MX2008008915A - Pharmaceutical compositions containing mixtures of polymers and active agents poorly soluble in water - Google Patents

Abstract

The invention relates to a pharmaceutical composition, containing a mixture of at least one cationic water-soluble (meth)acrylate copolymer, at least one water-insoluble polymer and at least one active agent with a solubility in demineralised water of 3,3 g/l or less, characterised in that the water-insoluble polymer and the active agent are present in a ratio of at most 3.5 to 1 parts by weight and the pharmaceutical composition has the following properties:the contained active agent is released in dissolved form in a medium buffered at pH 1.2, which, after 2 hours at pH 1.2, corresponds to at least 16 times the solubility value of the active agent alone at pH 1.2.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING POLYMER MIXTURES AND MODERATELY SOLUBLE ACTIVE INGREDIENTS IN WATER The invention relates to various pharmaceutical compositions comprising mixtures of polymers and active ingredients moderately soluble in water. PREVIOUS TECHNOLOGY EP 0 058 765 Bl discloses compositions with a dilatable coating, soluble in gastric juice and its use in a process for coating pharmaceutical forms. These are in particular water-soluble (meth) acrylate copolymers which are partially or completely composed of alkyl acrylates and / or alkyl methacrylates having a tertiary amino group in the alkyl radical. US 6,391,338 describes the improvement in the solubility or increase in bioavailability of active ingredients essentially insoluble in water, for example ibuprofen, itraconazole and nifedipine by means of instantaneous flow or extrusion of the active ingredients and polymers of the EUDRAGIT® E type. processing, the active ingredients can be converted into a higher state energetically (solid dispersion) and then released in the form of nanoparticles in a dissolved state.

US 6,319,520 discloses pharmaceutical compositions for released active controlled ingredients, consisting of mixtures that are thermally formed of by at least one active ingredient and one or more pH independent polymers from the group of polymethacrylates. The pharmaceutical compositions can be prepared by means of injection molding, co-molding by injection, extrusion or coextrusion. The (meth) acrylate copolymers are preferably EUDRAGIT® RL and RS, which can also optionally be used together with EUDRAGIT® E or EUDRAGIT® L100, L100-55 and / or S100. In the examples, the active ingredients include benfluorex hydrochloride, rilmetidine dihydrogen, fenspiride hydrochloride are processed with EUDRAGIT® RL, RS and mixtures thereof by means of extrusion or injection molding. WO 01/39751 A1 describes a process for producing moldings by means of injection molding. The process steps comprise: a) casting a (meth) acrylate copolymer which is composed of 30 to 80% by weight of Ci to C4 alkyl esters polymerized with free radical of acrylic acid or methacrylic acid and 70 to 20% by weight of (meth) acrylate monomers having a tertiary ammonium group in the alkyl radical, the (meth) acrylate copolymer which is present in a mixture with 1 to 70% by weight of a plasticizer and a dryer in a ratio of 1: 1 to 1:20, at least 1% by weight of plasticizer present, and 0.05 to 5% by weight of a release agent and also present and additionally additives or customary excipients and optionally an active pharmaceutical ingredient may be present in the mixture, and the mixture, before melting, have a low content in low boiling constituents having a vapor pressure of at least 1.9 bars at 120 ° C or above 0.5% by weight, degassing the mixture in a thermoplastic state at temperatures of at least 120 ° C, lowering the content of the low boiling constituents having vapor pressure of at least 1.9 bar at 120 ° C until as maximum 0.5% by weight and c) injection of the melt and degassed mixture into the cavity in the form of an injection mold, the mold cavity has a temperature that is at least 10 ° C below the temperature of the mold. The glass portion of the (meth) acrylate copolymer, cooling the molten mixture and removing the mold from the mold. The (meth) acrylate copolymer, which may preferably be an EUDRAGIT® E, may be present in a mixture with additional polymers to control the release of the active ingredient. The content of the additional polymers should not be more than 20% by weight, preferably at most 10% by weight, in particular 0-5% by weight. Additional polymers for blends include EUDRAGIT® NE 30 D, EUDRAGIT® RS and EUDRAGIT® RL. The process can be applied to any active ingredient, and ranitidine