A1 - Methods for coating substrates for pharmaceutical uses with a mixture of two film-forming coating agents

Info

Publication number: EP1534247A1
Application number: EP03772234A
Authority: EP
Inventors: Hans-Ulrich Petereit; Christian Meier; Erna Roth
Original assignee: Roehm GmbH Darmstadt
Current assignee: Roehm GmbH Darmstadt
Priority date: 2002-12-20
Filing date: 2003-10-18
Publication date: 2005-06-01
Also published as: US20050281871A1; MXPA05006284A; DE10260921A1; KR20050088200A; PL375986A1; JP2006512376A; AU2003280392A1; BR0317452A; WO2004058226A1; CA2510778A1

Abstract

The invention relates to methods for producing pharmaceuticals or parts of pharmaceuticals or food supplements or parts thereof, by coating substrates with a mixture of two film-forming coating agents that can contain other pharmaceutically standard additives, especially softeners and/or a pharmaceutical active ingredient.

Description

Process for coating substrates for pharmaceutical applications with a mixture of two film-forming coating agents

The invention relates to a method for coating substrates for pharmaceutical applications with a mixture of two film-forming coating agents.

State of the art

Abletshauser CB, in "Film coating of ellets with insoluble polymers obtained in situ crosslinking in fluidized bed" in Journal of Controlled Release 27 (1993), pp. 149-156, describes a process in which a film-forming polymer, sodium alginate, in aqueous solution and a crosslinking agent, for example a CaCl ₂ solution or a (meth) acrylate copolymer with tertiary amino group residues (EUDRAGIT E®), are simultaneously sprayed onto pellets containing active ingredient from two separate spray nozzles For example, in a fluidized bed device with two spray nozzles installed in it. The result of the method is approximately equivalent to a sequential application of both components, but has the advantage of saving time.

WO 00/05307 describes a process for the production of a coating and binder for oral or dermal pharmaceutical forms consisting of (a) 35-98% by weight of a copolymer consisting of radically polymerized C1 to C4 esters of acrylic or methacrylic acid and further (meth) acrylate monomers which have functional tertiary ammonium groups and (b) 1-50% by weight of a plasticizer and 1-15% by weight of an emulsifier with an HLB value of at least 14, components (a), (b) and (c) with or without addition of water and optionally with the addition of an active pharmaceutical ingredient and other customary additives, and the coating and binder are produced by melting, pouring, spreading or spraying, the copolymer (a) being introduced in powder form with an average particle size of 1-40 μm.

EP-A 0 848 960 describes an adhesive and binder for dermal or transdermal therapy systems consisting of (a1) 55-99.9% by weight of a (meth) acrylate copolymer of structural and functional monomers, the functional monomers being tertiary or quaternary amino groups have (a2) 0.1-45% by weight of an acid group-containing acrylate or (meth) acrylate polymer or copolymer and (b) 25-80% by weight, based on the sum of (a1) and (a2) , a plasticizer. A transdermal therapy system can be produced by incorporating a pharmaceutical active ingredient by coating or by spraying or brushing on solutions, dispersions, suspensions or melts of an adhesive and binder and then drying or cooling

US 6,368,629 describes pH-dependent colon release systems which have a core, an inner polymer coating, e.g. B. have a mixture of EUDRAGIT® E and EUDRAGIT® RS and are coated on the outside by a polymer with anionic groups, for. B. an EUDRAGIT® L. Task and solution

The mixture of two (meth) acrylate copolymers described in EP-A 0 848 960 can be used to produce transdermal therapy systems with advantageous properties with regard to the release of the active ingredient. It would be desirable to also apply this release system to coatings for pharmaceutical substrates, such as. B. active ingredient-containing tablet cores.

In principle, this is easily possible if you mix organic solutions of both components and thus carry out spray jobs. The disadvantage of this procedure lies in the use of organic solvents, which are known to cause problems in occupational safety and environmental protection.

If aqueous dispersions of the (meth) acrylate copolymers are chosen as the starting point instead of organic solutions, the difficulty arises that mixtures of both (meth) acrylate copolymers behave incompatible and remain sprayable only for a short time. This means that mixed dispersions become unstable after a short time and tend to clump or coagulate. Since even slight aggregate formation leads to blockage of spray nozzles, such mixtures are currently not technically usable in an acceptable manner.

The formation of aggregates mentioned can be avoided in aqueous systems by using comparatively large amounts, 10% by weight or more, of non- ionic emulsifiers can be added. However, this is problematic, since pharmaceutical applications always strive to keep the use of emulsifiers low. The presence of large amounts of these substances often leads to problems with the long-term stability of the pharmaceutical forms produced. In the course of storage, undesirable interactions with the active substance can occur. Separation phenomena can also occur in the polymer coatings. Both are undesirable and of course unacceptable for pharmaceuticals.

It was therefore seen as an object to make (meth) acrylate copolymer mixtures, as described in EP-A 0848 960 for transdermal systems, also available for aqueous spray application systems. The use of non-ionic emulsifiers should either be completely avoidable or should only take place in small quantities. The coatings obtained should be of perfect quality, not sticky and long-term stable.

The task is solved by a

Process for the production of pharmaceutical forms or parts of pharmaceutical forms or nutritional supplements or parts thereof,

by coating substrates with a mixture of two film-forming coating compositions, which may contain other pharmaceutically customary additives, in particular plasticizers and / or a pharmaceutical active ingredient

the first film-forming coating agent is a (meth) acrylate copolymer of 30 to 80% by weight of free-radically polymerized C to C ₄ alkyl esters of acrylic or methacrylic acid and 70 to 20% by weight of (meth) acrylate monomers with a tertiary amino group in the alkyl radical .

and the second film-forming coating agent is a polymer with anionic groups,

with the proviso that, based on the dry weight of the mixture, the film-forming coating compositions contain no or no more than 20% by weight of a plasticizer and no or no more than 5% by weight of a nonionic emulsifier,

characterized in that

the film-forming coating compositions are initially separated from one another as liquid, sprayable solutions or dispersions and

by spray application by means of one or more spray devices which individually or together atomize liquids separately and overlap their spray jets,

are simultaneously sprayed so that the incompatible individual portions mix during the spraying process, the mixture hits the substrate and then forms a film coating after the water has evaporated off, as a result of which the pharmaceutical form, the dietary supplement or parts thereof, are obtained.

