MXPA06005199A - Multilayer dosage form comprising a matrix that influences release of a modulatory substance - Google Patents

Abstract

The invention relates to a multilayer dosage form for the controlled release of active substances, which substantially comprises a) optionally a neutral core (nonpareilles), b) an inner control layer, comprising a modulatory effective substance that is embedded in a matrix that influences release of a modulatory substance, said matrix comprising pharmaceutically acceptable polymers, waxes, resins and/or proteins and optionally an active substance, c) an active substance layer, comprising a pharmaceutically active substance and optionally a modulatory effective substance, d) an outer control layer, comprising at least 60%by weight of one or more mixtures from a plurality of (meth)acrylate copolymers, 98 to 85 C1 to C4 alkyl esters of the (meth)acrylic acid and 2 to 15%by weight of methacrylate monomers with a quaternary ammonium group in the alkyl group, and optionally up to 40%by weight of additional pharmaceutically acceptable polymers. The dosage form is further characterized in that the layers additionally contain, in a manner known per se, pharmaceutically common adjuvants.

Description

Multiple Layer Pharmaceutical Forms with a Matrix that Influences the Administration of a Modulating Substance The invention relates to a multi-layered dosage form with a matrix that influences the release of a modulating substance. Prior Technology EP-A-0 463 877 discloses pharmaceutical compositions with delayed release of the active ingredient consisting of a core with a pharmaceutical active ingredient as a layer coating film comprising a water-repellent salt and a water insoluble copolymer of ethyl acrylate, methyl methacrylate, and trimethyl ammonium ethyl methacrylate chloride. The water repellent salt can be, for example, Ca stearate or Mg stearate. Sigmoidal release plots were obtained. EP-A 0 225 085, EP-A 0 122 077 and EP-A 0- 123 470 describe the use of an organic acid in drug cores that are provided with various coatings of organic solutions. Resulting essentially sigmoidal release characteristics. EP-A 0 436 370 discloses pharmaceutical compositions with delayed release of the active ingredient of a core with an active pharmaceutical ingredient and an organic acid and an outer coating film which has been applied through aqueous spray and is an ethyl acrylate copolymer , methyl and ethyl methacrylate of trimethylammonium. In this case, the sigmoidal release charts are obtained in the same way. WO 00/19984 discloses a pharmaceutical preparation consisting of (a) a core comprising an active ingredient, where appropriate, a carrier and conventional pharmaceutical additives, and the salt of an organic acid whose proportion by weight of the amounts of core from 2..5 to 97.5 by weight, and (b) an outer coating film consisting of one or more (meth) acrylate copolymers and, where appropriate, conventional pharmaceutical excipients, where 40 to 100% by weight of the (meth) acrylate copolymers consist of 93 to 98% by weight of C_ alkyl esters. C4 polymerized with free radical of acrylic acid or methacrylic acid 7 to 2% by weight of monomers of (meth) acrylate with a group of quaternary ammonium present in a mixture, with 1 to 60% by weight of one or more copolymers of (meth) acrylate of one or more additional (meth) acrylate copolymers which are deferent from the abovementioned (meth) acrylate copolymers and are composed of from 85 to 100% by weight of free radical polymerized C to C4 alkyl esters of acrylic acid or methacrylic acid and, where appropriate, up to 15% by weight of additional (meth) acrylate monomers with basic groups or an acid group in the alkyl radical. WO 00/74655 describes an active ingredient release system with a double release pulse that is administered through a three layer structure. The core comprises an active ingredient and a substance that swells in the presence of water, for example a crosslinked polyacrylic acid. An internal coating consisting of a water-insoluble carrier material, for example, a cationic (meth) acrylate copolymer and comprises a water-soluble particulate material, for example, a pectin, where pore formation can be achieved. An outer coating comprises the same or a different active ingredient. In the gastrointestinal tract there is the initial release of the active ingredient located on the outside, while the active ingredient present in the core is released after a delay time through the pores in the middle layer. The three layer pharmaceutical form can optionally also have an additional coating, for example composed of a (meth) acrylate copolymer containing a carboxyl group. US 5,508,040 describes a pharmaceutical form of 'multiple particles consisting of a large number of granules held together in a binder. The granules have an active ingredient and an osmotically active modulator, for example, NaCl or an organic acid in the nucleus. The cores of the granule are provided with coatings of different thicknesses, for example, compounds of copolymers of (meth) acrylate with quaternary ammonium groups. To reduce permeability, the coatings also comprise hydrophobic substances, for example, fatty acids, in amounts of 25% by weight or greater. The pharmaceutical form of multiple particles is released through the active ingredient contained in a large number of pulses corresponding to the number of granule populations with coatings of different thicknesses. EP 1 064 938 A1 discloses a pharmaceutical form having an active ingredient and a surface active substance (surfactant) in the core. The core may additionally comprise an organic acid and is coated with (meth) acrylate copolymers with quaternary ammonium groups. "Pulsatile" release charts are obtained. The stepped release charts can be obtained by combining the granules with different coatings in a pharmaceutical form. -WO 01/13895 describes two-way release systems for active ingredients that have a hypnotic sedative effect. Release profiles are achieved through mixtures of different granule populations. WO 01/37815 describes multi-layer release systems for a controlled pulsatile release of the active ingredients. In this case, the inner membrane that can be dissolved through the formulation of active ingredient present in the cores is present. An outer membrane that additionally has a pore-forming substance is also present. WO 01/58433 describes the multi-layer release systems for controlled pulsatile release of the active ingredients. In this case, the active ingredient is present in the core and is surrounded by a polymer membrane that is soluble in the intestinal juice. An outer membrane consists of a polymer mixture that is soluble in the intestinal juice with a water-insoluble polymer in defined ranges of amounts. An intermediate layer comprises an organic acid which may be present between the inner and outer membrane. Problem and solution Starting from EP-A 0 436 370 and WO 00/19984, an attempt has been made to develop a form that allows the permeability of film