is one mentioned. WO 01/12935 A2 discloses a process for producing molds by means of injection molding, comprising the steps of: A) melting a mixture of: a) a (meth) acrylate copolymer consisting of 40 to 100% by weight of Cx to C4 alkyl esters polymerized with free radical of acrylic acid or methacrylic acid and 0 to 60% by weight of (meth) acrylate monomers having an anionic group in the alkyl radical containing: b) 0.1 to 3% by weight of a release agent, and optionally c) 0 to 50% by weight of a secant d) 0 to 30% by weight of a plasticizer e) 0 to 100% by weight of additives or excipients f) 0 TO 100% by weight of an active pharmaceutical ingredient g) 0 to 20% by weight of a polymer or copolymer additional amounts may be present in the mixture, the amounts of components b) to g) are based on the copolymer of (meth) acrylate a) and the mixture, prior to casting, having a content of low boiling constituents which have a high pressure of steam of at least 1.9 bar at 120 ° C of more than 0.5% by weight, B) degassing the mixture in a thermoplastic state at temperatures of at least 120 ° C, which lowers the content of the low boiling constituents that have a vapor pressure of at least 1.9 bar at 120 ° C up to a maximum of 0.5% by weight, C) injecting the melted and degassed mixture into the mold-forming cavity by injection, where the shape cavity has a temperature which is at least 10 ° C below the glass transition temperature of the (meth) acrylate copolymer, cooling the molten mixture and removing the resulting molding from the mold. The mixture may contain from 0 to 20% by weight of an additional polymer or copolymer g). To control the release of the active ingredient, it may be advantageous in the individual case to add additional polymers. The content of additional polymers in the mixture is, however, not more than 20% by weight, preferably at most 10% by weight, in particular from 0-5% by weight, based on the (meth) acrylate copolymer. Examples of these additional polymers are: polyvinylpyrrolidones, polyvinyl alcohols, copolymers of methyl methacrylate cationic (meth) acrylate and / or ethyl acrylate and 2-dimethylaminoethyl methacrylate (EUDRAGIT® E100), salts of carboxymethylcellulose, hydroxypropylcellulose (HPMC) ), methyl methacrylate (meth) acrylate neutral copolymers and ethyl acrylate (dry substance formed from EUDRAGIT® NE 20 D), copolymers of methyl methacrylate and butyl methacrylate (PLASTOID® B) or (meth) acrylate copolymers having quaternary ammonium groups, containing trimethylammonioethyl methacrylate chloride as a monomer (EUDRAGIT® RL and EUDRAGIT® RS). WO 2204/019918 discloses a process for preparing a suitable granule or powder as a coating and binder composition for oral or dermal pharmaceutical forms, for cosmetics or dietary supplements, consisting essentially of (a) a copolymer of Cl to C4 esters polymerized with radical free of acrylic acid or methacrylic acid and furthermore (meth) acrylate monomers having functional tertiary amino groups, (b) from 3 to 25% by weight, based on (a) of an emulsifier having a HLB value of at least 14, (c) from 5 to 50% by weight, based on (a), of a monocarboxylic acid Ci2 to Ci8 or of a hydroxy compounds Ci 2 to C 8, the components of (a), (b) and (c) are combined or mixed together simultaneously or optionally in succession with the addition of an active pharmaceutical ingredient and / or additional customary additives, melts in a mixer with heating and mixing and the melt is cooled and crushed to a granule or powder. The granules and powders obtained by means of the process are suitable in particular for the formulation of active ingredients sensitive to humidity, for example acetylsalicylic acid, carbenoxolone, cefalotin, epinephrine, imipramine, potassium iodide, ketoprofen, levodopa, nitrazepam, nitroprusside, oxytetracycline -HCl, promethazine, omeprazole and other benzimidazoles derivatives, ranitidia or streptomycin. Problem and Solution US 6,391,338 describes the improvement in solubility or increase in bioavailability of active ingredients essentially insoluble in water, for example ibuprofen, itraconazole and nifedipine by means of instantaneous flow or extrusion of active ingredients or polymers of the EUDRAGIT® E type. By processing, the active ingredients can be converted to an energetically higher state (solid dispersion) and then released in the form of nanoparticles in a dissolved state. This is a scientifically surprising approach that leads to good results in many cases. Pharmaceutical compositions formulated in accordance with US 6,391,338 generally have the property of releasing an active