It is through the simultaneous spraying of the otherwise incompatible components according to the invention and their mixing in the spray jet possible to apply the polymer mixture in a spray application. Another advantage of this procedure is, inter alia, that additives such as plasticizers or non-ionic emulsifiers can be kept in quantitative terms or avoided entirely.

Implementation of the invention

The invention relates to a process for the production of pharmaceutical forms or parts of pharmaceutical forms or nutritional supplements or parts thereof by coating substrates with a mixture of two film-forming coating compositions which may contain further pharmaceutically customary additives, in particular plasticizers and / or a pharmaceutical active ingredient,

the first film-forming coating agent comprising a (meth) acrylate copolymer of 30 to 80% by weight of radically polymerized Ci to C ₄ alkyl esters of acrylic or methacrylic acid and 70 to 20% by weight of (meth) acrylate monomers is a tertiary amino group in the alkyl radical,

and the second film-forming coating agent is a polymer with anionic groups,

with the proviso that, based on the dry mass of the mixture, the film-forming coating compositions contain no or no more than 20% by weight of a plasticizer and no or no more than 5% by weight of a nonionic emulsifier,

characterized in that the film-forming coating compositions are initially separated from one another as liquid, sprayable dispersions and

by spray application by means of one or more spray devices which, individually or together, have at least two separate nozzles for liquids and overlap their spray jets,

The film-forming coating agents

The film-forming coating compositions are in the form of solutions or sprayable dispersions. Both coating agents can each be in one form or another. The dispersions can e.g. B contain a solids content of 10 to 60, preferably 20 to 40% by weight of (meth) acrylate copolymer. The (meth) acrylate copolymers are finely distributed in water in the form of particles with particle sizes in the range of, for. B. 5 nm to 30 μ, voruzgt 10nm to 500 nm before. The dispersions are stable on their own. When water is removed by drying after spraying, the particles combine and give continuous (meth) acrylate copolymer coatings on the respective substrate.

Furthermore, customary pharmaceutical auxiliaries can be included, but with the proviso that the film-forming coating agents, based on the dry mass of the mixture, contain no or not more than 20% by weight of one Plasticizer and contain no or no more than 5 wt .-% of a nonionic emulsifier.

The film-forming coating compositions (dispersions) contain, in total, based on the dry mass of the mixture, no or no more than 20% by weight of a plasticizer and no or no more than 5% by weight of a nonionic emulsifier.

The first film-forming coating agent

The (meth) acrylate copolymer consists of 30 to 80% by weight of radically polymerized C to C ₄ alkyl esters of acrylic or methacrylic acid and 70 to 20% by weight of (meth) acrylate monomers with a tertiary amino group in the Alkyl group together.

Suitable monomers with functional tertiary amino groups are listed in US Pat. No. 4,705,695, column 3, line 64 to column 4, line 13. Particular mention should be made of dimethylaminoethyl acrylate, 2-dimethylaminopropyl acrylate, dimethylaminopropyl methacrylate, dimethylaminobenzyl acrylate, dimethylaminobenzyl methacrylate, (3-dimethylamino-2,2-dimethyl) propyl acrylate, dimethylamino-2,2-dimethyl) propyl methacrylate, (3-diethylamino) propyl acrylate and diethylamino-2,2-dimethyl) propyl methacrylate. Dimethylaminoethyl methacrylate is particularly preferred.

The content of the monomers with tertiary amino groups in the copolymer can advantageously be between 20 and 70% by weight, preferably between 40 and 60% by weight. The proportions of the C to C ₄ alkyl esters of acrylic or Methacrylic acid is 70-30% by weight. Mention should be made of methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.

A suitable (meth) acrylate copolymer with tertiary amino groups can e.g. B. from 20-30% by weight methyl methacrylate, 20-30% by weight butyl methacrylate and 60-40% by weight dimethylaminoethyl methacrylate.

A specifically suitable commercial (meth) acrylate copolymer with tertiary amino groups is e.g. B. from 25 wt .-% methyl methacrylate, 25 wt .-% butyl methacrylate and 50 wt .-% dimethylaminoethyl methacrylate (EUDRAGIT® E100).

The (meth) acrylate copolymer can be obtained in a manner known per se by free-radical substance, solution, bead or emulsion polymerization. Before processing, it can be brought into suitable particle size ranges by suitable grinding, drying or spraying processes.

Suitable devices for the production of the powder are known to the person skilled in the art, e.g. B. air jet mills, pin mills, fan mills. If necessary, appropriate screening steps can be included. A suitable mill for large industrial quantities is, for example, a counter jet mill (Multi No. 4200), which is operated at approx. 6 bar overpressure.

The average particle size of the powder can be determined as follows:

- By air jet sieving for easy division of the grinding product into a few fractions. In this measuring range, this method is somewhat less precise than the alternatives. - Another well-suited measuring method is laser diffraction to determine the grain size distribution. Commercial devices allow measurement in air (Malvern S3.01 particle sizer) or preferably in liquid media (LOT, Galai CIS 1). Precondition for the measurement in liquids is that the polymer does not dissolve in it or that the particles change in another way during the measurement. A suitable medium is e.g. B. a highly diluted (about 0.02%) aqueous polysorbate 80 solution.

- At least 70, preferably 90% of the particles based on the mass (mass distribution) can preferably be in the size range of 1-40 μm.

Preferred are (meth) acrylate copolymers with an average particle diameter in the range between 1 and 40, preferably between 5 and 35, in particular between 10 and 20 μm. (Type EUDRAGIT® EPO).

The second film-forming coating agent

The second film-forming coating agent is a polymer with anionic groups and can be a cellulose derivative, e.g. B. cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), cellulose acetate trimelitate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), a polyvinyl acetate derivative, e.g. B. polyvinyl acetate phthalate, (PVAP) or a (meth) acrylate copolymer.