coatings to be influenced through intrinsic modulation of. so that the release profiles with an order of zero, first order, first order with initial accelerated phase, slow-fast, fast-slow profiles can be adjusted individually depending on the active ingredient and the therapeutic requirements. The problem is solved through: A multi-layered dosage form for releasing the controlled active ingredient, which essentially comprises: a) optionally a neutral core (colored tablets), b) an inner control layer comprising a substance having a modulating effect, which is embedded in a matrix that influences the release of the modulating substance and which comprises polymers, waxes, resins and / or proteins that can be used pharmaceutically and where it is correct, an active ingredient. c) A layer of active ingredient comprising an active pharmaceutical ingredient and, where appropriate, a substance having a modulating effect, d) An external control layer comprising at least 60% by weight of one or a mixture of one plurality of (meth) acrylate copolymers composed of 98 to 85 C_ to C4 alkyl esters of (meth) acrylic acid and 2 to 15% by weight of methacrylate monomers with a quaternary ammonium group in the alkyl radical, and where it is correct, up to 40% by weight of additional polymers usable pharmaceutically. Where the layers may additionally and in a manner known per se comprise conventional pharmaceutically excipients. Implementation of the Invention The invention relates to a multi-layered pharmaceutical form for the 'release of a controlled active ingredient comprising essentially a core a) and layers b), c) and d). It is also possible . the addition of customary topcoat layers, which may be, for example, pigmented. Core a) optional A neutral core (colored tablets) may be present. The inner control layer b) The inner control layer comprises a substance having a modulating effect, which is embedded in the matrix influencing the release of the modulating substance and which comprises polymers, waxes, resins and / or pharmaceutically utilizable proteins or which consist of the same, and additionally may comprise, where appropriate, an active ingredient. To aid in the formulation it is possible to further mix customarily pharmaceutically excipients such as, for example, binders such as cellulose and derivatives thereof, plasticizers, polyvinylpyrrolidone (PVP), humectants, disintegration promoters, lubricants, disintegrants, starch and derivatives thereof, sugars and / or solubilizers. Suitable processes for producing the internal control layer b) are direct compression, drying compression, wet or sintered granules, extrusion and subsequent rounding, wet or dry granulation or direct granulation (for example in plates) or, if a core is present a) optional, by agglutinating the powders (powder layer preparation) in the free nuclei of active ingredient (colored tablets). The inner control layer b) influences the release of the substance having a modulating effect and the active ingredient that is present where it is correct from the core layer. The interior control layer consists of polymers, waxes, proteins and / or other customary excipients in the pharmaceutical that are used pharmaceutically. Examples of suitable polymers are the following: Copolymers of methyl methacrylate and / or ethyl acrylate and methacrylic acid, copolymers of methyl methacrylate, methyl acrylate and methacrylic acid, copolymers of methyl methacrylate, butyl methacrylate, and methacrylate of dimethylethyl, copolymers of methyl methacrylate, ethyl acrylate and trimethylaminoethyl methacrylate, copolymers of methyl methacrylate and ethyl acrylate, copolymer of ethyl acrylate, methyl acrylate, butyl methacrylate and methacrylic acid. Polyvinylpyrrolidones (PVP), polyvinyl alcohols, polyvinyl alcohol polyethylene glycol graft copolymer (Kollicoat®), starch and derivatives thereof, polyvinyl acetate phthalate (PVAP, Coateric®), polyvinyl acetate (PVAc, Kollicoat), vinyl acetate / vinylpyrrolidone copolymer (Kollidon® VA64), vinyl acetate: 9: 1 protonic acid copolymer (VAC: CRA, Killicoat® VAC), polyethylene glycols with a molecular weight greater than 1000 (g / mol) and / or lacquer. Celluloses such as, for example, anionic carboxymethyl cellulose and salts thereof (CM, Na-CMC, Ca-CMC, Blanosa, Tilopur), carboxymethylethylcellulose (CMEC, Duodcell®), hydroxyethylcellulose (HEC, Klucel), hydroxypropylcellulose (HPC) , hydroxypropylmethylcellulose (HPMC, Pharacoat, Methocel, Sepifilm, Ciscontran, Opadry), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC, Etocel®, Aquacoat®, Surelease®), methylcellulose (MC, Viscontran, Tilopur, Methocel), cellulose esters, cellulose glycolate, cellulose acetate phthalate (CAP, Cellulosi acetates, PhEur, cellulose acetate phthalate, NF Aquateric®) (, cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), phthalate hydroxypropylmethylcellulose (HPMC, HP50, HP55), hydroxypropyl ethyl cellulose acetate succinate (HPMCAS-LF, -MF, -HF) The inner control layer b) may preferably consist of a polymer or contain one that is insoluble in water or only inflatable in water. The inner control layer may consist of wax such as, for example, carnauba wax and / or beeswax, or comprise the latter. The inner control layer may comprise the resin lacquer or consist of the same. The inner control layer may comprise a protein such as, for example, albumin, gelatin, zein, gluten, collagen, and / or lecithins or consisting of the same. The protein of the inner control layer preferably should not have a therapeutic function, as in the case with protein active ingredients or peptides, so that the technical effect of the active ingredient layer c) on the one hand and on the other hand internal control b), if the latter comprises an active ingredient, on the other does not overlap where possible. Substances having a modulating effect Substances having a modulating effect that are used as steel with the invention can have a molecular weight below 500, be solid and be ionic. The substance having a modulating effect is preferably soluble in water. The substance having a modulating effect can be, for example, an organic acid or a salt of an organic or inorganic acid. The substance having a modulating effect can be, for example, succinic acid, citric acid, tartaric acid, lauryl sulfuric acid, a salt of these acids or a salt of the following anions: taurocholate and other cholates, chlorides, acetates, lactates, phosphates and / or sulfates. Mode of operation of the components with each other The mode of operation of the substance having a modulating effect in the multilayer dosage form can be described approximately as follows: Na succinate, succinic acid, Na and citric acid increase the release rate of the active ingredient. NaCl and Na citrate decrease the release rate of the active ingredient. If layer c) of active ingredient comprises in addition to inner core layer a), a substance having a modulating effect, the release of active ingredient is first determined by the substance having a modulating effect that is present