ingredient present having a solubility in demineralized water of 3.3 g / 1 or less, after dissolution of an EUDRAGIT® E matrix at acid pH, in dissolved form in a concentration that initially corresponds at least twice the solubility value of the active ingredient in demineralized water. However, the inventors have found that this effect continues only over a relatively short period. After the initial rise in the concentration of the measured active ingredient measurably, it falls again below the limit of twice the solubility value of the active ingredient in demineralized water. The measurement of the dissolved active ingredient can be monitored, depending on the type of active ingredient or nature of the active ingredient, for example, by means of chromatographic or spectroscopic methods, for example UV or HPLC measurement, or by other methods. The inventors suspect that the initially higher energy state of the active ingredient, after dissolution of the EUDRAGIT® E matrix, degenerates rapidly again and the active ingredient is converted to a moderately soluble or insoluble form which is then in a better bioavailable degree or to a limited degree, in case it is found, and possibly still crystallizes, adds and / or precipitates. This proportion of the active ingredient is therefore available only to a limited extent when it is transferred into the duodenum. There is a risk that originally desired blood levels will not be obtained. In the case of active ingredients moderately soluble in water, which are intended to be released and absorbed again immediately in the stomach or after passing through the stomach, for which a certain blood level has been obtained for a therapeutic action, the problem then exists in that the blood level often can not be obtained, since the active ingredient recrystallizes or precipitates again too quickly, and if originally increased bioavailability is lost again in this way. WO 01/39751 Al discloses a process for producing molds through injection molding. In particular, the object of providing copolymers of (meth) acrylate in tertiary amino groups in a form that is processed in injection molding must be achieved, so that the corresponding molds are obtained in pharmaceutical quality. It is mentioned that, like (meth) acrylate copolymers with tertiary amino groups only, it is also possible to process mixtures with EUDRAGIT® NE, EUDRAGIT® RS or RL. Examples of these mixtures alone or in combination with active ingredients are not present. WO 01/39751 Al does not provide a person skilled in the art with any indication of the solution to the aforementioned problem, which is to provide a relatively long lasting improvement in solubility for the moderately soluble active ingredients in water. WO 01/43935 A2 describes a process for the production of moldings by means of injection molding. In particular, the aim of providing copolymers of (meth) acrylate with anionic groups in a processable form in injection molding should be achieved, so that the corresponding molders obtained have pharmaceutical quality. It is mentioned that, just like copolymers of (meth) acrylate with anionic groups only, it is also possible to process mixtures with EUDRAGIT® NE EUDRAGIT® RS or RL. Examples of these mixtures alone or in combination with the active ingredients are not present. WO 1/43935 A2 does not provide a person skilled in the art with any indication of the solution to the aforementioned problem, in terms of providing a relatively long lasting improvement in solubility for moderately active ingredients. soluble in water. Therefore, from the prior art, the intention is to provide a pharmaceutical formulation for moderately water-soluble active ingredients, for which an improved solubility and associated bioavailability of the active ingredient is obtained and remains in a juice-like environment. gastric, pH 1.2, entirely or at least partially stable for a period of at least 120 minutes. The test environment similar to gastric juice represents the high requirement, so it can be assumed that the high solubility state, when it can be stably obtained in Vi tro with a pH of 1.2 after 120 minutes, will not change significantly from a Disadvantageously still in vivo after transferring to the bowel section with higher pH values that might exist there. The objective is achieved by: a pharmaceutical composition comprising a mixture of at least one cationic copolymer of water soluble (meth) acrylate, at least one water insoluble polymer and at least one active ingredient having a solubility in demineralized water of 3.3 g / 1 or less, characterized in that, the water insoluble