MXPA06005200A - Multilayer pharmaceutical dosage form containing a substance that acts in a modulatory manner with regard to the release of active substances - Google Patents

Abstract

The invention relates to a multilayer pharmaceutical dosage form for the controlled release of active substances, containing:a) a core layer containing a substance that acts in a modulatory manner with regard to the release of active substances, optionally a neutral core and/or an active substance;b) an inner control layer that influences the release of the substance that acts in a modulatory manner and of the optionally contained active substance from the core layer, containing pharmaceutically useable polymers, waxes, resins and/or proteins;c) an active substance layer containing a pharmaceutical active substance and, optionally, a substance that acts in a modulatory manner;d) an outer control layer containing a (meth)acrylate copolymer or a mixture consisting of a number of (meth)acrylate copolymers comprised of 98 to 85 C1-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 optionally containing pharmaceutically useable polymers that are insoluble in water, whereby the layers can contain, in addition and in a known manner, pharmaceutically conventional adjuvants.

Description

FORM OF PHARMACEUTICAL DOSAGE OF VARIOUS LAYERS THAT CONTAINS A SUBSTANCE THAT WORKS MODULATELY WITH RESPECTING THE RELEASE OF ACTIVE SUBSTANCES The invention relates to a multi-layered pharmaceutical form for the controlled release of active ingredients. PREVIOUS TECHNIQUE EP-A 0 463 877 discloses pharmaceutical compositions with delayed release of the active ingredient comprising a core with a pharmaceutical active ingredient as a single-layer coating film comprising a water-repellent salt and a water-insoluble copolymer of ethyl acrylate , ethyl methacrylate and trimethylammonioethyl methacrylate chloride. The water-repellent salt can be, for example, calcium stearate or magnesium stearate. Sigmoidal release traces are obtained. EP-A 0 225 085, EP-A 0 122 077 and EP-A 0 123 470 describe the use of 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 active ingredient comprising a core with an active pharmaceutical ingredient and an organic acid and an outer coating film which has been applied by aqueous atomization and is a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride. In this case, the sigmoidal release traces are obtained in the same way. WO 00/19984 discloses a pharmaceutical preparation comprising (a) a core comprising an active ingredient, when a carrier and conventional pharmaceutical additives are appropriate, and the salt of an organic acid whose proportion in the weight of the core amounts to 2.5 to 97.5% by weight, and (b) an outer coating film consisting of one or more methacrylate copolymers and, where appropriate, conventional pharmaceutical excipients, where 40 to 100% by weight of the methacrylate copolymers comprise 93 to 98% by weight of alkyl esters of 1 to 4 carbon atoms polymerized from free radicals of acrylic or methacrylic acid and 7 to 2% by weight of methacrylate monomers with a quaternary ammonium group in the alkyl radical and when appropriate may be present in a mixture, with 1 to 60% by weight of one or more additional methacrylate copolymers which are different from the methacrylate copolymers that were mentioned first and which - est compounds of 85 to 100% by weight of alkyl esters of 1 to 4 carbon atoms polymerizable with free radicals of acrylic or methacrylic acid and, where appropriate, up to 15% by weight of other methacrylate monomers with basic groups or group acid in the alkyl radical. WO 00/74655 describes an active ingredient release system with double release impulse that is caused by 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 inner liner comprises a water-insoluble carrier material, for example, a copolymer of cationic methacrylate and comprises a water-soluble particulate material, for example a pectin, by means of which pore formation can be obtained. An outer coating comprising the same or a different active ingredient. In the gastrointestinal tract there is an initial release of the active ingredient located on the outside, while the active ingredient present in the core is released after a time interval through the pores in the intermediate layer. The three layer pharmaceutical form may optionally have another coating, for example composed of a methacrylate copolymer containing carboxyl group. US 5,508,040 describes a multiparticulate pharmaceutical form comprising a large number of tablets that are held together in a binder. The tablets have an active ingredient and an osmotically active modulator, for example NaCl or an organic acid in the core. The nuclei of Dragees are provided with coatings of different thicknesses, for example compounds of methacrylate copolymers with quaternary ammonium groups. To reduce permeability, the coatings also comprise hydrophobic substances, for example fatty acids, in amounts of 25% by weight or more. The multiparticulate pharmaceutical form is released through the active ingredient contained in a large number of pulses corresponding to the number of dragee 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 methacrylate copolymers with quaternary ammonium groups. "Pulsatile" release traces are obtained. Stepped release traces can be obtained by combining the tablets with different coatings in a pharmaceutical form. WO 01/13895 describes bimodal release systems for active ingredients that have a hypnotic sedative effect. The release profiles are achieved through mixtures of different dragee populations. WO 01/37815 describes multilayer release systems for controlled pulsatile delivery of ingredients assets. In this case, an internal membrane that can be dissolved by the formulation of the active ingredient present in the core is present. Also present is an outer membrane that also has a pore-forming substance. WO 01/58433 describes multi-layered release systems for controlled pulsatile delivery of active ingredients. In this case, the active ingredient is present in the nucleus and is surrounded by a polymer membrane that is soluble in the intestinal juice. An outer membrane consists of a mixture of a polymer that is soluble in intestinal juice with a water insoluble polymer in defined ranges of quantities. An intermediate layer comprising an organic acid may be present between the inner and outer membrane. Problem and solution Beginning from EP-A 0 436 370 and WO 00/19984, it was intended to develop a pharmaceutical form that allows the permeability of film coatings that were influenced by intrinsic modulation so that release profiles with zero order , first order, first order with initial accelerated phase, slow / fast, and slow / fast profiles can be individually adjusted depending on the active ingredient and the therapeutic requirements.

The problem is solved by a multi-layered dosage form for controlled release of active ingredient, comprising a) a core layer comprising a substance having a modulatory effect in relation to delivery of the active ingredient, when a neutral core is appropriate and / or an active ingredient; b) an inner controlling layer that influences the delivery of the substance having a modulatory effect and the active ingredient that is present when appropriate from the core layer, which first comprises pharmaceutically usable waxes, resins and / or proteins; c) a layer of active ingredient comprising an active pharmaceutical ingredient and, when appropriate, a substance having a modulating effect; d) an outer controller layer comprising at least 60% by weight of a mixture or a mixture of a plurality of methacrylate copolymers composed of 98 to 85 alkyl esters with 1 to 4 carbon atoms of methacrylic acid and 2 to 15% by weight of methacrylate monomers with a quaternary ammonium group in the alkyl radical and, where appropriate, up to 40% by weight of other polymers pharmaceutically usable, wherein the layers can additionally and in a manner known per se comprise pharmaceutically customary excipients. Implementing the invention The invention concerns a multi-layered pharmaceutical form for controlled release of active ingredient comprising essentially a layer a) of core and layers b) c) and d). It is also possible to top layers, which for example can be pigmented, are present. The core layer a) The multi-layer dosage form has a core layer a) comprising a substance with a modulating effect in relation to the delivery of the active ingredient, when a core (colored tablets) and / or a active ingredient . Suitable processes for producing the core layer a) are direct compression, compression of dry, wet or sintered granules, extrusion and subsequent rounding, wet or dry granulation or direct pelletizing (for example in plates) or joining powders (forming of powder layers) in ingredient-free beads or cores (colored pills) or particles containing active ingredient. In addition to the active ingredient, the substance modulating effect in relation to the delivery of the active ingredient and the neutral core (colored tablets) which is present when appropriate, the core layer a) may also comprise pharmaceutical excipients: binders such as cellulose and derivatives thereof, polyvinylpyrrolidone ( PVP), humectants, disintegration promoters, lubricants, disintegrators, starch and derivatives thereof, sugar solubilizers or others. Alternatives for the structure of the core layer a) The core layer alternatively comprise essentially the following ingredients: I. a substance having a modulating effect, for example, in crystalline, granular or coprecipitated form. The size of the granules or crystals can for example be between 0.01 and 2.5 mm; II. a substance having a modulatory effect and an active ingredient, which may be present in successive layers in any sequence or in a mixture; III. a neutral core (without colored tablets) coated with a substance that has a modulating effect; IV. a neutral core (colored tablets) coated with a substance with a modulating effect and with an active ingredient, which can be present in successive layers in any sequence or in a mixture.