in the layer outside, the active ingredient layer c). If this substance is substantially consumed, the effect of the substance has a modulating effect on the inner layer, the inner control layer b) initiates and determines the further release of the active ingredient. The various release profiles of the active ingredient can be adapted to the active ingredient and the therapeutic objective by combining different amounts of one and / or different substances having a modulating effect in the two layers. There is additionally the effect of the matrix itself which in turn controls by itself the release of the substance that has a modulating effect. The amount of the active ingredient released is essentially controlled by the outer control layer d). If the inner control layer additionally comprises an active ingredient, this layer can be used to adjust the release profile of the active ingredient towards the end of the release of the active ingredient. If the active ingredients by themselves comprise ionic groups or are present in salt form, the active ingredient itself can influence the effect of the substance or substances having a modulating effect so that the latter is decreased or improved. This interaction can be used as an additional control element. Layer c) of active ingredient Layer c) of active ingredient comprises an active pharmaceutical ingredient, and where appropriate, a substance having a modulating effect, which may be identical or different from the substance having a. modulator effect in the core layer. Active Ingredients The multilayer dosage form of the invention is in principle suitable for any active ingredient. The medicinal substances in use can be found in reference works, such as - Rote Liste or Merck Index. The active ingredients or medicinal substances employed for the purposes of the invention have. the intention to be used in the human or animal body in order to: 1. cure, alleviate, avoid or diagnose disorders, ailments, physical damage or pathological symptoms. 2. Reveal the condition, state or functions of the body or mental states. 3. Replace the active substances or body fluids produced by the human or animal body. 4. protect, eliminate or remove without damage pathogens, parasites or exogenous substances, or 5. influence the condition, state or functions of the body or mental states. The pharmaceutically active substances corresponding to one or more of the active ingredient classes such as ACE inhibitors, adrenergic, adrenocorticosteroids, therapeutic agents. acne, aldose reductase inhibitors, aldosterone antagonists, alpha-glucosidase inhibitors, alpha 1 antagonists, remedies for alcohol abuse, amino acids, amibacides, anabolics, analeptics, anaesthetic, anaesthetic (non-inhalatory), anaesthetic (local) additions , analgesics, androgens, angina therapeutic agents, antagonists, anti-allergens, anti-allergens as PDE inhibitors, anti-allergens for the treatment of asthma, additional anti-allergens (for example, leukotriene antagonists, antianemic agents, antiandrogens, anti-anxiety agents, antiarthritics, antiarrhythmics, anti-atherosclerosis, antibiotics, anticholinergics, anticonvulsants, antidepressants, antidiabetics, antidiarrheals, antidiuretics, antidotes, antiemetics, antiepileptics, antifibrolytics, antiepileptics, anthelmintics, antihistamines, antihypertensives, anticoagulants, antifungals, antiestrogens, antiestrogens (non-steroids) , antiparkinson agents, anti-inflammatory agents, antiproliferative active ingredients, active antiprotozoic, antirheumatic, antischistosomicidal, antispasmodic, antithrombocytic, antitussive, appetite suppressants, arteriosclerosis, bacteriostatic, beta-blockers, beta receptor blockers, bronchodilators, carbonic anhydrase inhibitors, agonists cholinergic agents, cholinesterase inhibitors, agents for the treatment of ulcerative colitis, cyclooxygenase inhibitors, diuretics, ectoparaciticides, emetics, enzymes, enzyme inhibitors, active ingredients to counteract vomiting, fibrinolytics, fungistatics, gout remedies, glaucoma therapeutic agents , glucocorticoids, flucocorticosteroids, haemostats, cardiac glycosides, H2 histamine antagonists, hormones and their inhibitors, immunotherapeutic agents, cardiotonics, coccidiostats, laxatives, low-dose agents lipid nutrition, gastrointestinal therapeutic agents, therapeutic agents for malaria, migraine remedies, microbiocides, Crohn's disease, metastasis inhibitors, migraine remedies, mineral preparations, active ingredients that increase motility, muscle relaxants, neuroleptics, active ingredients for the treatment of estrogens, osteoporosis, otological, antiparkinson agents, phytopharmaceuticals, proton pump inhibitors, prostaglandins, active ingredients for the treatment of prostatic hyperplasia, active ingredients for the treatment of pruritus, active ingredients for psoriasis, psychoactive drugs, free radical scavengers, renin antagonists, thyroid therapeutic agents, active ingredients for the treatment of seborrhea, active ingredients to counteract motion sickness , spasmolytics, ala and beta sympathomimetics, platelet aggregation inhibitors, tranquilizers, therapeutic agents for ulcer, additional therapeutic agents for ulcer, agents for the treatment of urolithiasis, virustatics, vitamins, cytokines, active ingredients for combination therapy with cytostatics, cytostatics. Active ingredients Examples of suitable active ingredients are acarbose, acetylsalicylic acid, adacavir, aceclofenac, aclarugicin, acyclovir, actinomycin, adalimumab, adefovir, adefovirdipivoxil, adenosylmethionine, adrenaline and adrenaline derivatives, alpha agalsidase, beta agalsidase, aletuzumab, almotriptan, alfacept, allopurinol , almotriptan, alosetron, alprostadil, amantadite, amboxol, amisulpride, amlodipine, amoxicillin, 5-aminosalicylic acid, amitriptyline, amlodipine, amoxicillin, amprenavir, anakinra, anastrozole, androgen and androgen derivatives, apomorphine, aripiprazole, arsenic trioxide, arremeter, atenolol , atorvastatin, atosiban, azathioprine, acid. azelaic, barbituric acid derivatives, balsalazide, basiliximab, beclapermin, beclomethasone, bimiparin, benzodiazepines, betahistine, ezaroten, bezafibrate, bicalutamide, bimatoprost, besentan, botulinus toxin, brimonidine, brinzolamide, budesonide, budipine, bufezamac, bumetanide, buprenorphine, bupropion, butizine, calcitonin, antagonists of. calcium, calcium salts, candesartan, capecitabine, captopril, carbamazepine, carifenacin, carvedilol, caspofungin, cefaclor, cefadroxil, cefalexin, cephalosporins, cefditoren, cefprozil, celecoxib, cepecitabine, cerivastatima, cetirizine, cetrrelix, cetuximab, chenodeoxycholic acid, chorionic gonadotropin, cyclosporine, cidofovir, cimetidine, ciporloxacin, cisplatin, cladribine, clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidine, clopidogrel, codeine, caffeine, cholestyramine, glycolic acid, cotrimoxazole, comarin, and derivatives of comarin, darbepoetin, cysteamine, cistern, cytarabine , cyclophosphamide, cyproterone, cytarabine, daclizumab, dalfopristin, danaparoid, dipiprazole, darbepoetin, defepripone, desipramine, ddesirudin, desloaratadine, desmopressin, desogestrel, desohida, dexibuprofen, dexketoprofen, disoproxil, diazepam and derivatives of diazepam, dihydralazine, diltiazem, dimenhydrnamate, sulfoxide of dimethyl, dimeticon, dipivoxil, dipi ridarnol, dolasetron, doperidone, and domperidane derivatives, donepzil, dopamine, doxazosin, doxorubizine, doxylamine, diclofenac, dicalproex, dronabinol, drospirenone, drotrecogin alfa, dutasteride, ebastine, econazole, efavirenz, eletripan, emidastine, emtricitabine, enalapril, encepur, entacapone, enfurvirtide, ephedrine, apinephrine, eplerenone, epoetin and epoetin derivatives, eprosartan, eptifibatide, ertapenem, esomeprazole, - estrogen and derivatives of estrogen, etanercept, etenzamide, atinestradiol, etofenamate, etofobrate, etofilin, etonogestrel, etoposide, exemestane, exetimib, famciclovir, famotidine, faropenan, daloxato, felodipine, fenofibrate, fentanyl, fenticonazole, fexofenadine, finasteride, fluconazole, fludarabine, flunarizine, fluorouracil, fluoxetine, flurbiprofen, flupirtine, flutamide, fluvastatin, follitropin, fomivirsen, fondaparinux, formoterol, fosfomycin , frovatripartan, furosemide, fusidic acid, gadobenate, felantamine, falopamil, ganciclovir, ganirelix, gatiflozacin, 'gefitinig,' gemfibrosil, gentamicin, fepirone, progestogen and progestogen derivatives, ginkgo, glatiramer, flibenclamide, glipizide, glucagon, glucitol and glucitol derivatives, glucosamine and glucosamine derivatives , glycoside antibiotics, glutathione, glycerol and glycerol derivatives, hormones of the hypothalamus, goserelin, grepafloxacin, gyrase inhibitors, guanethidine, gyrase inhibitors, hemin, halofantrine, haloperidol, urea derivatives such as oral antidiabetics, heparin, and heparin derivatives , cardiac glycosides, hyaluronic acid, hydralazine, hydrochlorothiazide and derivatives of hydrochlorothiazide, hydroxyomeprazole, hydroxyzine, ibritumonab, ibuprofen, idarubicin, ifliximab, ifosfamide, iloprost, i atinib, imidapril, imiglucerase, imipramine, imiquimod, imidarpil, indomethacin, indoramin, inflixi ab , insulin, insulin glargine, interferons, irbesartan, irinotecan, isoconazole, isoprenaline, itraconazole, ivabradine, iodine and iodine derivatives, John must, potassium salts, ketoconazole, ketoprofen, ketotifen, lacidipine, lansoprazole, laronidase, latanoprost, leflunomide, lepirudin, lercanidipine, leteprim, letrozole, levacetylmethadol, levetiracetam, levocetririzine, levodopa, levodropropicina, levomethadone, licofelone, linezolid, lipinavir, lipoic acid and lepromatous acid derivatives, lisinopril, lisurid, lofepramina, lodoxamide, lomefloxacin, lomustine, loperamid, lopinavir, loratadine, lornoxicam, losartan, lumefantrine, lutropin, magnesium salts, antibiotics macrolides, mangafodipir, maprotiline, mebendazole, mebeverine, meclozine, mefenamic acid, mefloquine, meloxicam, memantine, mapindolol, meprobamate, meropenem, mesalazine, mesuximide, metamizole, metformin, methadone, methotrezate, methyl 5-amino-4-oxopentanoate, methylnaloxone, methylnaloxone, methylnaltrexones, methylphenidate, methylprednisolone, metixen, metoclopramide, metoprolol, m etronidazole, mianserin, mibefradil, miconazole, mifepristone, miglitol, miglustad, minocycline, minoxidil, misoprostol, motomycin, mizolastin, modafinil, moexipril, montelukast, moroctocog, morphine, morphine and morphine derivatives, moxifloxacin, ergot alkaloids, nalbuphine, naloxin, naproxen , naratriptan, narcotin, natamycin, nateglinide, nebivolol, nefazodone, nelfinavir, neostigmine, neramexan, nevirapine, nicergoline, nicotolide, nifedipine, niflumic acid, ninodipine, nimorazol, nimustine, niseritid, nisoldipine, norfloxacin, novamine sulphone, noscapine, nystatin, ofloxacin, oktotrid, olanzapine, olmesartan, olsalazine, oseltamivir, omeprazole, omoconazole, ondansetron, orlistat, oseltamivir, oxaveprol, oxacillin, oxaliplatin, oxaprozin, oxcarbazepine, oxycodone, oxiconazole, oxymetazoline, palivizumab, palanosetron, pantoprazole, paracetamol, parecoxib, paroxetine, pegaspargase, peginterferon, pegfilgrastrim, penciclovir, oral penicillins, pentazocine, pentifillin, pentoxifylline, peptide antibiotics, perindopril, perphenazine, pethidine, plant extracts, phenazone, pheniramine, phenylbutyric acid, phenytoin, phenothiazines, phenserin, phenylbutazone, phenytoin, pimecrolimus, pimozid, pindolol, pioglitazone, piperazine, piracet.am, pironzepine, piribedil, pirlindol, piroxicam, pramipexole, pramlintide, pravatatin, praxosine, procaine, promazine, propiverine, propranolol, propionic acid derivatives, propifenazone, prostaglandins, protionamide, proxifilin, quetiapine, quinapril, quinaprilate, quinupristin, ramipril, ranitidine, rabeprazole, raloxifen, ranolazine, rasburicase, reboxetine, repaclinides, reproterol, reserpine, revofloxacin, ribavirin, rifampin, riluzoles, rimexolone, risedronate, risperidone, ritonavir, rituximab, rivastimen, risatriptan, rofecoxib ,. ropinirole ropivacaine, rosiglitazone, roxatidine, orxithromycin, ruscogenin, rosuvastatin, rutoside and derivatives of rutoside, sabadilla, salbutamol, silicates, salmeterol, saperconazoles, thyroid hormones, scopolamine, selegiline, sertaconazole, sertindole, sertraline, sevelamer, sibutramine, sildenafil, silicates, simvastatin, sirolimus, sitosterol, sotalol, spagulamic acid, sparfloxacin, spectinomycin, spiramycin, espirapril, eespironolactone, stavudine, streptocimine, escralfate, sufentanil , sulbactam sulfonamides, sulfazalazine, sulpiride, sultamicillin, sultiam, sumatriptan, suxamethonium chloride, tacrine, tacrolimus, tadalafil, taliolol, talsaclidine, tamoxifen, tasonermin, tazaroten, tegafur, tegaserod, telithromycin, telmisartan, temoporfin, temozolomide, tenatoprazole, tenecteplase, teniposide, tenofovir, tenoxicam, teriparatide, terazosin, terbinafine, terbutaline, terfenadine, terparatide, terlipressin, tertatolol, testosterone and derivatives of testosterone, tetracyclines, tetrizolin, tezosentan,. theobromine, toefilin, theophylline derivatives, thiamazole, thiotepa, thr. growth factors, tiagabine,. tiaprid, tibolone, ticlopidine, tilidine, timolol, tinidazole, thioconazole, thioguanine, tiotropium, thioxolone, tirazetam, tiropramide, trofiban, tizamidine, tolazoline, tolbutamide, tolcapone, tolnaftate, tolperisone, tolterodine, topiramate, topotecan, torasemide, tramadol tramazoline, trandolapril , tranylcypromine, trapidil, trastuzumab, travoprost, trazodone, trepostinil, triamcinolone and derivatives of triamcinolone, tramterene, trigluperidol, trigluridine, trimetazidine, trimethoprim, trimipamine, tripelenamine, triprolidine, triphosphamide, tromantadine, trometamol, tropalpine, trovafloxacin, troxerutin, tulobuterol, trypsin , tyramine, thyrothricin, urapidil, ursodeoxycholic acids, ursodeoxycholic acid theophylline, valaciclovir, valdecoxib, valganciclovir, valproic acid, valsartan, vancomycin, cardenafil, vecuromium chloride, venlafaxine, verapamil, verteprofin, vidarabine, vigabatrin, viloxazine, vinglastin, vincamine, cincristine, vindesine, vinorelbine, vinpocetin