The second film-forming coating agent is preferably a (meth) acrylate copolymer of 40 to 95% by weight of free-radically polymerized C to C ₄ alkyl esters of acrylic or methacrylic acid and contains 5 to 60% by weight of (meth) acrylate monomers with an anionic group in the alkyl radical The (meth) acrylate copolymer consists of 40 to 100, preferably 45 to 99, in particular 85 to 95% by weight of free-radically polymerized C to C alkyl esters of acrylic or methacrylic acid and can be 0 to 60, preferably 1 contain up to 55, in particular 5 to 15 wt .-% (meth) acrylate monomers with an anionic group in the alkyl radical.

As a rule, the proportions mentioned add up to 100% by weight. However, in addition, without this leading to an impairment or change in the essential properties, small amounts in the range from 0 to 10, e.g. B. 1 to 5 wt .-% of other vinyl copolymerizable monomers, such as. B. hydroxyethyl methacrylate or hydroxyethyl acrylate may be included.

C 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 with an anionic group in the alkyl group can e.g. As acrylic acid, but preferably methacrylic acid.

Anionic (meth) acrylate copolymers of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate (types EUDRAGIT® L or EUDRAGIT® L100-55) are also suitable. EUDRAGIT® L100-55 is a copolymer of 50% by weight ethyl acrylate and 50% by weight methacrylic acid. EUDRAGIT® L 30-55 is a dispersion containing 30% by weight EUDRAGIT® L 100-55.

Anionic (meth) acrylate copolymers of 20 to 40% by weight methacrylic acid and 80 to 60% by weight methyl methacrylate (type EUDRAGIT® S) are also suitable.

(Meth) acrylate copolymers consisting of 10 to 30% by weight, methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weight methacrylic acid (type EUDRAGIT® FS) are particularly suitable.

EUDRAGIT® FS is a copolymer of 25% by weight, methyl methacrylate, 65% by weight methyl acrylate and 10% by weight methacrylic acid. EUDRAGIT® FS 30 D is a dispersion containing 30% by weight EUDRAGIT® FS.

The copolymers are obtained in a manner known per se by radical substance, solution, bead or emulsion polymerization. Before processing, they have to be brought into the particle size range according to the invention by suitable grinding, drying or spraying processes. This can be done by simply breaking extruded and cooled granulate strands or by hot cutting.

The use of powders can be particularly advantageous when mixed with other powders or liquids. Suitable devices for the production of the powder are known to the person skilled in the art, e.g. B. air jet mills, pin mills, fan mills. If necessary, appropriate screening steps can be included. A suitable grinder for industrial large quantities is Example a counter jet mill (Multi No. 4200), which is operated with approx. 6 bar overpressure.

The film-forming polymers are each in the form of a solution or aqueous disperse system which allows film formation under the usual conditions of pharmaceutical coating processes.

Other commercially available anionic polymers:

Cellulose glycolate (Duodcell®)

Cellulose acetate phthalate (CAP, Cellulosi acetas, PhEur, Cellulose acetate phthalate, NF, Aquateric®)

Cellulose Acetate Succinate (CAS)

Cellulose acetate trimeliate (CAT)

Hydroxypropyl methyl cellulose phthalate (HPMCP, HP 50. HP 55)

Polyvinyl acetate phthalate (PVAP)

Vinyl acetate-vinyl pyrolidone copolymer (PVAc, Kollidon® VA64)

substrates

The substrates for pharmaceutical applications can be active substance crystals, active substance-containing cores, granules, tablets, pellets or capsules. These can be 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 e.g. B. from gelatin, starch or cellulose derivatives.

The substrates can contain a biologically active substance (active ingredient) up to 95% and further pharmaceutical auxiliaries up to 99.9% by weight. Usual manufacturing processes are direct pressing, pressing of dry, moist or sinter granules, extrusion and subsequent rounding, moist or dry granulation or direct pelleting (e.g. on plates) or by binding powders (powder layering) to active substance-free balls (nonpareilles) or active substance-containing ones particles.

In addition to the active ingredient, other pharmaceutical excipients may be included, such as. B. binders such as cellulose and its derivatives, polyvinylpyrrolidone (PVP), humectants, disintegrators, lubricants, disintegrants, (meth) acrylates, starch and their derivatives, sugar solubilizers or others.

sprayer

Those with two or more two-substance nozzles or one or more three-substance nozzles can be used or used as the spray device.

In the case of a two-substance nozzle or a three-substance nozzle, one of the nozzle openings for compressed air is used to atomize the simultaneously sprayed liquid. The further or the two further spray nozzles serve to eject the respective film-forming coating agent. To carry out the process, therefore, either at least two two-substance nozzles are required, one spraying the first film-forming coating agent and the liquid with the other substance, or a three-substance nozzle spraying both at the same time.

The flow rates of the sprayed liquids can be adjusted independently of one another by setting parameters such as. B. the Influence pump performance or spray pressure and / or air flow rates. In principle, the settings of the spray devices can be made manually during the spraying process. In order to obtain reproducible results, it is preferred to influence the delivery quantities of the sprayed liquids by means of defined programs, e.g. B. to control or regulate electronically.

Examples of commercially available spray devices are e.g. B. the spray gun Pilot SIL XII, (two-substance nozzle; manufacturer: Walther, Wuppertal, Germany), the model "Concentric Dual-Feed Nozzle" (three-substance nozzle, manufacturer: ShinEtsu, Japan) or model 946-S15 (three-substance nozzle, Manufacturer: Düsen Schlick GmbH, D-96253 Untersiemau, Germany).

spraying

The spray application is carried out by means of one or more spray devices which, individually or together, have at least two separate nozzles for liquids and overlap their spray jets.

The two film-forming coating agents are initially separated from one another as sprayable dispersions and are simultaneously sprayed in such a way that the incompatible individual portions mix when sprayed, hit the substrate and then form a uniform film coating after the water contained has evaporated.

The spray solutions are fed to the nozzles through hoses using pumps that generate low shear forces. Peristaltic pumps are preferred. In order to ensure a good mixture, the simultaneous spraying is preferably carried out at a respective spray pressure in the range from 0.8 to 1.5 bar.