polymer and the ingredient active is present in a ratio with a maximum of 3.5 to 1 part by weight and the pharmaceutical composition has the property of releasing the active ingredient present in a buffered medium with a pH of 1.2 in dissolved form in a concentration which, after 2 hours with a pH of 1.2, it corresponds at least to sixteen times the solubility value of the active ingredient only with a pH of 1.2. The invention also relates to two alternative processes for preparing the inventive pharmaceutical compositions. The invention further relates to a process for producing a pharmaceutical form comprising the inventive pharmaceutical composition, and to the resulting pharmaceutical forms. The invention also relates to the use of inventive pharmaceutical compositions to produce a pharmaceutical form. Implementation of the Invention The invention relates to a pharmaceutical composition preferably in the form of a powder, comprising a mixture of at least one cationic copolymer of water-soluble (meth) acrylate, at least one polymer insoluble in water and at least one active ingredient having a solubility in demineralized water of 3.3 g / 1 or less, characterized in that the water-insoluble polymer and the active ingredient are present in a ratio of at most 3.5 to 1 part by weight and the pharmaceutical composition has the property of releasing the active ingredient present in a buffered medium with a pH of 1.2 (SGFsp, Simulated Gastric Fluid sine pancreatin) in dissolved form in a concentration that after 2 hours at a pH of 1.2, corresponds at least to sixteen times the solubility value of the active ingredient only at a pH of 1.2. Water-soluble (meth) acrylate cationic copolymers It is understood that water-soluble (meth) acrylate cationic copolymers are copolymers of (meth) acrylate with cationic groups, which are soluble in water at least within a certain pH range . In general, the pharmaceutical compositions comprise only one cationic copolymer of water-soluble (meth) acrylate if it is correct for two or more water-soluble (meth) acrylate cationic copolymers are present together with one another or in a mixture. The water-soluble (meth) acrylate cationic copolymer possibly has the function of converting the moderately soluble active ingredient into water, in the case of a molten extrusion similar to US 6,391,338, to a state of higher solubility in the polymer blend.

Examples of water-soluble (meth) acrylate cationic copolymers are in particular: Type EUDRAGIT® E The water-soluble (meth) acrylate cationic copolymer can be partially or completely composed of alkyl acrylates and / or alkyl methacrylates with a Tertiary amino group in the alkyl radical. Suitable copolymers of (meth) acrylate are known from EP 0 058 765 Bl. The water-soluble (meth) acrylate cationic copolymer can be composed, for example, from 30 to 80% by weight of Ci to C4 alkyl esters polymerized with free radical of acrylic acid or methacrylic acid and from 70 to 20% by weight of monomers of (meth) acrylate with a tertiary amino group in the alkyl radical. Suitable monomers with functional tertiary amino groups are detailed in US 4 705 695, column 3 line 64 to column 4 line 13. Particular mention should be made of dimethylaminoethyl acrylate, 2-dimethylaminopropyl acrylate, dimethylaminopropyl methacrylate, dimethylaminobenzyl acrylate, dimethylaminobenzyl methacrylate, (3-dimethylamino-2, 2-dimethyl) propyl acrylate, (dimethylamino-2, 2-dimethyl) propyl methacrylate, 3-diethylamino-2, 2-dimethyl) propyl acrylate and (diethylamino) methacrylate -2, 2- dimethyl) propyl. Particular preference is given to dimethylaminoethyl methacrylate. The content of the monomers with tertiary amino groups in the copolymer can advantageously be between 20 and 70% by weight, preferably between 40 and 60% by weight. The proportion of C to C4 alkyl esters of acrylic acid or methacrylic acid is 70-30% by weight. Mention should be made of methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate. A (meth) acrylate copolymer can be formed with suitable tertiary amino groups, for example, 20-30% by weight of methyl methacrylate, 20-30% by weight of butyl methacrylate and 60-40% by weight of methacrylate of dimethylaminoethyl. A copolymer of (meth) acrylate with commercially suitable tertiary amino groups is, for example, formed of 25% by weight of methyl methacrylate, 25% by weight of butyl methacrylate and 50% by weight of dimethylaminoethyl methacrylate (EUDRAGIT ® E100 or EUDRAGIT® E PO (powder form)). EUDRAGIT® El00 and EUDRAGIT® E PO are soluble in water below about pH 5.0 and thus are also soluble in gastric juice.