a, viquidil, vitamin D and derevados of vitamin D, voriconazole, warfarin, xanthinol, nicotinate, ximelafatran, xipamida-, zafirlukast, zalcitabine, zaleplon, zanamavir, zidovidin, ziprasidone, zoledronic acid, zolmitriptan, zolpidem, zoplicon, zotepine and the like. The active ingredients can, if desired, also be used in the form of their salts or pharmaceutically derivatives and in the case of chiral active ingredients it is possible to use optically active y-racemic isomers or mixtures of diastereomers. If desired, the compositions of the invention may also comprise two or more active pharmaceutical ingredients. The outer control layer d) The external control layer d) comprises at least 60, preferably at least 80, particularly preferably 90 to 100% by weight of one or more mixtures of a plurality of (meth) copolymers acrylate compounds of 98 to 85 Cx to C4 alkyl esters of (meth) acrylic acid and 2 to 15% by weight of methacrylate monomers with a quaternary ammonium group in the alkyl radical, and, where correct, up to 40, preferably up to 20, in particular from 0 to 10% by weight of additional pharmaceutically usable polymers. However, it is particularly preferred that additional pharmaceutically usable polymers are not present. The data on the percentage by weight of the aforementioned polymers in the outer control layer d) are further calculated without taking into account any usual pharmaceutically excipient that is present additionally. Correct (meth) acrylate copolymers are disclosed, for example, in EP-A 181 515 or DE 1 617 751. These are polymers which are soluble or swellable without regard to pH and are suitable for drug coatings. A possible production process to be mentioned is batch polymerization in the presence of an initiator which forms free radicals and which dissolves in the monomer mixture. The polymer can likewise be produced by means of a solution or precipitation polymerization. The polymer can be obtained in this way in the form of a fine powder, which is achieved in the case of batch polymerization when grinding and in the case of solution and precipitation polymerization, for example, by spray drying. The (meth) acrylate copolymer is composed of 85 to 98% by weight of polymeric C_ to C4 alkyl esters of free radical of acrylic acid or methacrylic acid and 15 to 2% by weight of monomers of (meth) acrylate with a quaternary ammonium group in the alkyl radical. C_ to C4 alkyl esters of acrylic or methacrylic acid are preferably methyl acrylate, ethyl acrylate, butyl acrylate, buryl methacrylate and methyl methacrylate. The (meth) acrylate monomer with quaternary ammonium groups of particular preference is 2-trimethylammonioethyl methacrylate chloride. A correct copolymer can be, for example, 50-70% by weight of methyl methacrylate, 20-40% by weight. weight of ethyl acrylate and 7-2% by weight of 2-trimethylammoniomethyl methacrylate chloride. A specifically suitable copolymer comprises 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammoniomethyl methacrylate chloride (EUDRAGIR® RS). An additionally suitable (meth) acrylate copolymer can be composed, for example, of 85 or less than 93% by weight of C_ to C alkyl esters of acrylic acid or methacrylic acid and more than .7 to 15% by weight of monomers of ( met) acrylate with a quaternary ammonium group in the alkyl radical. These (meth) acrylate monomers are commercially available and have been used for a long time as prolonged release coatings. A specifically suitable copolymer comprises, for example, 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammonioethyl methacrylate chloride. It is possible, where it is correct that up to 40, preferably up to 20, in particular from 0 to 10% by weight of additional pharmaceutically usable polymers be present in the outer control layer d). Examples of suitable polymers are: Copolymers of methyl methacrylate and / or ethyl acrylate and methacrylic acid, copolymers of methyl methacrylate, methyl acrylate and methacrylic acid, copolymers of methyl methacrylate, butyl methacrylate and dimethylethyl methacrylate, copolymers of methyl methacrylate, ethyl acrylate and trimethylammonioethyl methacrylate, copolymers of methyl methacrylate and ethyl acrylate, copolymers of ethyl acrylate, methyl acrylate and butyl methacrylate and methacrylic acid. Polyvinylpyrrolidones (PVP), polyvinyl alcohols, polyvinyl alcohol polyethylene glycol graft copolymer (Kollicoat®), starch and derivatives thereof, polyvinyl acetate phthalate (PVAP, Coateric®) polyvinyl acetate (PVA). Kollicoat), vinyl acetate / vinylpyrrolidone copolymer (Kollidone® VA65), vinyl acetate copolymer: protonic acid 9: 1 (VAC: CRA, Kollicoat® VAC), polyethylene glycols with a molecular weight. greater than 1000 (g / mol), chitosan, a (meth) acrylate copolymer consisting of 20-40% by weight of methyl methacrylate and 60 to 80% by weight of methacrylic acid, a crosslinked and / or uncrosslinked polyacrylic acid , an alginate of Na and / or a pectin Celluloses such as, for example, anionic carboxymethyl cellulose and salts thereof (CMC, Na-CMC, Ca-CMC, Blanosa, Tilopur), carboxymethylethylcellulose (CMEC, Duodcell®), hydroxyethylcellulose (HEC, Klucel), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC, Pharmacoat, Methocel, Sepifilm, Viscontran, Opadry), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC, Ethocel®, Aquacoat®, Surelease®), methylcellulose (MC, glycolate of cellulose, cellulose acetate phthalate (CAP, Cellulosi acetates, PhEur, cellulose acetate phthalate, NF, Aquateric®), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), hydrocitropylmethylcellulose phthalate ( HPMCP, HP50, HP55), succinate acetate droxypropylmethylcellulose (HPMCAS-LF, -MF. -HF) Layer weights and proportions by weight Core a) optional If neutral cores (colored tablets) are used as carriers, these can have the range of an average diameter of around 50 to 1599 μm. Interior control layer b) The interior control layer comprises: a) a substance having a modulating effect, b) polymers, waxes, resins and / or pharmaceutically usable proteins c) optionally an active ingredient d) can be added in relation to ) from 50 to 400, preferably from 10 to 200% by weight. e) It may be present in relation to a) and b) in quantities of 10 to 100% by weight. Layer c) of active ingredient Layer c) of active ingredient can account for 10 to 400, preferably 50 to 200% by weight based on core layer a) and inner control layer b). External control layer d) The external control layer d may have a weight ratio of 2.5 to 100, preferably 10 to 70, particularly preferably 20 to 60% by weight based on a core layer a), layer b) of internal control and layer c) of active ingredient. The thickness of the layer is from about 4 to 150, in particular from 15 to 75, particularly preferably from 30 to 70 μm. Excipients customary in pharmaceutical The layers a), b), c) and d) can additionally and in a manner known per se comprise customary excipients in pharmaceutical. The customary excipients in pharmaceuticals are occasionally also referred to as customary