Substances having a modulating effect Substances having a modulatory effect which are to be used according to the invention can have a molecular weight of below 500, have solid forms and be ionic. The substance having a modulatory effect is preferably soluble to water. The substance having a modulating effect may for example be an organic acid or the salt of an organic or inorganic acid. The substance having a modulating effect can for example be succinic acid, citric acid, tartaric acid, lauryl sulfuric acid, a salt of these acids or a salt of the following anions: taurocholates and other cholates, chlorides, acetates, lactates, phosphates and / or sulfates. How the components work together The mode of operation of the substance having a modulating effect in the multi-layer dosage form can be described approximately as follows: Na succinate, Na acetate and citric acid increase the delivery speed of the active ingredient. NaCl and Na citrate reduce the delivery rate of the active ingredient. If the layer c) of active ingredient further comprises, to the inner core layer a) a substance which has a modulating effect, the delivery of the active ingredient is mainly determined by the substance having a modulating effect which is present in the outer layer, layer c) of active ingredient. If this substance is considerably consumed, the effect of the substance having a modulating effect on the inner layer, the inner core layer a), starts and further determines the release of the active ingredient. The various delivery profiles of the active ingredient can be adapted to the active ingredient and the therapeutic auxiliary by combining different amounts of one and / or different substances having a modulating effect on the two layers. In addition, the effect of the inner controlling layer b) which itself controls the delivery of the substance having a modulating effect from the core layer a). The amount of active ingredient delivered is essentially controlled by the outer d) controller layer. If the inner controlling layer further comprises an active ingredient, this layer can be used to adjust the delivery profile of the active ingredient towards the end of delivery of the active ingredient. If the active ingredients themselves comprise ionic groups or are present in the salt form, the active ingredient itself can influence the effect of the substance or substances that have a modulating effect so that the latter is reduced or increased. This interaction can be as another element of control. For example, the case with the active ingredients metoprolol succinate and terbutaline sulfate. The inner controlling layer b) The inner controlling layer influences the delivery of the substance having a modulating effect and the active ingredient that is present when appropriate from the core layer. The inner controlling layer essentially comprises pharmaceutically usable polymers, waxes and / or proteins. To aid in the formulation it is possible to additionally mix conventional pharmaceutically excipients such as, for example, binders such as cellulose and derivatives thereof, plasticizers, polyvinylpyrrolidone (PVP), humectants, disintegration promoters, lubricants, disintegrators, starch and derivatives thereof. , sugars and / or solubilizers. The inner controlling layer b) may for example comprise a polymer that is insoluble in water or only swellable in water. 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 dimethylethyl methacrylate, copolymers of methyl methacrylate, ethyl acrylate and trimethylammoniomethyl methacrylate, copolymers of methyl methacrylate and ethyl acrylate, copolymers of ethyl acrylate, methyl acrylate, butyl methacrylate and methacrylic acid. Polyvinylpyrrolidone (PVPs), polyvinyl alcohols, polyvinyl alcohol polyethylene glycol graft copolymer (Kollicoat®), starch and derivatives thereof, polyvinylacetate phthalate (PVAP, Coateric®), polyvinyl acetate (PVAc, Kollicoat), vinyl acetate / vinylpyrrolidone copolymer (Kollidon® VA64), vinyl acetate copolymer: crotonic acid 9: 1 copolymer (VAC: CRA, Kollicoat® VAC), polyethylene glycols with molecular weight above 1000 (g / mol) chitosan, a copolymer of methacrylate comprising from 20 to 40% by weight of methyl methacrylate and 60 to 80% by weight of methacrylic acid, a crosslinked and / or non-crosslinked polyacrylic acid, an Na alginate and / or a pectin. Celluloses such as, for example, anionic carboxymethylcellulose and salts thereof (CMC, Na-CMC, Ca-CMC, Blanose, Tylopur), carboxymethylethylcellulose (CMEC, Duodecell®), hydroxyethylcellulose (HEC, Klucel), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC, Pharmacoat, Methoel, Sepifilm, Viscontran, Opadry), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC, Ethocel® Aquacoat®, Surelease®), methylcellulose (MC, Viscontran, Tylopur, Methocel), cellulose esters, cellulose glycolate, cellulose acetate phthalate (CAP, Cellulose acetates, Pharmaceutical European, cellulose acetate phthalate, NF, Aquateric®), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP, HP50, HP55), hydroxypropylmethylcellulose acetate succinate (HPMCAS -LF, -MF, -HF). The inner controlling layer may comprise a wax such as, for example, carnauba wax and / or beeswax or comprises the second. The internal controller layer may comprise the resin shellac or consist thereof. The internal controlling layer may comprise a protein such as, for example, albumin, gelatin, zein, gluten, collagen and / or lectins, or consist of the same. The protein of the internal controlling layer should preferably not have a therapeutic function, as is the case with active ingredients of proteins or peptides, so that the technical effects of the internal layer b) on the one hand and the layer c) do not coincide of active ingredient or layer a) of core layer, if the latter comprises an active ingredient, on the other hand, when possible. Layer c) of active ingredient The layer c) of active ingredient comprises an active pharmaceutical ingredient which may be identical to or different from the active ingredient of the core layer, and when appropriate a substance having a modulating effect which may be identical to or different from the substance having a modulator effect of the core layer. Active ingredients The multilayer pharmaceutical form of the invention is suitable in principle for any active ingredient. The medicinal substances in use can be found in reference works such as, for example, the list of Rote or the Merck index. The medicinal substances used for the purposes of the invention are intended to be used on or in the human or animal body in order to: 1. Cure, alleviate, prevent or diagnose disorders, conditions, physical damage or pathological symptoms. 2. Reveal the condition, state or functions of the body or mental states. 3. Replace active substances or body fluids produced by the human or animal body. 4. Reject, eliminate or neutralize pathogens, parasites or exogenous substances, or 5. Influence the condition, state or functions of the body or mental states.