The film-forming coating compositions are preferably used in a mixing ratio of 9 to 1 to 1 to 9, based on the total polymer mass of the film coating.

The spray application can e.g. B. in a drum coater, a coating pan, a fluidized bed device or a spray classifier.

The spray application can be carried out by means of hand-operated spray devices. However, better and more reproducible results are usually achieved by means of permanently installed spray devices, so that these are preferred.

equipment

Drum coaters, coating pans, fluidized bed devices or spray classifiers containing one or more, in particular permanently installed, three-substance nozzles as the spray device are particularly preferred for carrying out the method.

Coated drug form or coated food supplement

In particular, coated pharmaceutical forms or parts of pharmaceutical forms or dietary supplements or parts thereof can be produced or obtained by means of the method according to the invention. The sprayed individual portions are mixed with one another in fractions of a second during the spray application and form a polymer matrix on the practically simultaneous evaporation of the water Surface of the substrates. The molecular matrix structure obtained is therefore likely to be different from a matrix structure which is formed when both film-forming coating agents are already contained in a polymer dispersion before spraying. Despite this difference, the quality of the coating, e.g. B. gloss or uniformity, no impairments compared to conventional methods found, but get new, different properties from the starting polymers. It is surprising that sustained-release forms which release pH independently and have partially sigmoid release profiles are obtained.

The amount of polymer applied depends on the shape and size of the substrate. A complete coating is generally necessary for reliable release control. This amount of polymer is above 1% by weight for tablets and above 5% by weight for granules, powders or pellets, in each case based on the uncoated substrate.

The air pressure generating the spray mist is between 0.5 and 3 bar, preferably between 1 and 2 bar. Only in rare cases where the viscosity of one or both spray liquids is significantly higher than that of water may it be necessary to further increase the spray pressure.

The spraying speed of the two individual components can be different and depends heavily on the batch size, the individual recipe and the drying capacity of the device used, which is determined by the air throughput. As a rule, the sum of the spraying rates of the two liquids is 1 to 15 g / kg cores x min, preferably 5 to 10 g / kg cores x min). The product temperature to be maintained during spraying depends on the formulation of the individual components used and the properties of the film former determined as a result. 15 to 50 ° C., preferably 20 to 40 ° C., particularly preferably 25 to 35 ° C. are used as guide values.

If necessary, a quick-releasing initial dose can also be applied. The active ingredient is embedded in a water-soluble binder.

The dosage form can a drug from the class analgesics, antiallergics, antiarrhythmics, antibiotics, chemotherapeutics, antidiabetics, antidotes, antiepileptics, antihypertensives, antihypotensives, anticoagulants, antifungal, anti-inflammatory drugs, beta-blockers, calcium antagonists and ACE inhibitors, bronchodilators / anti-asthmatics, cholinergics, corticoids ( interna), diuretics, enzyme inhibitors, enzyme preparations and transport proteins, expectorants, geriatrics, gout remedies, flu remedies, hormones and their inhibitors, hypnotics / sedatives, cardiac, lipid-lowering drugs, parathyroid hormones / calcium metabolism regulators, psychopharmaceuticals, sex hormones and their inhibitors, spasmolytics, sympatholytic, sympathomimetics, vitamins , Wound treatment agents, cytostatics, nucleic acids, proteins or peptides.

Common drugs are available in reference books, e.g. can be found in the Red List or the Merck Index.

Biologically active substances:

The medicinal substances used in the sense of the invention are intended to be used on or in the human or animal body in order to 1. heal, alleviate, prevent or recognize diseases, ailments, physical damage or pathological complaints. 2. reveal the nature, state or functions of the body or mental states.

3. to replace active substances or body fluids produced by the human or animal body.

4. To ward off, eliminate or render pathogens, parasites or foreign substances foreign, or

5. to influence the nature, the condition or the functions of the body or mental states.

The formulation according to the invention is suitable for the administration of any pharmaceutical active substances or biologically active substances which can preferably be administered in a delayed form.

These pharmaceutically active substances can belong to one or more classes of active substance, such as ACE inhibitors, adrenergics, adrenocorticosteroids, acne therapeutics, aldose reductase inhibitors, aldosterone antagonists, alpha-glucosidase inhibitors, alpha-1 antagonists, agents for alcohol abuse, amino acids, amoebicides, anabolic steroids , analeptics, anesthetic additions, anesthetics (non-inhalational), anesthetics (local), analgesics, androgens, angina therapeutic agents, antagonists, antiallergics, antiallergics such as PDE inhibitors, antiallergics for asthma treatment, further antiallergics (for example leukotriene antagonists antianaemic, antiandrogens Antianxiolytika, Antiarthritic, antiarrhythmic, antiatheriosclerotic, antibiotic, anticholinergic, anticonvulsant, antidepressant, antidiabetic, antidiarrheal, antidiuretic, antidote, antiemetic, antiepileptic, antifibrinolytic, antiepileptic, antihypertensive, antihypertensive, antihypertensive, antihypertensive, antihypertensive, antihypotensic, antihypertensive, antihypotensive gulants, antifungals, anti-oestrogens, anti-oestrogens (non-steroids), anti-Parkinson agents, anti-inflammatory drugs, anti-proliferative agents, anti-protozoal agents, Antirheumatics, Antischistosomizide, Antispasmolytika, antithrombotics, antitussives, appetite suppressants, arteriosclerosis, bacteriostats, Betabiocker, beta-receptor blockers, bronchodilators, carbonic anhydrase inhibitors, chemotherapeutic agents, choleretics, cholinergics, cholinergic agonists, cholinesterase inhibitors, agents for treating ulcerative colitis, diuretics, ectoparasiticides, Emetics, enzymes, enzyme inhibitors, enzyme inhibitors, active substances against vomiting, fibrinolytics, fungistatics, gout agents, glaucoma therapeutics, glucocorticoids, glucocorticosteroids, hemostats, cardiac glycosides, histamine H2-antagonists, hormones and their inhibitors, cardiostatic agents, cardiostatic agents, immunotherapy agents, immunotherapy agents, immunotherapy agents, immunotherapy agents, immunotherapy agents, immunotherapy agents, immunotherapy drugs Gastrointestinal therapeutics, malaria therapeutics, migraine drugs, microbicides, Crohn's disease, metastasis inhibitors, migraine drugs, mineral supplements, motility-increasing agents, muscle relaxants, neuroleptics, agents for the treatment of estrogens, osteoporosis, otologi n / a, Parkinson drugs, phytopharmaceuticals, proton pump inhibitors, prostaglandins, active substances for the treatment of benign prostatic hyperblasia, active substances for the treatment of pruritus, psoriasis active substances, psychopharmaceuticals, radical scavengers, renin antagonists, thyroid therapies, active substances for the treatment of seborrhea, active substances against seolytic drugs, anti-seismic agents, anti-seismic agents and beta sympatomimetics, platelet aggregation inhibitors, tranquilizers, ulcer therapies, other ulcer therapies, agents for the treatment of urolithiasis, antivirals, antivirals, vitamins, cytokines, active substances for combination therapy with cytostatics, cytostatics.