Water-insoluble polymers Water-insoluble polymers are understood to mean those polymers which are insoluble in water throughout the pH range from 1 to 14 and only swell in water. In general, only one water-insoluble polymer is present in the pharmaceutical composition. However, it is also possible that two or more correct water-insoluble polymers are present together with another or in a mixture. It is suspected that the water-insoluble polymer has the function of stabilizing the moderately water-soluble active ingredient in the state of higher solubility after being released from the pharmaceutical composition for a prolonged period, and thus slowing down or avoiding Aggregation, recrystallization or precipitation reducing solubility. Examples of water-insoluble polymers preferably are in particular neutral (meth) acrylate copolymers and (meth) acrylate copolymers with quaternary amino groups. Neutral (meth) acrylate copolymers (EUDRAGIT® type NE or EUDRAGIT® type NM) Neutral or essentially neutral methacrylate copolymers consist of at least 95% by weight, in particular up to a measure of at least 98% by weight, preferably at least 99% by weight, in particular by at least 99% by weight, more preferably 100% by weight, of monomers of ( met) acrylate with neutral radicals, especially Cx to C4 alkyl radicals. Suitable (meth) acrylate monomers with suitable neutral radicals are, for example, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate. Preference is given to methyl methacrylate, ethyl acrylate and methyl acrylate. The methacrylate monomers with anionic radicals, for example, acrylic acid and / or methacrylic acid, can be present in small amounts of less than 5% by weight, preferably not more than 2% by weight, more preferably not more than 1% by weight. 0.05 to 1% by weight. Suitable examples are neutral or virtually neutral (meth) acrylate copolymers composed of 20 to 40% by weight of ethyl acrylate, 60 to 80% by weight of methyl methacrylate and 0 or less than 5% by weight, preferably 0 at 2 or 0.05 to 1% by weight (EUDRAGIT® type NE). EUDRAGIT® NE and EUDRAGIT® NM are copolymers of % by weight of ethyl acrylate and 70% by weight of methyl methacrylate. Preference is given to neutral or essentially neutral methyl acrylate copolymers which, according to WO 01/68767, have been prepared as dispersions using 1-10% by weight of a nonionic emulsifier having an HLB value of 15.2 at 17.3. The latter offers the advantage that there is no phase separation with the formation of crystal structures through the emulsifier (EUDRAGIT® NM). According to EP 1 571 164 A2corresponding, to neutral (meth) acrylate copolymers with small portions of 0.05 to 1% by weight of mono-olefinically unsaturated C3-C8 carboxylic acids can, however, also be prepared through the emulsion polymerization in the presence of amounts comparatively small of anionic emulsifiers, for example 0.001 to 1% by weight. Copolymers of (meth) acrylate with quaternary ammonium groups (EUDRAGIT® type RS / RL) Copolymers of water-insoluble (meth) acrylates, for example from EP-A 181 515 or DE-C 1 617 751. Regardless of pH, only expandable polymers, which are suitable for drug coatings, are insoluble in water, respectively in water. A possible preparation process in Bulk polymerization in the presence of an initiator that forms free radical dissolved in the monomer mixture. Likewise, the addition of the polymer can also be prepared by means of a solution or precipitation polymerization. The addition polymer can thus be obtained in the form of a fine powder, which is achieved in the case of bulk polymerization, by grinding, and in the case of solution polymerization and precipitation, for example, through spray dried. A suitable water-insoluble (meth) acrylate copolymer is composed of 85 to 98% by weight of