additives, which are added to the formulation of the invention, preferably during the production of granules or powders. This is, of course, always necessary for all substances used to be toxicologically acceptable and usable in particular in medicines without risk to patients. The amounts used and used of customary excipients in pharmaceuticals for coatings of medicaments or layers are familiar to the skilled worker. Examples of possible excipients or additives customary in the pharmaceutical are release agents, pigments, stabilizers, antioxidants, formers. of pores, penetration promoters, gloss agents, flavoring or flavoring substances. These serve as processing aids and are intended to ensure a reliable and reproducible production process and good long-term storage stability or can achieve additional advantageous properties in the pharmaceutical form. These are added to the polymer preparations before processing and can influence the permeability of the coating, being possible to use it where appropriate as an additional control parameter. Release agents: Release agents usually have lipophilic properties and are usually added to spray suspensions. These avoid the agglomeration of nuclei during the coating of. movie. Talc, stearate of Mg or stearate of. Ca, earth silica, kaolin or non-ionic emulsifiers with an HLB of between 3 and 8 are preferably employed. The usual amounts of release agent used are between 0.5 to 100% by weight based on the weight of the cores. Pigments Pigments which are incompatible with a coating agent are, in particular, pigments which, if added directly to the dispersion of the (meth) acrylate copolymer, for example by stirring them, in the usual amounts used, for example, from 20 to 400% by weight. Weight, based on the dry weight of the (meth) acrylate copolymer, lead. to the destabilization of the dispersion, coagulation, to signs of inhomogeneity or similar undesired effects. The pigments to be used and even more, of course non-toxic and suitable for pharmaceutical purposes. Concerning this, also see, for example, Deutsche Forschungsgemeinschaft, Farbs toffe Für Lebensmi ttel, Harald, Boldt Verlag Kg, Boppard (1978); Deutsche Lebensmittelrundschau 74, No. 4, p. 156 (1978); Arzeneimittelfarbstoffverordnung AmFarbV dated 08.25.1980.

The pigments incompatible with coating agent can be, for example, alumina pigments. Examples of incompatible pigments are yellow orange, cochineal red lake, colored pigments based on alumina and azo dyes, sulphonic acid temples, nara ja yellow S (E110, CI 15985, FD &C Yellow 6), indigo carmine (E132, CI 73015, FD &C Blue 2), tartrazine (E 102, CI 19140, FD &C Yellow 5), Ponceau 4R (E 125, CI 16255, FD &C Red Cochineal), quinoline yellow (E 104 , CI '47005, FD &C Yellow 10), erythrosine (E127, CI 45430, FD &C Red 3), amaranth (E 123, CI 16185, FD &C Red 2), bright green acid (E 142, CI 44090 , FD &C Green S). The numbers E indicated for the pigments are related to the EU numbering. Concerning this, see also "Deutsche Forschungsgemeinschaft, Farbstoffe Für Lebensmittel, Harald Boldt Verlag KG, Boppard (1978), Deutsche Lebensmittelrundschau 74, No. 4, p.156 (1978), Arzneimittelfarbostoffverordnung AmFarbV of 25.08.1980, The numbers FD & C are related to the food, drug and cosmetic approval of the Food and Drug Administration of the United States (FDA) described in: United States Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors: Code of Federal Regulations - Title 21 - Color Additive Regulations Part 82, Color Hearing Scheduled Certificates and Specification (CFR 21 Part 82) Plasticizers Additional additives may also be plasticizers. 0 and '50, preferably 50 to 30% by weight based on the example on (meth) acrylic copolymer layer ilato d) outside. Plasticizers can influence the functionality of the layer. of the polymer, depending on the type (lipiphilic or hydrophilic) and amount added. The plasticizers are achieved through physical interaction with polymers a reduction in vitreous transition temperature and promote film formation, depending on the amount added. Suitable substances usually have a molecular weight of between 100 and 20,000 and comprise one or more hydrophilic groups in the molecule, for example, hydroxyl, ester or amino groups. Examples of suitable plasticizers are alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacate, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate, and polyethylene glycols 200 to 12,000. Preferred are triethyl citrate (TEC), acetyl triethyl citrate (ATEC) and dibutyl sebacate (DBS). Additional mention is made of esters that are usually at room temperature, such as citrates, phthalates, sebacates or castor oil. Preferably the esters of citric acid and sebacic acid are used. Additionally, the plasticizers for the formulation can be carried out in a known manner, directly in aqueous solution or after. pre-heat treatment of the mixture. It is also possible to use plasticizer mixtures. Processes to produce a multi-layer pharmaceutical form The pharmaceutical form of layers. Multiple can be produced in a manner known per se, by means of conventional pharmaceutical processes such as direct compression, drying compression, wet or sintered granules, extrusion and subsequent rounding, wet or dry granulation or direct granulation (for example, in plates). ) or through the binding of powders (making powder layers) into tablets or nuclei free of active ingredient (colored tablets) or particles containing active ingredients, by means of dew or fluidized bed granulation processes. The application of the outer control layer d) can be carried out through known and usual processes such as, for example, spray application of polymer solutions or polymer dispersions. Possible release characteristics The multi-layer dosage form is particularly suited to achieve the specific active ingredient release characteristics. Mention should be made of the release characteristics of the active ingredient in the order of zero (linear), first order (accelerated), rapid release characteristics - slow, slow-fast. Dosage Forms / Uses The multilayer dosage forms of the invention are initially in the form of tablets or granules. These can, in turn, be used as ingredients of a pharmaceutical form of multiple particles, of tablets containing granules, mi? Itabletas, capsules, sachets, effervescent tablets or powders for reconstitution. If possible, in accordance with the invention for the multi-particle dosage forms, mixtures of formulated granules containing different active ingredients can also be included in particular. A further possibility is that the multiple particle dosage forms of the invention are to comprise populations of granules that are loaded with the same active ingredient but are formulated differently and show different release profiles. It is thus possible to mix the release profiles of one or more active ingredients to achieve and to obtain a more refined adaptation of the desired therapy to be carried out through blends. Examples EUDRAGIT® RS = copolymer of 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and '5% by weight of 2-trimethylammonioethyl methacrylate chloride, 30% dispersion; EUDRAGIR® RS 30D = 30% dispersion. EUDRAGIT® RS PO = product in powder form; EUDRAGIT® NE 30D = copolymer of 50% by weight of methyl methacrylate and 50% by weight of ethyl acrylate. Examples 1-5 (not according to the invention) In order to examine the influence of various substances that have a modulating effect on the outer layer, granules were produced without a matrix that influences the release of the substance having a modulating effect but with microcrystalline cellulose (Example 5) was used for the comparison. It is thus possible to ensure effects such as an accelerated release or deceleration of the release of the active ingredient without respect to the matrix. A mixture of 1290 g of theophylline powder, 65 g of Kollidon 25 and 6.5 g of Aerosol 200 were sprayed on 700 g of the core material in a coating pan and bonded to the core material by spraying a solution of 33 g. g of theophylline 10 of Kollidon 25 in 500 g of demineralized water. A spray suspension of 400 g of EUDRAGIT® RS 30 D (corresponding to 120 g of polymer), 60 g of talc, 24 g of triethylene citrate, 0.6 g of yellow iron oxide and 538.3 g of demineralized water were applied in a bed system fluidized to 600 g of the theophylline granules produced in this way with a non-slow release modulator core. The applied amount of the polymer corresponds in this way to 20% of the starting material. The granules produced in Example 1-5 were investigated for the release of the active ingredient in a PhEur phosphate buffer with a pH of 6.8 in a USP dissolution tester.

The release values show the characteristics of the first order profile of the diffusion processes. Thus, without control of the release of the modulator, a balance obtained very quickly results in the coated granulate, which definitely adjusts the permeability of the final coated at the start of the release. The release profile of the granulate with microcrystalline cellulose (Example 5) is among those containing sodium acetate and sodium chloride. In this way, an acceleration effect is obtained for sodium acetate, citric acid and sodium succinate, and a reducing effect results from sodium hydrochloride. Example 6"linear (zero order)" 1000 g of sodium chloride are granulated in a compulsory mixer with 300 g of EUDRAGIT® NE 30 D (equivalent to 100 g of copolymer). A mixture of 1290 g of theophylline powder, 65 g of Kollidon 25 and 6.5 g of Aerosol 200 is sprinkled on 700 g of cores produced in this way with a release of medium release modulator in a coating pan and agglomerated to the material of the nucleus through simultaneous dew of a solution of 33 g of theophylline and 10 of Kollindon 25 in 500 g of deminerialized water. A spray suspension of 400 g of EUDRAGIT® RS 30 D (corresponding to 120 g of polymer), 60 g of talc, 24 g of triethyl citrate, 0.6 g of yellow iron oxide and 538.3 g of demineralised water are applied to 600 g of theophylline granules produced in this way with the slow release modulator core in a fluidized bed system. The release graph shows a profile of the order of 0, that is, it is virtually linear. Example 7"fast / slow" 500. g of sodium chloride are mixed in a compulsory mixer with 500 g of EUDRAGIT® RS PO (copolymer powder), and then lOOg of triethyl citrate, granulated by melting at a temperature, is added. of 70 ° C. A mixture of 1100 g of theophylline powder, 190 g of sodium succinate, 65 g of Kollidon 25 and 6.5 g of Aerosol 200 are sprinkled on 700 g of cores produced in this manner with release of slow modulator in a coating pan and they are agglutinated to the core material, through simultaneous dew of a solution of 33 g of theophylline and 10 of Kollidon 25 in 500 g of demineralized water. A spray suspension of 400 g of EUDRAGIT® 30 D (corresponding to 120 g of polymer), 60 g of talc, 24 g of triethyl citrate, 0.6 g of yellow iron oxide and 538.3 g of demineralized water were applied to 600 g of theophylline granulate produced in this way with slow release modulator core in a fluidized bed system. The applied quantity of the polymer corresponds in this way to 20% of the starting material. There is a very fast linear release of around 40% of the active ingredient within a period of 2 hours. Then the release suddenly becomes slower and distinctly delayed, with the remaining 60% of the active ingredient going through a linear release over a period of 10 hours. Example 8"slow / fast" 200 g of glycerol monostearate and 300 g of carnauba wax were melted at 70 ° C. 200 g of sodium acetate were mixed there. The melt was applied to 700 g of neutral granulate (colored pellets) through a melt coating process in a fluidized bed system. In a mixture of 1100 g of theophylline powder, 190 g of sodium chloride, 65 g of Kollidon 65 and 6.5 g of Aerosol 200 were sprinkled in 700 g of the cores produced in this way with a slow modulator release in a coating pan and bonded to the core material through simultaneous dew of a solution of 10 Kollidon 25 in 500 g of demineralized water. A spray suspension of 400 g of EUDRAGIT® RS 30D (corresponding to 120 g of polymer), 60 g of talc, 24 g of triethyl citrate, 0.6 g of yellow iron oxide and 538.3 g of demineralized water were applied to 600 g of theophylline granulate produced in this way with a slow release modulator core in a fluidized bed system. The amount of polymer applied corresponds in this way to 20% of the initial material. There is a very slow linear release of about 20% of the active ingredient over a period of 4 hours. Then the release suddenly becomes faster, with the remaining 80% of the active ingredient going through the linear release for a period of 6 hours. Example 9"Accelerated" 500 g of sodium acetate were mixed in a compulsory mixer with 500 g of EUDRAGIT® RS PO and 500 g of theophylline powder and then 100 g of triethyl citrate, melted granules were added at a temperature of 70 ° C. A mixture of 760 g of theophylline powder, 560 g of sodium chloride, 65 g of Kollidon 25 and 6.5 g of Aerosol 200 were dusted into 700 g of cores produced in this manner with slow modulator release / active ingredient release in a coating pan and agglutinated to the core material by simultaneously spraying a solution of 10 g of Kollidon 25 into 500 g of demineralized water. A spray suspension of 400 g of EUDRAGIT® D (corresponding to 120 g of polymer), 60 g of talc, 24 g of triethyl citrate, 0.6 g of yellow iron oxide and 538.3 g of demineralized water were applied to 600 g of theophylline granulate produced in this way with a modulator core. of 'slow release in a fluidised bed system. The amount of polymer that was applied corresponds in this way to 20% of the starting material. The active ingredient was released in a period of 10 hours, with the initial release very small. A long continuous acceleration in release was observed throughout the investigated period. Perspective of Examples 6 to 9 EUDRAGIT® RS = copolymer of 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammonium ethyl methacrylate chloride.