Examples of suitable active ingredients are acarbose, acetylsalicylic acid, aclarubicin, acyclovir, cisplatin, actinomycin, adenosylmethionine, adrenaline and adrenaline derivatives, alemtuzumab, allopurinol, almotriptan, alosetron, amprostadil, amantadine, ambroxol, amiodinylinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxin, Anastrozole, androgen and Androgen derivatives, atenolol, atorvastatin, azathioprine, azelaic acid, barbituric acid derivatives, balsalazide, beclomethasone, benzodiazepines, betahistine, bezafibrate, bicalutamide, bimatoprost, budesonide, bufexamac, buprenorphine, calcium pentagonin, carbinate, carbinate, carbinate, carbinate, carbinate, chirinate Cefadroxil, cefalosporine, cefditoren, cefprozil, celetoxib, cetirizine, chenodeoxycholic acid, ciclosporin, cimetidine, clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidine, codeine, caffeine, colestyramine, comotrimidoin, comeine, cyclomimidoxin, comeine Cytarabine, Dapiprazole, Desipramine, Desogestrel, Desonide, Disoproxil, Diazepam and Diazepam Derivatives, Dihydralazine, Diltiazem, Dimenhydrinate, Dimethylsulfoxide, Dimeticon, Dipyridarnoi, Domperidon and Domperidane Derivatives, Donepzil, Dopacodinolone, Doxaminconinolone, Doxaminopinolone, Doxaminosolonidone, Doxaminosolonidone, Doxaminopinolone, Doxaminosinolone, Doxaminosinolone, Doxaminosolone Done, Doxaminosolone Done, Doxaminosolone Done, Doxaminosolone Done, Doxaminosolone Done, Doxamino Done, Doxaminosolone Done, Doxaminosinone Done, Doxamino Done, Doxamino Done, Doxaminosinone Done, Doxaminosinone Done, Done Done, Done, emtricitabine , Enalapril, ephedrine, epinephrine, epoetin and epoetin derivatives, eprosartan, esomeprazole, estrogens and estrogen derivatives, ethenzamide, ethinoestradiol, etofenamate, etofibrate, etofylline, etonorgestrel, etoposide, famciclovir, fipinolone fodomolinol , Flunarizine, Fluorouracil, Fluoxetine, Flurbiprofen, Flupirtin, Flutamide, Fluvastatin, Follitropin, Formoterol, Fosfomicin, Frovatriptan, Furosemide, Fusidic Acid, Galantamine, Gallopamil, Ganciclovir, Gemfibrozil, Gentamicin, Glucidoclucine, Glucoglucone, Glucogenucone, Gestagenucin, and Gestaginclucentin , Glucosamine and glucosamine derivatives, glycoside antibiotics, urea derivatives as oral antidiabetics, glutathione, glycerol and glycerol derivatives, hypothalamic hormones, goserelin, gyrase inhibitors, guanethidine, gyrase inhibitors, halofantrine, haloperidol, heparin and hydrochloride hydrazide and hydrochloride derivatives, hydrochloride and hydrochloride derivatives ydroxyomeprazole, hydroxyzine, ibuprofen, idarubicin, ifosfamide, imatinib, imipramine, indomethacin, indoramine, insulin, Interferons, irinotecan, isoconazole, isoprenaline, itraconazole, Ivabradine, iodine and iodine derivatives, St. John's wort, potassium salts, ketoconazole, ketoprofen, ketotifen, lacidipine, lansoprazole, letrozole, levodopa, levomethadone, lipoic acid and lipoic acid derivatives, lisinopril, lisuride, lofepramine, lomustine, loperamide, loratadine, magnesium salts, macrolide antibiotics, maprotiline, mebendazole, mebeverine, meclozine, mefenamic acid, mefloquine, meloxicam, mepindolol, Meprobamat.Meropenem, mesalazine, mesuximide, metamizole, metformin, methadone, methotrexate, methylnaloxone, Methylnaltrexone, methylphenidate, methylprednisolone, metixen, metoclopramide, Metoprolol, metronidazole, mianserin, miconazole, minocycline, minoxidil, misoprostol, mitomycin, mizolastine, modafinil, moexipril, morphinans, morphine and morphine derivatives, mother comalkaloids, nalbuphin, naloxone, naproxen, niccamexinidininatin, nataminopheninatin, nincotinostatin, nataminophenin, nincotinostatin, nataminophen Niflumic acid, nimodipine, nimorazole, nimustine, nesiritide, nisoldip in, norfloxacin, novaminsulfone, noscapin, nystatin, ofloxacin, olanzapine, olsalazine, omeprazole, omoconazole, ondansetron, orlistat, oseltamivir, oxaceprol, oxacillin, oxiconazole, oxymetazoline, pantoprazole, paracetamoline, paracetamoline , Pentoxifylline, peptide antibiotics, perindopril, perphenazine, pethidine, plant extracts, phenazone, pheniramine, phenytoin, phenothiazine, phenylbutazone, phenytoin, pimozide, pindolol, piperazine, piracetam, pirenzepine, piribedil, piroxicam, pramipin, pramipin, pramipin, pramipin, pramipin, pramipin , Propranolol, propyphenazone, prostaglandins, protionamide, proxyphylline, quetiapine, quinapril, quinaprilat, ramipril, ranitidine, ranolazine, reproterol, reserpine, ribavirin, rifampicin, riluzole, risedronate, risperidon, ritonavinoxinoxinolitone, ritonavinoxinoxinolitone, ritonavinoxinoxinolitone, ritonavinoxinoxin, ritonavinoxin, ritonavinoxin, ritonavinoxin, ritonavinoxin, ritonavin oxin , Rutoside and rutoside derivatives, Sabadilla, salbutamol, salicylates, salmeterol, thyroid g ormone, scopolamine, selegiline, sertaconazole, sertindol, sertralion, sildenafil, silicates, simvastatin, sitosterol, sotalol, Spaglumic acid, sparfloxacin, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptomycin, sucralfate, sufentanil, sulbactam, sulfonamides, sulfasalazine, sulpirid, sultamicillin, sultiam, sumatriptan, suxamethonium tolacolacl tilacolacolacl, tamaclazolamazolafin, tamolacid, tamaclazolafin, tamolacid, tamolacid, tamolacid, tamacolacid, tamacolacid, tamacolacid, tamacolacid Tegaserod, temazepam, teniposide, tenofovir, tenoxicam, terazosin, terbinafine, terbutaline, terfenadine, terlipressin, tertatolol, testosterone and testosterone derivatives, tetracyclines, tetryzoline, theobromine, theophylline, theophylline derivatives, trazolidione, trazolidione, trazolidine, trazolidine, trypsolidine, trypsolidine, trypsolidine, trypsolidine, trypsolidine, trypsolidine, trypsolidine, trypsolidine, trypolizine tilidine, timolol, tinidazole, tioconazole, thioguanine, tioxolone, tiropramide, tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate, tolperisone, topiramate, topotecan, torasemide, tramadol, tramazoline, trandolapril, tranylcypromine, trapidil, trazodone, triamcinolone and Triamcinolonderivate, triamterene , Trifluperidol, trifluridine, trimetazidine, trimethoprim, trimipram in, tripelennamine, triprolidine, trifosfamide, tromantadine, trometamol, tropalpin, troxerutin, tulobuterol, tyramine, tyrothricin, urapidil, ursodeoxycholic acid, theophylline ursodeoxycholic acid, valaciclovir, valdecoxib, valganprocinolidolamylvilvil, valganicinicidolafin, valganicicidolafin, valecinicidolafin, valecinicidolafin , viloxazine, vinblastine, vincamine, vincristine, vindesine, vinorelbine, vinpocetine, Viquidil, vitamin D and derivatives of vitamin D, warfarin, xanthinol nicotinate, xipamide, zafirlukast, zalcitabine, zanamivir, zidovudine, ziprasidone, zoledronic acid, zolmitriptan, zolpidem, Zoplicon, zotepine and the same.