Ci to C4 alkyl esters polymerized with free radical of acrylic acid or methacrylic acid and 15 to 20% by weight of (met) monomers ) acrylate having a quaternary amino group in the alkyl radical. The alkyl esters C? to C4 of acrylic acid or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and methyl methacrylate. A (meth) acrylate monomer particularly preferably with quaternary ammonium groups is 2-trimethylammonioethyl methacrylate chloride. A corresponding copolymer can be formed, for example 50-70% by weight of methyl methacrylate, 20-40% by weight of ethyl acrylate and 7-2% by weight of 2-trimethylammonioethyl methacrylate chloride. A suitable copolymer specifically contains 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammonioethyl methacrylate chloride (EUDRAGIT® RS). A further suitable (meth) acrylate copolymer can be formed, for example, from 85 to less than 93% by weight of Cx to C4 alkyl esters polymerized with free radical of acrylic acid or methacrylic acid and more than 7 to 15% by weight. monomer weight of (meth) acrylate with a quaternary ammonium group in the free radical. These (meth) acrylate monomers are commercially available and have been used for some time for retardant coatings. A specifically suitable copolymer contains, for example, 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of trimethylaminoethyl methacrylate chloride (EUDRAGIT® RL). In particular, useful mixtures of the (meth) acrylate copolymers also include in particular mixtures of EUDRAGIT® RS and EUDRAGIT® RL, for example in the ratio of 9: 1 to 1: 9 parts by weight. Copolymers of polyvinyl acetate / polyvinyl acetate, ethyl and methylcellulose The pharmaceutical composition can also be to comprise, as the water-insoluble polymer, a polyvinyl acetate, a polyvinyl acetate copolymer (for example Kollicoat® SR 30D or Kollidon® type SR), an ethylcellulose or a methylcellulose. Proportions The water-soluble (meth) acrylate copolymer or copolymers and the water-insoluble polymer or polymers in the pharmaceutical composition may be present in the relative ratio of another 40:60 to 99: 1 parts by weight, preferably in a ratio relative to others from 50:50 to 95: 5 parts by weight, particularly in a relative relation with another from 70:30 to 92: 8 parts by weight. Surprisingly, even the small additions of water-insoluble polymer to the water-soluble (meth) acrylate copolymer are sufficient to achieve the inventive effect. The ratio of the water-insoluble polymer, based on the active ingredient having a solubility in demineralized water of 3.3 g / 1 or less, should not be too high, since the desired improvement in solubility after 120 minutes with a pH of 1.2 in at least 16 times it is not achieved otherwise. The water-insoluble polymer and the active ingredient should be present in a ratio of at most 3.5 parts by weight of water insoluble polymer to 1 part by weight of the active ingredient, preferably of how maximum 3.5: 1 to 0.25: 1 parts by weight, in particular from maximum 2.5: 1 to 0.25: 1 parts by weight. In the case of the presence of a plurality of water insoluble polymers and / or a plurality of active ingredients side by side, the proportions are each based on their own sum. Active Ingredients The pharmaceutical compositions comprise at least one, generally one, active ingredient, but if correct also combinations of two or more active ingredients. Therefore, the active ingredient present can consist of a single active ingredient or if it is also correct of a plurality of individual active ingredients. The active ingredient (s) has (s) a solubility in demineralized water of 3.3 g / 1 or less, preferably 2.2 g / 1 or less, in particular of 1.1 g / 1 or less. The active ingredient (s) may belong, for example, to the group of BCS classes II and IV (biopharmaceutical