The formulation of the invention is suitable for administration in principle of any active pharmaceutical ingredient or biologically active substances that can preferably be administered as an ingredient of a multiparticulate pharmaceutical form, of tablets containing dragees, mini-tablets, capsules, sachets, effervescent tablets or powders for reconstitution. Therapeutic Classes These pharmaceutically active substances may belong to one or more classes of active ingredients such as ACE inhibitors, adrenergics, adrenocorticosteroids, acne therapeutic agents, aldose reductase inhibitors, aldosterone antagonists, alpha-glucosidase inhibitors, alpha 1 antagonists. , remedies for alcohol abuse, amino acids, amedicides, anabolics, analeptics, anesthetic additions, anesthetics (non-inhaled), (local) anesthetics, analgesics, androgens, angina pain therapeutic agents, antagonists, antiallergics, antiallergics such as PDE inhibitors, antiallergics for asthma treatment, other antiallergics (for example, leukotriene antagonists, antianemic agents, antiandrogens, antiaxiolytics, antiarthritics, antiarrhythmics, antiaterioscleróticos, antibiotics, anticholinergics, anticonvulsants, antidepressants, antidiabetics, antidiarrheals, antidiuretics, antidotes, antiemetics, antiepileptics, antifibrinolytics, antiepileptics, anthelmintics, antiestamines, antihypotensive, antihypertensive, antihypertensive, antihypertensive, anticoagulants, antifungals, antiestrogens, antiestrogens (non-spheroidal), antiparkinson agents, anti-inflammatory agents, antiproliferative active ingredients, antiprotozoal active ingredients, antirheumatics, antieschistosomicidas, antispasmolíticos, antithrombotic ,. antitussives, appetite suppressants, atherosclerosis remedies, bacteriostats, beta blockers, beta-receptor blockers, boncodilatadores, carbonic anhydrase inhibitors, chemotherapeutic agents, choleretics, cholinergics, cholinergic agonists, cholinesterase inhibitors, agents for the treatment of ulcerative colitis, inhibitory diuretics of cyclooxygenase, ectoparasiticides, emetics, enzymes, enzyme inhibitors, active ingredients to counteract vomiting, fibrinolytics, fungistatics, drops remedies, glaucoma therapeutic agents, glucocorticoids, glucocorticosteroids, haemostats, cardiac glycosides, H2 histamine antagonists, hormones and their inhibitors, immunotherapeutic agents, cardiotonic agents, coccidiostats, laxatives, lipid reducing agents, gastrointestinal therapeutic agents, therapeutic agents against malaria, remedies against migraine, microbiocides, Crohn's disease, metastasis inhibitors, migraine remedies, mineral repairs, active ingredients motility enhancers, muscle relaxants, neuroleptics, active ingredients for the treatment of estrogen, osteoporosis, otological, antiparkison agents, phytopharmaceuticals , proton pump inhibitors, prostaglandins, active ingredients to treat benign hyperglacia of the prostate, active ingredients for treating pruritus, ingredients active against psoriasis, psychoactive drugs, free radical scavengers, renin antagonists, therapeutic agents for the thyroid, ingredients active to treat seborrhea, active ingredients to counteract motion sickness, spasmolytics, alpha- and beta-sympathomimetics, tenatoprazole, inhibitors of platelet aggregation, tranquilizers, therapeutic agents against ulcers, in addition to therapeutic agents against ulcers, agents for ra 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, abacavir, aceclofenac, aclarubicin, acyclovir, actinomycin, adalimumab, adefovir, adefovirdipivoxil, adenosylmethionine, adrenaline and derivatives of adrenaline, agalsidase alfa, agalsidase beta, alemtuzumab, amotriptan, alfacept, allopurinol, almotriptan, alosetron, alprostadil ,. amantadine, ambroxol, amisulpride, amlodipine, oxycillin, 5-aminosalicylic acid, amitriptyline acid, amlodipine, amoxicillin, amprenavir, anakinra, anastrozole, androgens and androgen derivatives, apomorphine, aripiprazole, arsenic trioxide, artemether, atenolol, atorvastatin, atosigan , azathioprine, azelaic acid, barbituric acid derivatives, balsalacid, basiliximab, beclapermine, beclomethasone, bemiparin, benzodiazepines, betahistine, bexarotene, bezafibrate, bicalutamide, bimatoprost, bosentan, botulinum toxin, brimonidine, brinzolamide, budesonide, budipine, bufexamac, bumetanide, buprenorphine, bupropion, butizine, calcitonin, calcium antagonist, calcium salts, candesartan, capecitabine, captopril, carbamazepine, carifenacin, carvedilol, caspofungin, cefaclor, cefadroxil, cafaosinin of cafalexin, cefditoren, cefprozil, celecoxib, cepecitabine, cerivastati , cetirizine, cetrorelix, cetuximab, chenodeoxycholic acid, chorionic gonadotropin, cyclosporine, cidofovir, cimetidine, ciprofloxacin, cisplatin, cladribine, clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidine, clopidogrel, codeine, caffeine, cholestyramine, cromoglicic acid, cotri oxazole, coumarin and coumarin derivatives, darbepoetin, cysteamine, cistern, cytarabine, cyclophosphamide, cyproterone, cytarabine, declizumab, dalforpristin, danaparoid, dapiprazole, darbepoetin, defepripone, desipramide, desirudin, desloaratadine, desmopressin, desogestrel, desonide, dexibuprofen, desketoprofen, disoproxil, diazepam and derivatives of diazepam, dihydralazine, diltiazem, dimenhydrinate, sulfoxide dimethyl, dimeticon, dipivoxil, dipiridarnoi, dolasetron, dopidone, and derivatives of dopidone, donepzil, dopamine, doxazosin, doxorubicin, doxylamine, diclofenac, divalproex, dronabinol, drospirenone, alpha drotrecogin, dutasteride, ebastine, econazole, efavirenz, eletripan, emidataine, emtricitabine, enalapril, encepur, entacapone, enfurvirtide, ephedrine, epinephrine, eplerenone, epoetin and epoetin derivatives, eprosartan, eptifibatide, ertapenem, esomeprazole, estrogen and estrogen derivatives, etanercept, etenzamide, etinestradiol, etofenamate, etofibrate, etofilin, etonogestrel, etoposide, exemestane, exetimib, famciclovir, famotidine, faropenan, dalo xato, felopidine, fenofibrate, fentanyl, fenticonazole, fexofenadine, finasteride, fluconazole, fludarabine, flunarizine, fluorouracil, fluoxetine, flurbiprofen, flupirtine, flutamide, fluvastatin, folitropin, fomivirsen, fondaparinux, formoterol, fosfomycin, frovatriptan, furosemide, fusidic acid, gadobenate , galantamine, gallopamil, ganciclovir, ganirelix, gatifloxacin, gefitinib, gemfibrozil, gentamicin, gepirone, progesterone and progesterone derivatives, ginkgo, glatiramer, glibenclamide, glipizide, glucagon, glucitol and glucitol derivatives, glucosamide and glucosamide derivatives, glucoside antibiotics, glutathione, glycerol and glycerol derivatives, hypothalamus hormones, goserelin, grepafloxacin, antihistants gyrase, guanethidine, gyrase inhibitors, hemin, halofantrine, halperidol, urea derivatives such as oral antidiabetics, heparin and heparin derivatives, cardiac glycosides, hyaluronic acid, hydralazine, hydrochlorothiazide and hydrochlorothiazide derivatives, hydroxymeprazole, hydroxyzine, ibritumomab, ibuprofen, idarubicin, ifliximaba, ifosfamide, iloprost, imatinib, imidapril, imiglucerase, imipramide, imiquimob, imidapril, indomethacin, indoramin, infliximab, insulin, glargine