EUDRAGIT® NE = copolymer of 50% by weight of methyl methacrylate and 50% by weight of ethyl acrylate.

Claims (10)

1. CLAIMS 1. A pharmaceutical form with multiple layers for controlled release of an active ingredient comprising: a) Optionally a neutral core (colored tablets) b) An inner control layer. which comprises a substance having a modulating effect, which is embedded in a matrix which influences the libration of a modulating substance and which comprises polymers, waxes, resins and / or pharmaceutically usable proteins, and where an active ingredient is correct. c) a layer of active ingredient, comprising a pharmaceutical active ingredient, and where a substance having a modulating effect is correct, d) an outer control layer comprising at least 60% by weight of one. or a mixture of a plurality of (meth) acrylate copolymers composed of 98 to 85 C1 to C4 alkyl esters of (meth) acrylic acid and 2 to 15% by weight of methacrylate monomers with a quaternary ammonium group in the radical of alkyl and, where appropriate, up to 40% by weight of additional pharmaceutically utilizable polymers, where the layers can, additionally and in a manner known per se comprise pharmaceutically customary excipients.
2. 2. The multi-layer pharmaceutical form according to claim 1, characterized in that the matrix of the inner control layer comprises one or more of the following polymers: Copolymers of methyl methacrylate and / or ethyl acrylate and methacrylic acid, copolymers of methyl methacrylate, methyl acrylate and methacrylic acid, copolymers of methyl methacrylate, butyl methacrylate and di-ethylethyl methacrylate, copolymers of methyl methacrylate, ethyl acrylate and trimethylaminoethyl methacrylate, copolymers of methyl methacrylate and ethyl acrylate , copolymers of ethyl acrylate, methyl acrylate, butyl methacrylate and methacrylic acid, polyvinylpyrrolidones (PVP), alcohols. of polyvinyl, polyvinyl alcohol polyethylene glycol-graft copolymer (Kollicoat®), starch and derivatives thereof, polyvinyl acetate phthalate (PVAP, Coateric®) polyvinyl acetate (PVAc). Kollicoat), vinyl acetate / vinylpyrrolidone copolymer (Kollidone® VA65), vinyl acetate copolymer: protonic acid 9: 1 (VAC: CRA, Kollicoat® VAC), polyethylene glycols with a molecular weight greater than 1000 (g / mol), chitosan, a (meth) acrylate copolymer consisting of 20-40% by weight of methyl methacrylate and 60 to 80% by weight of methacrylic acid, a crosslinked and / or uncrosslinked polyacrylic acid, a Na alginate and / or a Pectin Celluloses, such as, for example, anionic carboxymethyl cellulose and salts thereof (CMC, Na-CMC, Ca-CMC, Blanosa, Tilopur), carboxymethylethylcellulose (CMEC, Duodcell®), hydroxyethylcellulose (HEC, Klucel), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC, Pharmacoat, Methocel, Sepifilm, Viscontran, Opadry), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC, Ethocel®, Aquacoat®, Surelease®), methylcellulose (MC, cellulose glycolate, cellulose acetate phthalate (CAP, Cellulosi acetas, PhEur, cellulose acetate phthalate, NF, Aquateric®), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), Hydrocipropylmethylcellulose phthalate (HPMCP, HP50, HP55), hydroxypropylmethylcellulose acetate succinate (HPMCAS-LF, -MF.HF).
3. 3. A multi-layer pharmaceutical form according to claim 1, characterized in that the matrix of the inner control layer comprises a wax such as, for example, carnauba wax and / or beeswax.
4. 4. A multi-layer pharmaceutical form according to claim 1, characterized in that the interior control layer matrix comprises a resin lacquer.
5. 5. A multi-layered pharmaceutical form according to claim 1, characterized in that the matrix of the inner control layer comprises a protein such as, for example,, albumin, gelatin, zein, collagen, gluten and / or a lecithin.
6. 6. A multi-layer dosage form according to claims 1 to 5, characterized in that the substance has a modulating effect having a molecular weight of less than 500 and is in solid form and is ionogenic.
7. 7. A multi-layer dosage form according to Claim 6 characterized in that the substance having a modulating effect is water soluble.
8. A multi-layered dosage form according to Claims 6 or 7, characterized in that the substance having a modulating effect is an organic acid or the salt of an organic or inorganic acid.
9. 9. A multi-layer pharmaceutical form according to claims 1 to 8, characterized in that the substance having a modulating effect is a succinic acid, citric acid, tartaric acid, lauryl sulfuric acid, a salt of these acids or a salt of the following anions: taurocholate and other cholates, chlorides, acetates, lactates, phosphates and / or sulfates.
10. 10. The process for producing a multilayer pharmaceutical form according to one or more of Claims 1 to 9 in a manner known per se by means of fluidized bed spray or granulation processes. SUMMARY OF THE INVENTION The invention relates to a multi-layer pharmaceutical form for the controlled release of an active ingredient comprising essentially: a) Optionally a neutral core (colored tablets) b) An internal control layer comprising a substance which has a modulating effect, which is embedded in a matrix which influences the libration of a modulating substance and which comprises polymers, waxes, resins and / or pharmaceutically usable proteins, and where an active ingredient is correct. c) a layer of active ingredient, comprising a pharmaceutical active ingredient, and where a substance having a modulating effect is correct, d) an outer control layer comprising at least 60% by weight of one or a mixture of one plurality of (meth) acrylate copolymers composed of 98 to 85 C to C4 alkyl esters of (meth) acrylic acid and 2 to 15% by weight of methacrylate monomers with a quaternary ammonium group in the alkyl radical and, where it is correct, in addition pharmaceutically usable polymers insoluble in water, where the layers can additionally and in a manner known per se, comprise usual pharmaceutically excipients.