If desired, 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. If desired, the compositions according to the invention can also contain two or more active pharmaceutical ingredients. It is preferably a multiparticulate dosage form for. B. in the form of capsules, sachets, dry juices or disintegrating tablets.

Pharmaceutical excipients

Based on the dry mass of the mixture, the film-forming coating compositions should contain no or no more than 20% by weight of a plasticizer and no or no more than 5% by weight of a nonionic emulsifier.

Plasticizers: Suitable plasticizers generally have a molecular weight between 100 and 20,000 and contain one or more hydrophilic groups in the molecule, e.g. B. hydroxyl, ester or amino groups. Citrates, phthalates, sebacates, castor oil are suitable. Examples of suitable plasticizers are alkyl citrate, propylene glycol, glycerol ester, alkyl phthalate, alkyl sebacate, sucrose ester, sorbitan ester, diethyl sebacate, dibutyl sebacate and polyethylene glycols 4,000 to 20,000. Preferred plasticizers are tributyl citrate, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate and diethyl sebacate. Usual amounts are between 1 and 20, preferably 2 to 10 wt .-%, based on the (meth) acrylate copolymer.

emulsifiers

If emulsifiers are contained in the coating agents, they should be toxicologically safe. In principle, nonionic emulsifiers are preferred for pharmaceuticals. Suitable emulsifier classes are ethoxylated fatty acid esters or ethers, ethoxylated sorbitan ethers, ethoxylated alkylphenols, glycerol or sugar esters or wax derivatives

Suitable emulsifiers are, for example, polyoxyethylene glycerol monolaurate, polyoxyethylene glycerol monostearate, polyoxyethylene 25-cetyl stearate, polyoxyethylene (25) oxypropylene monostearate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 16-tert.-octylphenol, polyoxyethylene-20-methylene glycol, ethoxylated ethoxylate (1000) methylene glycol, ethoxylated ethoxylated ethoxylated ether , Polyoxyethylene sorbitol wool wax derivatives, polyoxyethylene (25) propylene glycol stearate, polyoxyethylene sorbitol ester polyoxyethylene 25 cetyl stearate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 16 tert-octylphenol and polyoxyethylene 20 cetyl ether.

Drying agents (non-stick agents): Drying agents have the following properties: they have large specific surfaces, are chemically inert, are easy to pour and have fine particles. Because of these properties, they can advantageously be distributed homogeneously in melts and reduce the stickiness of polymers which contain highly polar comonomers as functional groups.

Examples of drying agents are:

Aluminum oxide, magnesium oxide, kaolin, talc, silica (Aerosile),

Barium sulfate, carbon black and cellulose. Release agent (mold release agent)

Examples of release agents are:

Esters of fatty acids or fatty acid amides, aliphatic, long-chain carboxylic acids, fatty alcohols and their esters, montan or paraffin waxes and metal soaps, particularly mentionable are glycerol monostearate, stearyl alcohol, glycerol behenic acid esters, cetyl alcohol, palmitic acid, cannula wax, beeswax etc.

Other auxiliaries: B to name stabilizers, dyes, antioxidants, wetting agents, pigments, glossing agents etc. They primarily serve as processing aids and are intended to ensure a safe and reproducible manufacturing process and good long-term storage stability. Further pharmaceutically customary auxiliaries can be present in amounts of 0.001% by weight to 30% by weight, preferably 0.1 to 10% by weight, based on the copolymer.