insulin, interferons, irbesartan, irinotecan, isoconazole, isoprenaline, itraconazole, ivabradins, iodine and iodine derivatives , St. John's wort, potassium salts, ketoconazole, ketoprofen, ke totifen, lacidipine, lansoprazole, laronidase, latanoprost, leflunomide, lepirudin, lercanidipine, leteprinim, letrozole, levacetylmethadol, levetiracetam, levocetiricin, levodopa, levodrpropicin, levomethadone, licofelone, linezolid, lipinavir, lipoic acid and lipoic acid derivatives, lisinopril, lisuride, lofepramina, lodoxa ida, lomefloxacin, ustin, loperamide, lopinavir, loratadine, lornoxicam, losartan, lumefantrine, lutropin, magnesium salts, macrolide antibiotics, mangafodipir, maprotiline, mebendazole, mebeverine, meclocin, mefenamic acid, mefloquine, meloxicam, memantine, mepindolol, eprobamate, meropenem, mesalazine, esuximide, metamizole, metformin, methadone, methotrexate, 5-amino-4 methyl-oxopentanoate, methylnaloxone, methylnaloxone, methylnaltrexones, methylphenidate, methylprednisolone, metixen, metoclopramide, metoprolol, metronidazole, mianserin, mibefradil, miconazole, ifepristone, iglitol, miglustad, minocycline, minoxidil, misoprostol, mitomycin, mizolastin, modafinil, moexipril, montelukast , moroctocog, morphine, morphine and morphine derivatives, moxifloxacin, ergot alkaloids, nalbuphine, naloxone, naproxen, naratriptan, narcotin, natamycin, nateglinide, nebivolol, nefazodone, nelfinavir, neostigne, neramexan, nevirapine, nicergoline, nicetamide, nifedipine, acid niflumic, nimodipine, nimorazole, nimustine, nesitridine, nisoldipine, norfloxacin, novamine sulfone, noscapine, n istamine, ofloxacin, octotamide, olanzapine, olmesartan, olsalazine, oseltamivir, omeprazole, omoconazole, ondansetron, orlistat, oseltamivir, oxaceprol, oxacillin, oxaliplatin, oxaprocine, oxcarbazepine, oxycodone, oxiconazole, oxymetazoline, palivizumab, palanosetron, pantoprazole, paracetamol, parecoxib, paroxetine, pegaspargase, peginterferon, pegfilgrastrim, penciclovir, oral penicillin, pentazocine, pentifillin, pentoxifylline, antibiotics peptides, perindopril, perphenazine, pethidine, plant extracts, phenazone, feniramine, phenylbutyric acid, phenytoin, phenothiazines, phenserin, phenylbutazone, phenytoin, pimecrolimus, pimozide, pindolol, pioglitazone, piperazine, piracetam, pirenzepine, piribedil, pirlindol, piroxicam, pramipexole , pramlintide, pravastatin, prazosin, procaine acid derivatives, promacin, propiverine, propranolol, propionic acid derivatives, propifenazone, prostaglandins, protionamide, proxifilin, quetiapine, quinapril, quinaprilat, quinupristin, ramipril, ranitidine, rabeprazole, raloxifen, ranolazine, rasburicase, reboxetin, repaclinides, reproterol, reserpine, revofloxacin, ribavirin, rifampicin, riluzoles, rimexolone, risedronate, risperidone, ritonavir, rituximab, rivasti in, risatriptan, rofecoxib, ropinirol, ropivacaine, rosiglitazone, roxatidine, roxitro icina, ruscogenin, rosuvastatin, rutoside and derivatives of rutoside, sabadila, salbuta ol, salicylates, salmeterol, sapercona zoles, thyroid hormones, scopolamine, selegiline, sertaconazole, sertindole, sertraline, sevelamer, sibutramine, sildenafil, silicates, if vastatin, sirolimus, sitosterol, sotalol, spagulamic acid, sparfloxacin, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptomycin, sucralfate, sufentanil, sulbactam, sulfonamides, sulfasalazine, sulpiride, sultamicillin, sultiam, sumatriptan, suxametonone chloride, tacrine, tacrolimus, tadalafil, taliolol, talsaclidine, tamoxifen, tasonermin, tazarotene, tegafur, tegaserod, telithromycin, telmisartan, temoporfin, temozolamide, tenatoprazole, tenecteplase, teniposide, tenofovir, tenoxicam, teriparatide, terazosin, terbinafine, terbutaline, terfenadine, teriparatide, terlipressin, tertatolol, testosterone and testosterone derivatives, tetracyclines, tetrizolin, tezosentan, theobromine, theophylline, theophylline derivatives, thiamazole, thiotepa, thyroid growth factors, tiagabine, tiapride, tibolone, ticlopidine, tilidine, timolol, tinidazole, thioconazole, thioguanine, tiotropium, thioxolone, tirazetam, tiropramide, trofiban, tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate, tolperisone, tolterodine, topiramate, topotecan, torasemide, screening, tramazoline, trandolapril, tranylcypromine, trapidil, trastuzumab, travoprost, trazodone, trepostinil , triamcinolone and triamcinolone derivatives, triamterena, trifluperidol, trifluridine, trimetazid inas, trimethoprim, trimipramine, tripelenamine, triprolidine, triphosphamide, tromantadine, tro etamol, tropalpine, trovafloxacin, troxerutin, tulobuterol, trypsins, tyramine, thyrothricin, urapidil, ursodeoxycholic acid, urofodexicholic acid of theophylline, valaciclovir, valdecoxib, valganciclovir, valproic acid valsartan, vancomycin, vardenafil, vecuronium chloride, venlafaxine, verapamil, verteporfin, vidarabine, vigabatrin, viloxacin, vinblastine, vincamine, vincristine, vindesine, vinorelbine, vinpocetine, viquidil, vitamin D and vitamin D derivatives, voriconazole, warfarin, xanthinol nicotine, ximelagatran, xipamide, zafirlukast, zalcitabine, zaleplon, zanamivir, zidovudine, ziprasidone, Zoledronic acid, zolmitriptan, zolpidem, zoplicone, zotepine and the like. Particularly preferred active ingredients Examples of particularly preferred active ingredients are metoprolol succinate and terbutaline sulfate. The active ingredients if desired may also be used in the form of their pharmaceutically acceptable salts or derivatives, and in the case of chiral active ingredients it is possible to employ both optimally active isomers and racemates as mixtures of diastereomers. If desired, the compositions of the invention may also comprise two or more active pharmaceutical ingredients. The outer controlling layer d) The outer controlling layer d) comprises at least 60, preferably at least 80, particularly preferably from 90 to 100% by weight of one or a mixture of a plurality of methacrylate copolymers composed of 98 to 85 alkyl esters with 1 to 4 carbon atoms of methacrylic acid and 2 to 15% by weight of methacrylate monomers with quaternary ammonium group in the alkyl radical and, where appropriate up to 40, preferably up to 20, in particular from 0 to 10%, by weight of other pharmaceutically usable polymers, however, it is particularly preferred that no other pharmaceutically usable polymer this present. The data on the percentage by weight of the aforementioned polymers in the outer controller layer d) is further calculated without taking into account any pharmaceutically customary excipients which are additionally present. Suitable methacrylate copolymers are disclosed, for example, in EP-A 181 515 or DE 1 617 751. These are polymers which are soluble or swellable independently of pH and are suitable for drug coatings. A possible production process that should be mentioned is bulk polymerization in the presence of an initiator that forms free radicals and that dissolve in the monomer mixture. The polymer can likewise be produced by precipitation solution or polymerization. The polymer can thus be obtained in the form of a fine powder, which can be obtained in the case of bulk polymerization by grinding and in the case of solution polymerization and precipitation for example by spray drying .