classification system according to Prof. Amidon; Amidon et al., Pharm. Res. , 413-420 (1995)) and / or the group of antiandrogens, antidepressants, antidiabetics, antirheumatics, glucocorticoids, cytostatics, migraine drugs, neuroleptics, antibiotics, estrogens, vitamins, psychotropic drugs, ACE inhibitors, ß-blockers, calcium channel blockers, diuretics, cardiac glycosides, antiepileptics, diuretics / antiglaucoma, uricostatics, H2 receptor blockers and virostats. The active ingredients of BCS class II and IV have a solubility in demineralized water of 3.3 g / 1 or less. The active ingredients of BCS class II have good permeability, those of BCS class IV have low permeability. Therefore, the advantages of the invention are exhibited in particular for the active ingredients of BCS class II, since the availability of the active ingredient in the solution here constitutes the only limitation of its bioavailability. However, the increased availability of the active ingredient in solution may also be useful in the case of the active ingredients of BCS class IV, in order to achieve some improvement in the bioavailability of at least gradually rather than limiting a poor absorption in the cells (permeability) of the active ingredients. It is possible, for example, for the active ingredient (s) that are present: bicalutamide, anastrozole, albendazole, amitriptyline, artometer, chloropromazine, ciprofloxacin, clofaximine, dapsone, diloxanide, efevirenz, folic acid, furosemide, glibenclamide, griseofulvin, haloperidol, ivermectin, ibuprofen, idinavir, lopinavir, lumefantrine, mebendazole, mefloquine, niclosamide, nelfinavir, nifedipine, nitrofurantoin, phenytoin, purantel, puremetamine, retinol, ritonavir, spironolactone, sulfadiazine , sulfasalazine, sulfamethoxazole, triclabendazole, trimethoprim, valproic acid, verapamil, arfarine, nalidixic acid, nevirapine, praziquantel, rifampin, glimipiride, nilutamide, bromocriptine, ketotifen, letrozole, naratriptan, ganciclovir, orlistat, misoprostol, granistron, pioglitazone, lamivudine, rosiglitazone , zidovudine, enalapril, atenolol, nadolol, felodipine, bepridil, digoxin, digitoxin, carbamazepine, acetazolamide, allopurinol, cimetidine, ranitidine or oxacarbazepine. Water Solubility The invention relates to active ingredients having a solubility in demineralized water of 3.3 g / 1 or less, preferably 3.3 g / 1 or less, in particular of 1.1 g / 1 or less. The solubility in water for the active ingredient can be defined according to DAR 10 (Deutsches Arzneibuch [German Pharmacopoeia] 10a. edition with 3rd revision 1994, Deutscher Apothekerverlag, Stuttgart and Govi Verlag, Vorschriften [General Methods IV] pg. 5-6, "Lóslichkeit und Lósungsmittel" ["Solubility and solvents"] see also Ph. Eur. 4.07, 2004). Solubility at pH 1.2 Solubility at pH 1.2, ie the amount of active ingredient present in dissolved form, can be determined, for example, chromatographically and / or spectrometrically in a buffered medium of pH 1.2 (SGFsp, Simulated Gastric Fluid sine pancreatin) according to USP (paddle method, 100 rpm). The values of the active ingredient formulated according to the invention and the unformulated active ingredient are compared after 120 min. This simulates the conditions of an average time of passage of the stomach. In this comparison, the solubility of the active ingredient formulated according to the invention must be increased at least 16 times, preferably at least 18 times, in particular at least 20 times. The methodology according to USP palette method is sufficiently known by the technology-enabled people (see, for example, USP 28- NF23, General Chapter <; 771 > , Dissolution Apparatus 2 (palette), Method < 724 > "Delayed Release (Layer Enteric) General Articles, General Drug Release Policy, Method B (100 rpm, 37 ° C)).