Preferred active ingredients are:

Morphine and its derivatives: tramadol, acetyisalicylic acid, diclofenac, indomethacin, lonazolac, ibuprofen, ketoprofen, propyphenazone, naproxen, paracetamol, flurbiprofen, dimetindene, quinidine, metoprolol, propranolol, oxprenolol, polololololololololololololololololololololololololololololololololpolol , nifedipine, nicardipine, nisoldipine, nimodipine, amlodipine, theophylline, salbutamol, terbutaline, ambroxol, aminophylline, choline, pyridostigmine, piretanide, furosemide, pentoxifylline, naftidrofuryl, buflomedil, xanthinol nicotinate, bencyclane, allopurinol, norephedrine, Clorphenamin isosorbide mononitrate, isosorbide dinitrate, nitroglycerin, Molsidomine, bezafibrate, fenofibrate, gemfibrozil, cerivastatin, pravastatin, fluvastatin, lovastatin, atorvastatin, simvastatin, xantinol, metoclopramide, amitriptyline, dibenzepine, Venlafaxine, thioridazine, oxazepam, lithium, nitrofurantoin, dry plant extract, ascorbic acid and potassium and their pharmaceutically used salts.

EXAMPLES

Example 1:

1.1 Production of the cationic spray suspension (first film-forming

Coating agent):

114.0 g of EUDRAGIT ^® E PO (copolymer of methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate in a ratio of 25: 25: 50 with a mean particle size of 15 μ), 8.0 g sodium lauryl sulfate, 17.1 g of dibutyl sebacate, 693.2 g of water and magnesium stearate 34.2 g are converted into a polymer dispersion by simple stirring at room temperature.

Preparation of the anionic spray dispersion (second film-forming coating agent):

114.0 g of talc are dispersed in 836.0 g of water with a homogenizer (Ultra Turrax) and in 760.0 g of EUDRAGIT ^® L 30 D-55 (copolymer of 50% by weight ethyl acrylate and 50% by weight methacrylic acid) stirred.

With the help of a three-component nozzle, e.g. Walther Pilot SIL XII, in which the EUDRAGIT ^® E PO dispersion and the EUDRAGIT ^® L 30 D55 dispersion (suspension) are fed separately and mixed immediately after the nozzle exit, in a conventional coating pan, at a Tablet bed temperature of about 30-45 ° C ° C, the recipe described above can be sprayed onto a 3 kg tablet (diameter 10 mm) within 170 min with a spray pressure of approx. 1.2 bar to form a homogeneous film. After drying for 15 minutes, you get smooth and shiny. Films that do not dissolve in water. Example 2:

Production of the cationic spray suspension (first film-forming

Coating agent):

114.0 g EUDRAGIT ^® E PO, 1, 14 g sodium lauryl sulfate, 17.1 g dibutyl sebacate,

651.8 g of water and magnesium stearate 34.2 g are made by simple

Stirring at room temperature converted into a polymer dispersion.

Preparation of the anionic spray dispersion:

57.0 g talc and 17.1 g triethyl citrate are dissolved in 486.4 g water

Homogenizer (Ultra Turrax) dispersed and stirred into 380.0 g EUDRAGIT ^® L 30 D-55.

With the help of a three - component nozzle, e.g. Walther Pilot SIL XII, in which the EUDRAGIT ^® E PO dispersion and the EUDRAGIT ^® L 30 D55 suspension are added separately and mixed immediately after the nozzle exit, it can be used in a conventional coating pan at a tablet bed temperature of approx 33- 41 ° C. the recipe described above is sprayed onto a 3 kg tablet (diameter 10 mm) with a spray pressure of approx. 1.2 bar within 117 min to form a homogeneous film. After drying for 15 minutes, smooth and shiny films are obtained which do not dissolve in water

Example 3 (exemption tests for tablets from example 1):

In a paddle apparatus with 700 ml of 0.1 N hydrochloric acid, 37 ° C. and 100 rpm, an approximately 300 mg coated quinidine sulfate tablet with 5% active ingredient content is placed and the active ingredient is released in this medium for 2 hours after 10, 20 , 30, 60, 90 and 120 min tested via a photometric absorption at the wavelength 250.0 nm. After 120 min in 0.1 N HCI is adjusted to pH 6.8 with 200 ml of 0.2 N Na P0 ₄ . Now the release examination is also carried out via the photometric determination, at the wavelength 234 nm after 135, 150, 180, 210, 240, 300 and 360 min. The mixture is then homogenized and the total active ingredient concentration is standardized to this value as a 100% value.

50 100 150 200 250 300 350 400

Release time [min]

Diagram 1: Release of quinidine sulfate tablets,

2 hours in 0.1 N HCl and 4 hours in pH 6.8

Curve with diamonds: uncoated tablets, curve with squares: 2.6 mg / cm ² polymer from EUDRAGIT® L 30 D-55 and 1.3 mg polymer from EUDRAGIT® E PO Curve with triangles: 5.3 mg / cm ² polymer from EUDRAGIT L 30 D-55 and 2.6 mg polymer from EUDRAGIT® E PO Curve with circles: 8.0 mg / cm ² polymer from EUDRAGIT® L 30 D-55 and 4.0 mg polymer from EUDRAGIT® E PO

Example 4 (Release studies of tablets from Example 2: in a paddle apparatus with 700 ml of 0.1 N hydrochloric acid, 37 ° C. and 100 rpm, an approximately 300 mg coated quinidine sulfate tablet with 5% active ingredient content is added and over 2 The active substance release after 10, 20, 30, 60, 90 and 120 min in this medium was tested via photometric absorption at a wavelength of 250.0 nm, after 120 min in 0.1N HCl with 200 ml of 0.2 N Na ₃ P0 _{4 is set} to pH 6.8 Now the release test is also carried out by means of photometric determination, at the wavelength 234.0 nm after 135, 150, 180, 210, 240, 300 and 360 minutes, followed by homogenization and the total concentration of active substance normalized this value as a 100% value.