The methacrylate copolymer is composed of 85 to 98% by weight of alkyl esters with 1 to 4 carbon atoms polymerized from free radicals of acrylic or methacrylic acid and 15 to 2% by weight of methacrylate monomers with a quaternary ammonium group in the alkyl radical. Preferred alkyl esters of 1 to 4 carbon atoms of acrylic or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and methyl methacrylate. Particularly preferred methacrylate monomer with the quaternary ammonium groups is 2-trimethylammoniomethyl methacrylate chloride. A suitable copolymer can be composed, for example, of 50-70% by weight of methyl methacrylate, 20-40% by 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-trimethylaminomethyl methacrylate chloride (EUDRAGIT® RS). Another suitable methacrylate copolymer can be, for example, from 85 to less than 93% by weight of alkyl esters with 1 to 4 carbon atoms of acrylic or methacrylic acid and more than 7 to 15% by weight of methacrylate monomers with group quaternary ammonium in the radical alkyl, said methacrylate monomers can be obtained commercially and have been used for a long time for slow 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-trimethylammoniomethyl methacrylate chloride (EUDRAGIT® RL). It is possible when appropriate that up to 40, preferably up to 20 and in particular from 0 to 10% by weight of other pharmaceutically usable polymers are present in the outer d) controller layer. 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 trimethylammoniomethyl methacrylate, copolymers of methyl methacrylate and ethyl acrylate, copolymers of ethyl acrylate, methyl acrylate, butyl methacrylate and methacrylic acid. Polyvinylpyrrolidone (PVPs), polyvinyl alcohols, polyvinylalcohol-polyethylene glycol graft copolymers (Kollicoat®), starch and derivatives thereof, polyvinyl acetate phthalate (PVAP, Cotaeric®), polyvinyl (PVAc, Kollicoat), vinyl acetate / vinylpyrrolidone copolymer (Kollidone®, VA64), vinyl acetate polymer: protonic acid 9: 1 (VAC: CRA, Kollicoat® VAC), polyethylene glycols with molecular weight greater than 1000 (g / mol), chitosan, a methacrylate copolymer comprising from 20 to 40% by weight of methyl methacrylate and 60 to 80% by weight of methacrylic acid, a crosslinked and / or non-crosslinked 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-cm. , Blanose, Tylopur), carboxymethylcellulose (CMEC, Duodcell®), hydroxyethylcellulose (HEC, Klucel), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC, Pharmacoat, Methocel, Sepifilm, Viscontran, Opadry), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC, Ethocel®, Aquacoat®, Surelease®), methylcellulose (MC, Viscontran, Tylopur, Methocel), cellulose esters, glycolate cellulose, cellulose acetate phthalate (CAP, Cellulosi acetas, European Pharmaceutical, cellulose acetate phthalate, NF, Aquateric®), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate ( HPMCP, HP50, HP55), hydroxypropylmethylcellulose acetate succinate (HPMCAS-LF, -MF, -HF). Layer thicknesses and proportions by weight Layer a) core The core layer a) (without colored pellets) can have an average diameter in the range of about 100 to 800, preferably 250 to 500 μm (corresponding to a mesh margin of about 60 to 40). Layer b) inner controller layer The inner controller layer b) may have a weight ratio from 0.5 to 80, preferably from 2.5 to 50, particularly preferably from 5 to 40% by weight based on the core layer a). It is favorable for the thickness of the layer to be approximately 1 to 100, preferably 5 to 50, in particular 10 to 40, μm. Layer c) of active ingredient Layer c) of active ingredient may have 10 to 400, preferably 50 to 200% by weight, based on core layer a) and inner layer b) controller. Layer d) external controller The outer controller layer d) may have a weight ratio from 2.5 to 100, preferably 10 to 70, particularly preferably 20 to 60% by weight, based on core layer a), layer b) inner controller and layer c) of the active ingredient. The layer thickness is approximately 4 to 150, in particular 15 to 75, particularly preferably 30 to 70, μm. Excipients usual in pharmacy Layers a), b), c) and d) can also, in a manner known per se, comprise traditional excipients in the pharmacy. The usual excipients in pharmacy are sometimes also referred to as traditional additives, ", which are added to the formulation of the invention, preferably during the production of the granules or powders, that is, of course, always necessary for all the substances used, that are toxicologically acceptable and can be used in particular in medicines which do not represent a risk for patients The amounts used and the use of traditional excipients in pharmacy for coatings of medicaments or layers are familiar to the person skilled in the art Examples of possible traditional excipients or additives in pharmacy are release agents, pigments, stabilizers, antioxidants, • pore formers, penetration promoters, gloss agents, flavoring substances or flavorings This serves as auxiliaries in the process and is intended to ensure a reliable and reproducible production process and long-term storage stability or achieve additional beneficial properties in the pharma form This is added to the polymer preparations before processing and can influence the permeability of the coatings, making it possible for them to be used when appropriate as additional control parameters. Release agents: Release agents typically have lipophilic properties and are normally added to the spray suspensions. They prevent the agglomeration of the nuclei during the film coating. Talc, magnesium stearate or calcium stearate, ground silica, kaolin or nonionic emulsions with a HLB of between 3 to 8 are preferably used. The normal amounts used of the release agency are between 0.5 to 100% by weight based on the weight of the nuclei. Pigments: Pigments incompatible with the coating agent are in particular those pigments which, if added directly to the methacrylate copolymer dispersion, for example by stirring, in the normal quantities used, for example, from 20 to 400% by weight with Based on the weight of methacrylate copolymer, they lead to destabilization of the dispersion, coagulation, signs of inhomogeneity or similarly undesired effects. The pigments that are going to be used are also non-toxic and suitable for pharmaceutical purposes. With regard to that, also see, for example: Deutsche Forschungsgemeinschaft, Farbstoffe für Lebensmí ttel, Harald, Boldt Verlag KG, Boppard (1978); Deutsche Lebensmittelrundschau 74, No. 4, p. 156 (1978); Arzneimittelfarbstoffverordnung AmFarbV of 08/25/1980. The pigments incompatible with the coating agent can, for example, be alumina pigments. Examples of incompatible pigments are orange yellow, coquineal red lacquer, color pigments based on alumina or azo dyes, sulfonic acid dyes, orange yellow S (E110, Cl 15985, FD &C Yellow 6), indigo red (E132, Cl 73015, FD &C Blue 2), tartrazine (E 102, Cl 19140, FD &C Yellow 5), Ponceau 4R (E 125, Cl 16255, FD &C Coquineal Network A), quinoline yellow (E 104, Cl 47005 , FD &C Yellow 10), erythrosine (E127, Cl 45430, FD &C Red 3), azorubine (E122, Cl 14720, FD &C Carmoisine), amaranth (E 123, Cl 16185, FD &C Red 2), bright green acid (E142, Cl 44090, FD &C Green S). The numbers E indicated for the pigments are related to a numbering of the EU. With regard to this, see also "Deutsche Forschungsgemeinschaft, Farbstoffe für Lebensmi ttel, Harald, Boldt Verlag KG, Boppard (1978), Deutsche Lebensmittelrundschau 74, No. 4, p.156 (1978), Arzneimittelfarbstoffverordnung AmFarbV of 08/25/1980 The FD &C numbers are related to the approval in food, medicines and cosmetics by the administration of US Food and Drug Administration (FDA) described in the United States Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors: Code of Federal Rules - Title 21 Part 82 of the Rules for Color Additives, List of Colors and Provisionally Listed Certified Specifications (C? R 21 Part 82). Plasticizers Other additives can also be plasticizers. The normal amounts are between 0 and 50, preferably 5 to 20% by weight, based for example on the methacrylate copolymer of the outer layer d). Plasticizers can have an influence on the functionality of the polymer layer, depending on the type (lipophilic or hydrophilic) and the amount added. The plasticizers achieve through physical interaction with the polymers a reduction in the transition temperature of the vitreous state and promote the formation of films, depending on the aggregate amount. 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 citrate, glycerol esters, alkyl phthalate, alkyl sebacates, sucrose esters, sorbitan esters, Diethyl sebacate, dibutyl sebacate and polyethylene glycols 200 to 12,000. Preferred plasticizers are triethyl citrate (TEC), acetyltriethyl citrate (ATEC) and dibutyl sebacate (DBS). Mention should also be made of esters that are normally liquid at room temperature, such as citrates, phthalate, sebacates, or resinous oil. The esters of citric acid and sebasic acid are preferably those used. Addition of the plasticizers to the formulation can be carried out in known manner, directly, in aqueous solution or after thermal pre-treatment of the mixture. It is also possible to use mixtures of plasticizers. Processes for producing a pharmaceutical form of various layers The pharmaceutical form of various layers can be produced in a manner known per se by means of conventional pharmaceutical processes such as direct compression, compression of dry, wet or sintered granules, extrusion and subsequent rounding, granulation. wet or dry or direct pelletizing (for example in plates) or particles containing active, average spray processes or fluidized bed granulation. Application of the layers -b) and c) interior and exterior controller can be carried out by means of known and normal processes such as, for example, application by spraying polymer solutions or polymer dispersions. Examples of normal process parameters The following normal process parameters are intended to explain possible examples of procedures in the production process. Step 1: (Formulation of a core layer a) The crystal nuclei in the range of 400 μm-800 are selected for the experiments. Stage 2: (Application of a layer b) interior controller) The modulating layer with EUDRAGIT® NE (50% by weight methyl methacrylate copolymer and 50% by weight of ethyl acrylate). Suspension of 20% by weight of EUDRAGIT® NE 30 D is used as the basic modulator layer for most experiments. The formulation comprises 15% solids in dispersion with 20% polymer, 5% glycerol monostearate (GMS-900), 2% Tween 80 and 0.5% of a pigment. This layer is applied to the crystal cores using a fluidized bed apparatus. Process parameters Inlet air temperature: 32 ° C Product temperature: 30 ° C Outlet air temperature: 23 ° C pump rpm: 8-10 (5-10 g / min) Processing time: 120-160 minutes Dry process: 2 hours in convection oven at 40 ° C. Step 3 (Application of a layer c) of active ingredient) The active ingredient can be applied to single crystal cores or to glass cores coated with a substance having a modulating effect, until a weight gain of 100 to 200% is obtained . The application of the active ingredient can also be carried out with additional salt integration in order to increase the concentration of the salts in the beads. The application of the active ingredient is carried out for example in a coating tray using the known process of separation by layers of powder. Parameters of the general process for the application of the active ingredient Time of atomization 90 minutes Total volume 543 g Weight / powder in portions: 15 g Nozzle: 1.00 mm Spray pressure: Low Casting tray speed: 24-25 rpm Pump speed: 12 rpm (9 g / min) Drying in the device: 5 minutes Final drying in one convection oven: 12 hours at 40 ° C Output air conditions On The coated beads of active ingredient obtained in this form can have the size ranging from 600 to 1200 μm and can be used for additional coating with EUDRAGIT ® RS (65% by weight copolymer) of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammonioethyl methacrylate chloride. Stage 4 (application of an outer control layer d) consisting of a slow-release coating with (EUDRAGIT® RS) The beads coated with active ingredient can be coated, for example, with EUDRAGIT® RS, applying various amounts (from 10-50) %) in a fluidized bed apparatus. A formulation may comprise, for example: 20% solids in the dispersion of EUDRAGIT® RS with 50% talc, 20% triethyl citrate, 0.5% pigments. Process parameters Inlet air temperature: 35 ° C Product temperature: 32 ° C Outlet air temperature: 24 ° C pump rpm: 8-16 (4-8 g / min) Processing time: 120-180 min Dry process: 2 hours in an oven convection at 40 ° C Specific examples: Example I Concentration of the modulated layer up to 10% weight on weight: The trisodium citrate crystals were coated with 10% weight-on-weight of EUDRAGIT® NE 30D. Theophylline is applied to this layer until the weight gain is 200%. These coated cores are additionally coated with 20-40% w / w of EUDRAGIT® RS 30D. Example II Modulated layer concentration up to 20% w / w: The trisodium citrate crystals are coated with 205 weight / weight of EUDRAGIT® NE 30D. Theophylline is applied to this layer until the weight gain is 200 ° C. These coated cores are also coated with 20-40% weight / weight of EUDRAGIT® RS30D. Example III Increase in the concentration of salts in the finished bead: The sodium chloride cores were first coated with a modulating layer of EUDRAGIT® NE 30D up to % weight / weight. Theophylline and milled sodium chloride crystals were applied to this layer until the weight gain was 200%. These coated beads were coated also with 20-40% weight / weight of EUDRAGIT® RS30D. Example IV Effect of the various salts: Sodium chloride and sodium acetate crystals were mainly coated with EUDRAGIT® NE 30D up to 20% w / w. Theophylline is applied to this layer until the weight gain is 200%. These coated beads are also coated with 20-40% weight / weight of EUDRAGIT® RS30D. Possible release characteristics The multilayer dosage form is particularly suitable to achieve specific release characteristics of the active ingredient. The release characteristic of the active ingredient of zero order (linear), first order (accelerated), fast / slow, slow / fast must be mentioned. The pharmaceutical form for the active ingredient metoprolol succinate The active ingredient metoprolol succinate that can be extended for the therapy of hypertension and angina is beneficially formulated into a pharmaceutical form that can be taken before going to the bed, initially releasing the active ingredient in linear mode but changes after 4 to 6 hours to an accelerated active ingredient delivery. It is therefore possible to counteract the risk of high blood pressure and myocardial infarctions that They are particularly high early in the morning. Four possible variants with which the desired release characteristics for the active ingredient sucked from metoprolol can be obtained are disclosed according to the invention.

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. EUDRAGIT® NE = is a copolymer of 50% by weight of methyl methacrylate and 50% by weight of ethyl acrylate. The release characteristics of the beads of Example M4 were evaluated in the dissolution test of USP < 711 > , apparatus 1, pH 6.8 phosphate buffer. It was found in this case that approximately 11% of the active ingredient contained was released in each case until the second and the second to the fourth hour. It was observed that there was an accelerated active ingredient delivery of approximately 15% from the fourth hour to the sixth hour and from % in each case from the sixth to the eighth and from the eighth to the tenth hour. The delivery of active ingredient was reduced again from the tenth hour onwards.

Pharmaceutical form for the active ingredient terbutaline sulfate The active ingredient terbutaline sulfate is a beta 2 agonist that can be used for the therapy of asthma. A formulation with approximately constant speed of delivery of the active ingredient is prepared according to the invention. Acute asthma symptoms can be relieved by the same after taking the pharmaceutical form. Therefore, uniform amounts of the active ingredient are delivered to suppress the recrudescence of other symptoms. Therefore it is not It is necessary to administer individual doses several times a day. Repeatedly and more or less punctually, as is the case with most pharmaceutical forms of the previous techniques. This in general is more convenient, more acceptable (patient compliance) and in many cases also more tolerable for the patient. Possible variants with which the desired release characteristics for the active ingredient terbutaline sulfate can be obtained, are disclosed according to the invention.