50 100 150 200 250 300 350 400

Release time [min] Diagram 2 Release of quinidine sulfate tablets,

2 hours in 0.1 N HCl and 4 hours in pH 6.8

Curve with diamonds: uncoated tablets,

Square: 2.0 mg / cm ² polymer from EUDRAGIT® L30 D-55 and 2.0 mg polymer from EUDRAGIT® E PO

Triangles: 4.0 mg / c ² polymer from EUDRAGIT® L 30 D-55 and 4.0 mg polymer from EUDRAGIT® E PO

Example 5:

A film-forming dispersion (cationic polymer dispersion) is prepared from 114.0 g of EUDRAGIT ^® E PO, 1.14 g of sodium lauryl sulfate and 651.8 g of water by stirring at room temperature. A fine-particle suspension is prepared from 17.1 g of triethyl citrate, 57.0 g of talc and 486.4 g of water at room temperature using a homogenizer (Ultra Turrax), added to 380.0 g of EUDRAGIT ^® L 30 D 55 and mixed by simple stirring (anionic polymer dispersion). Both liquids are fed and atomized via separate hose pumps to the nozzle heads of a multi-component nozzle (e.g. Walther Pilot SIL XII) so that the mist of the dispersions mix immediately after the nozzle exit. The coating process is carried out on 3 kg placebo tablets (diameter 10 mm) in a conventional Pouring kettle (35 cm diameter) was carried out while supplying warm air. The tablet bed temperature was kept at approximately 33-41 ° C. The spray pressure of both heads was set to approximately 1.2 bar. The spraying process lasted approximately 117 minutes After 15 minutes, you get smooth, glossy pigmented films that do not dissolve in water. Example 6 (comparative example):

A film-forming dispersion is produced from 114.0 g EUDRAGIT ^® E PO, 1.14 g sodium lauryl sulfate and 651.8 g water by stirring at room temperature (cationic polymer dispersion).

17.1 g of triethyl citrate, 57.0 g of talc and 486.4 g of water become

Room temperature using a homogenizer (Ultra Turrax) a finely divided

Suspension prepared, added to 380.0 g EUDRAGIT ^® L 30 D 55 and mixed by simple stirring (anionic polymer dispersion).

Both suspensions are fed from separate vessels via peristaltic pumps to a modified two-substance spray gun NBA 1 (Walther Trowal) so that the mixing of the two suspensions within the

Spray gun, i.e. shortly before the spray nozzle. The spray application cannot take place due to the formation of coagulum in the spray gun.

Claims

1. Process for the production of pharmaceutical forms or parts of pharmaceutical forms or food supplements or parts thereof,

wherein the first film-forming coating agent is a (meth) acrylate copolymer of 30 to 80 wt .-% radical-polymerized Cr to C ₄ alkyl esters of acrylic or methacrylic acid and 70 to 20 wt .-% (meth) acrylate monomers with a is tertiary amino group in the alkyl radical,

and the second film-forming coating agent is a polymer with anionic groups,

characterized in that

the film-forming coating compositions are initially separated from one another as liquid, sprayable solutions or dispersions and by spray application by means of one or more spray devices which individually or together atomize liquids separately and overlap their spray jets,

2. The method according to claim 1, characterized in that the substrates are active substance crystals, active substance-containing cores, cores coated with an active substance-containing binder, tablets, granules, pellets or capsules.

3. The method according to claim 1 or 2, characterized in that the first film-forming coating agent is a copolymer of 25 wt .-% methyl methacrylate, 25 wt .-% butyl methacrylate and 50 wt .-% dimethylaminoethyl methacrylate.

4. The method according to one or more of claims 1 to 3, characterized in that the second film-forming coating agent is a polymer with anionic groups, which is a cellulose derivative, a polyvinyl acetate derivative or a (meth) acrylate copolymer.

5. The method according to one or more of claims 1 to 4, characterized in that the film-forming coating agents are present in a mixing ratio of 9 to 1 to 1 to 9 based on the total polymer content of the film coating.

6. The method according to claim 1 or 5, characterized in that two or more two-substance nozzles or one or more three-substance nozzles are used as the spray device.

7. The method according to one or more of claims 1 to 6, characterized in that the spray application takes place in a drum coater, a coating pan, a fluidized bed device or a spray classifier.

8. The method according to claim 7, characterized in that the spray application is carried out by means of permanently installed spray devices.

9. dosage form, parts of dosage forms, food supplements or parts thereof, producible by a method according to or more of claims 1 to 8.

0. Dosage form or parts of dosage forms according to claim 9, characterized in that an active ingredient from the class analgesics, antiallergics, antiarrhythmics, antibiotics, chemotherapeutics, antidiabetics, antidotes, antiepileptics, antihypertensives, antihypotonic agents, anticoagulants, antifungal agents, antiphlogistic agents, calcium antagonists, beta-receptors ACE inhibitors, broncholytics / anti-asthmatics, cholinergics, corticoids (internals), diuretics, enzyme inhibitors, enzyme preparations and transport proteins, expectorants, geriatrics, gout agents, flu agents, hormones and their inhibitors, hypnotics / sedatives, cardiac drugs, anti-hormones, lipid stimulant drugs, anti-cardiac drugs, anti-lipid drugs, anti-cardiac drugs, anti-lipid drugs, anti-cardiac drugs, anti-lipid drugs, anti-cardiac drugs, anti-lipid drugs, anti-cardiac drugs, anti-cardiac drugs, anti-cardiac drugs, anti-cardiac drugs, anti-lipid drugs, anti-cardiac drugs, anti-cardiac drugs, anti-hormones, drugs Sex hormones and their inhibitors, antispasmodics, sympatholytics, sympathomimetics, vitamins, wound treatment agents, cytostatics, nucleic acids, proteins or peptides are contained.

11. dosage form or parts of dosage forms according to claim 9 or 10, characterized in that it is multiparticulate dosage forms.

12. drum coater, coating pan, fluidized bed device or spray classifier, suitable for carrying out a method according to one or more of claims 1 to 8, containing one or more three-component nozzles as a spraying device

13. Use of one or more spray devices for carrying out a method according to one or more of claims 1 to 8.