EUDRAGIT® RS = copolymer of 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammoniomethyl methacrylate chloride. EUDRAGIT® NE = copolymer of 50% by weight of methyl methacrylate and 50% by weight of ethyl acrylate.

The release characteristics of the beads of Example M4 were evaluated in the dissolution test of USP < 711 > , apparatus 1, pH 6.8 phosphate buffer. It was discovered in this case that approximately amounts of active ingredient are released at 2 hour intervals.

DOSAGE FORMS / USES The pharmaceutical forms of the various layers of the invention initially have the form of tablets or dragees. These in turn can be used as an ingredient of a multiparticulate pharmaceutical form, of tablets containing dragees, mini-tablets, capsules, sachets, effervescent tablets or powders for reconstitution. It is possible according to the invention for multi-particulate pharmaceutical forms that also include particular mixtures of formulated dragees comprising different active ingredients. Another possibility is that pharmaceutical forms multiparticulates of the invention comprise dragee populations that are loaded with one and the same active ingredient but are differently formulated and sample different release profiles. It is possible in this form that the combined release profiles of one or more active ingredients are obtained and that a more refined adaptation for the desired therapy is carried out through the blends. EXAMPLES EUDRAGIT® RS = copolymer of 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammoniomethyl methacrylate chloride. EUDRAGIT® NE = 50% copolymer by weight of methyl methacrylate and 50% 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 controlling layer d), dragees without a controlling inner layer b) were made. Dragees without a substance that has a modulating effect but with microcrystalline cellulose (Example 5) were used for comparison. It is possible in this form to affirm effects such as an accelerated or decelerated delivery of active ingredient independently of an inner controlling layer. A mixture of 1290 g of theophylline powder, 65 g of Kollidon 25 and 6.5 g of Aerosil are sprinkled in 700 g of the clinical material in fret coating and are bound to the core material by simultaneous atomization of a solution of 33 g of theophylline and 10 g of 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 is applied in a fluidized bed system at 600 g of theophylline tablets produced in this way with non-slow release modulator core. The amount of polymer applied corresponds to 20% of the initial material. The dragees produced in Example 1-5 were investigated for delivery of active ingredient in a European Pharmaceutical Phosphate buffer solution of pH 6.8 in a USP dissolution tester.

The release values show the first-order profile characteristics of the diffusion processes. In this way, without controlling the release of the modulator, a very rapid equilibrium results in the coated dragee, which definitely adjusts to the permeability of the final coating at the start of release. The release profile of the tablets with microcrystalline cellulose (Example 5) is between those with sodium acetate and sodium chloride. Thus, an accelerating effect results for sodium acetate, citric acid and sodium succinate and a reducing effect results for sodium chloride. Examples 6-10 (According to the invention, zero order release characteristics "linearity"). 1000 g of core material is coated in a fluidized bed system with a spray suspension of 666 g of EUDRAGIT® NE 30D (corresponding to 200 g of polymer), 4 g of polysorbate 80, 10 g of glycerol monostearate, 1 g of yellow iron oxide and 720 g of demineralized water. The applied amount of polymer thus corresponds to 20% initial material. A mixture of 1290 g of theophylline powder, 65 g of Kollidon 25 and 6.5 g of Aerosil 200 are sprinkled in 700 g of the cores produced in this way with delivery of slow release modulator in a coating tray and are joined to the core material by simultaneous atomization of a solution of 33. g of theophylline and 10 g of 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 is applied to 600 g of theophylline tablets produced in this way with slow release modulator core in a fluidized bed system. The applied amount of polymer thus corresponded to 20% of the initial material. The dragees made in Example 6-10 were investigated for delivery of active ingredient in a European Pharmaceutical Phosphate buffer solution of pH 6.8 in a USP dissolution tester: The release values show a zero order profile, that is, they are virtually linear. The release of the modulator from the core layer a) thus prevents early delivery of the active ingredient of the system in the case of sodium succinate and citric acid, and thereby the acceleration effect is retained for a longer period. In the case of sodium citrate and sodium acetate, the highest possible increase in the permeability of the EUDRAGIT® RS coating is never achieved by delaying the modulator supply, and therefore a continuous resupply results in a trace Longer and linear release compared to the uncontrolled modulator of Example 1 and 3. In the case of the sodium chloride core, the reducing effect is restricted more time through a continuous resupply, thus achieving a slower linear release. Example 11 (not according to the invention) To examine the theory that the control possibilities encountered require the use of an ionic coating material, the tablets were investigated with a neutral coating material in the following examples: A mixture of 1290 g of theophylline powder, 65 g of Kollidon 25 and 6.5 g of Aerosil 200 were sprinkled in 700 g of sodium acetate tals in a coating vessel and attached to the core material by simultaneously spraying a solution of 33 g of theophylline and 10 g of Kollidon 25 in 500 g of demineralized water. A spray suspension of 400 g of EUDRAGIT® NE 30D '(corresponding to 120 g of polymer), 2.4 g of polysorbate 80, 6 g of glycerol monostearate, 0.6 g of yellow iron oxide and 432 g of demineralized water were applied to 600 g of theophylline tablets produced in this form with a non-slow release modulator core in a fluidized bed system. Example 12 (not according to the invention) A mixture of 1290 g of theophylline powder, 65 g of Kollidon 25 and 6.5 g of Aerosil 200 were dusted into 700 g of sodium acetate tals in a container of coating and were attached to the core material by simultaneously spraying a solution of 33 g of theophylline and 10 g of Kollidon 25 into 500 g of demineralized water. A spray suspension of 400 g of EUDRAGIT® NE 30D (corresponding to 120 g of polymer), 2.4 g of polysorbate 80, 6 g of glycerol monostearate, 0.6 g of yellow iron oxide and 432 g of demineralized water was applied to 600 g of theophylline tablets produced in this way with a non-slow release modulator core in a fluidized bed system.

• The effect of the inner controlling layer b) is evident compared to Example 1 with the 6 • The effect of the controlling outer layer d) of the invention in Example 1 is evident in comparison with Example 1 with 11. • The effect of the absence of a controlling outer layer d) of the invention, independently of the presence of a controlling inner layer b), is evident compared to Example 11 with 12. Example 13 (accelerated) 1000 g of tals of sodium are coated in a fluidized bed system with a spray suspension of 666 g of EUDRAGIT® NE 30 D (corresponding to 200 g of polymer), 4 g of polysorbate 80, 10 g of glycerol monostearate, 1 g of oxide of yellow iron and 720 g of demineralized water. The applied amount of polymer thus corresponded to 20% of the initial material. A mixture of 760 g of theophylline powder, 560 g of sodium chloride, 65 g of Kollidon 25 and 6.5 g of Aerosil 200 700 g of the cores produced in this form were dusted with delivery of slow release modulator in a coating tray and attached to the core material by simultaneously spraying a solution of Kollidon 25 and 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 is applied to 600 g of the theophylline tablets produced in this way with the slow release modulator in the ) of core in a fluidized bed system. The applied amount of the polymer thus corresponds to 20% of the initial material. The dragees produced in Example 13 can be investigated for delivery of active ingredient in a European Pharmaceutical Phosphate buffer solution of pH 6.8 in a USP dissolution tester. The following principle of slow release will be possible to be confirmed in this way: The active ingredient is released within a period of 10 hours, with a very small initial release. A continuous acceleration of release will be observed during the investigated period.

Claims (15)

1. CLAIMS 1. Multilayer pharmaceutical form for controlled active ingredient release, comprising a) a core layer comprising a substance having a modulatory effect in relation to delivery of the active ingredient, when a core and / or a core is appropriate. active ingredient, b) an inner controlling layer that influences the delivery of the substance having a modulating effect and the active ingredient that is present when appropriate from the core layer, comprising pharmaceutically usable polymers, waxes, resins and / or proteins; c) 1 a layer of active ingredient comprising an active pharmaceutical ingredient, and when appropriate, a substance having a modulating effect, d) a controlling outer layer comprising at least 60% by weight of one or a mixture of one plurality of methacrylate copolymers composed of 98 to 85 alkyl esters with 1 to 4 carbon atoms of methacrylic acid and 2 to 15% by weight of methacrylate monomers with a quaternary ammonium group in the alkyl radical, and when appropriate up to 40% by weight of other pharmaceutically usable polymers. where the layers can also and in a known way itself comprise pharmaceutically customary excipients.
2. 2. Multilayer pharmaceutical form according to claim 1, characterized in that the alternative core layer a) and essentially comprises the following ingredients: I. a substance that has a modulating effect, in crystalline, granular or coprecipitated form; II. a substance having a modulatory effect and an active ingredient, which may be present in successive layers in some sequence or in a mixture; III. a neutral core (colored tablets) coated with a substance that has a modulating effect; IV. a neutral core (colored tablets) coated with a substance that has a modulating effect and an active ingredient, which can be present in successive layers and in any sequence or in a mixture.
3. 3. Multilayer pharmaceutical form according to claim 1 or 2, characterized in that the inner control layer consists of a polymer that is insoluble in water or only swellable in water.
4. 4. Multilayer pharmaceutical form according to claim 3, characterized in that the polymer is selected from: Copolymers of methyl methacrylate and / or ethyl acrylate and methacrylic acid, copolymers of methacrylate of methyl, methyl acrylate and methacrylic acid, copolymers of methyl methacrylate, butyl methacrylate and dimethylethyl methacrylate, copolymers of methyl methacrylate, ethyl acrylate and trimethylammoniomethyl methacrylate, copolymers of methyl methacrylate and ethyl acrylate, acrylate copolymers of ethyl, methyl acrylate, butyl methacrylate and methacrylic acid. Polyvinylpyrrolidone (PVPs), polyvinyl alcohols, polyvinyl alcohol polyethylene glycol graft copolymer (Kollicoat®), starch and derivatives thereof, polyvinylacetate phthalate (PVAP, Coateric®), polyvinyl acetate (PVAc, Kollicoat), vinyl acetate / vinylpyrrolidone copolymer (Kollidon® VA64), vinyl acetate copolymer: crotonic acid 9: 1 copolymer (VAC: CRA, Kollicoat® VAC), polyethylene glycols with molecular weight above 1000 (g / mol) chitosan, a copolymer of methacrylate comprising from 20 to 40% by weight of methyl methacrylate and 60 to 80% by weight of methacrylic acid, a crosslinked and / or non-crosslinked polyacrylic acid, an Na alginate and / or a pectin. Celluloses such as, for example, anionic carboxymethylcellulose and salts thereof (CMC, Na-CMC, Ca-CMC, Blanose, Tylopur), carboxymethylethylcellulose (CMEC, Duodecell®), hydroxyethylcellulose (HEC, Klucel), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC, Pharmacoat, Methoel, Sepifilm, Viscontran, Opadry), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC, Ethocel® Aquacoat®, Surelease®), methylcellulose (MC, Viscontran, Tylopur, Methocel), cellulose esters, cellulose glycolate, cellulose acetate phthalate (CAP, Cellulosi acetates, European Pharmaceutical, cellulose acetate phthalate, NF, Aquateric®), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP, HP50, HP55), hydroxypropylmethylcellulose acetate succinate (HPMCAS-LF, -MF, -HF ). A multilayer pharmaceutical form according to claim 1 or 2, characterized in that the inner control layer consists of a wax such as, for example, carnauba wax and / or beeswax. 6. Multilayer pharmaceutical form according to claim 1 or 2, characterized in that the matrix of the inner control layer comprises the resin shellac. 7. Multilayer pharmaceutical form according to claim 1 or 2, characterized in that the inner controlling layer consists of a protein such as, for example, albumin, gelatin, glutene, collagen and / or zein. 8. Multilayer pharmaceutical form according to one or more of claims 1 to 6, characterized in that the substance having a modulating effect it has a molecular weight below 500 and has solid and ionogenic form. 9. Multilayer pharmaceutical form according to claim 7, characterized in that the substance having a modulating effect is soluble in water. 10. Multi-layer pharmaceutical form according to claim 7 or 8, characterized in that the substance having a modulating effect is an organic acid or the salt of an organic or inorganic acid. 11. Multilayer pharmaceutical form according to one or more of claims 1 to 9, characterized in that the substance having a modulating effect is 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 sulphates. 12. Multilayer pharmaceutical form according to one or more of claims 1 to 10, characterized in that the layer c) of active ingredient comprises metoprolol succinate and the release of the active ingredient measured according to USP, 100 rpm. , pH 6.8 is slower in the intervals of 2 hours until the fourth hour than in the intervals of 2 hours from the fourth to the tenth hour. 13. Pharmaceutical form of several layers of agreement with one or more of claims 1 to 10, characterized in that the layer c) of the active ingredient comprises terbutaline sulfate and the release of the active ingredient measured according to UPS, 100 rpm, pH 6.8 is approximately constant at intervals of 2 hours until the twelfth hour. Process for producing a multi-layered dosage form according to one or more of claims 1 to 12 in a manner known per se through pharmaceutically traditional processes such as direct compression, compression of dry, wet or sintered granules, extrusion and subsequent rounding, wet or dry granulation or direct pelletizing or powder binding (separation into powder layers) into free beads of active ingredient or neutral cores (colored pellets) or particles containing active ingredient or by means of atomization or granulation of the fluidized bed. 15. Use of the multilayer dosage form according to one or more of claims 1 or 2 as an ingredient of a multiparticulate pharmaceutical form of tablets containing dragees, mini-tablets, capsules, sachets, effervescent tablets or reconstitution powders.