Process for producing the pharmaceutical composition "Solvent Process" The invention is further related to: A process for making a pharmaceutical composition in the form of a solid with the property of releasing the active ingredient present in a buffered medium at a pH of 1.2. form dissolved in a concentration which, after 2 hours with a pH of 1.2, corresponds at least to sixteen times the solubility value of the active ingredient only with a pH of 1.2, characterized in that a solution in an organic solvent, or a mixture of solvent composed of the water-soluble cationic (meth) acrylate copolymer, the active ingredient and the water-insoluble polymer are first obtained, then the solvent is removed, for example, by evaporation or by applying reduced pressure, for example, by freeze-dried or spray-dried, which offers a solid with the properties mentioned.The organic solvent can, if correct, also n being a solvent mixture with other organic solvents and / or water. When water is present, the content should only be so high that, instead of it, all the constituents, the two types of polymer and the active ingredient, continue to be a solution. Suitable solvents are, for example, acetone, isopropanol or ethanol or mixtures thereof. A suitable example is a mixture of isopropanol / acetone with 6: 4 parts by weight. Suitable examples are also mixtures of ethanol / water, preferably with not more than 50% by weight of water. The process makes use of the fact that the active ingredient is moderately soluble in water and therefore can be comparatively dissolved efficiently in an organic solvent. The (meth) acrylate copolymers are also dissolvable in an organic solvent. For example, EUDRAGIT® Type E polymers are also commercially available in the form of organic solutions with a solids content of 12.5%. The water-insoluble polymer, on the other hand, is easily soluble in an organic solvent. It is therefore possible to prepare a solution of the three components, in which case the active ingredient remains in the dissolved state even after the removal of the solvent in a solid. For unknown reasons, the content of water-insoluble polymer in the mixture has the effect that the original solubility of the active ingredient does not decline again below the threshold value after being released in a medium similar to intestinal juice at a pH of 7.2, this threshold value corresponds to at least twice the solubility value of the active ingredient in water demineralized after 4 hours. The solvent process has the advantage of being easy to implement. "Process of molten extrusion" The process of molten extrusion is preferred over the solvent process, one of the reasons is that the handling of solvents is problematic due to procedural reasons, health protection and environmental protection. According to the invention, this relates to a process for preparing a pharmaceutical composition in the form of an extrusion with the property of releasing the active ingredient present in a buffered medium with a pH of 1.2 in dissolved form in a concentration which after 2 hours with a pH of 1.2, corresponds at least to sixteen times the solubility value of the active ingredient only with a pH of 1.2, characterized in that the cationic copolymer of water-soluble (meth) crylate, the active ingredient and the insoluble polymer in water, melts are mixed and extruded at a temperature in the range of 60 to 220 ° C, preferably 80 to 180 ° C. The molten extrusion process can be carried out with the help of an extruder, especially by means of a double screw extruder. It is favorable when the extruder or double screw extruder are equipped with a degassing zone. The water-soluble and water-insoluble cationic polymer can be incorporated as a solid, as a polymer solution or as a polymer dispersion. The active ingredient may be added as a solid, as a solution or as a suspension. The extrudate is preferably processed by means of a chain granulation and hot cutting methods to give cylindrical and elongated chain granules, or through hot cutting with cooling to give rounded pellets. EP 1 563 987 Al describes an apparatus suitable for producing rounded pellets (pelletizer). The granules can preferably be ground to powder with, for example, a particle size of less than / equal to 1 mm, preferably in the range of 50 to 500 μm. Process for producing a pharmaceutical form The invention relates to a process for producing an inventive pharmaceutical form comprising a pharmaceutical composition characterized in that a pharmaceutical composition is prepared through the solvent process described above or the molten extrusion process, further processed to granules, pellets or powders, if formulated correctly by means of pharmaceutically customary excipients, and processed in a manner known per se same, for example, when mixing, compressing, powdering and / or encapsulating to a pharmaceutical form, for example in tablets, or preferably to a pharmaceutical form of multiple particles, especially tablets containing pellets, mini-tablets, capsules, sachets or reconstitutable powders. Production of multiple-particle tablets and dosage forms The inventive pharmaceutical composition is suitable as particles for producing pharmaceutical forms in the form of tablets and for use in multiple-particle dosage forms. The inventive pharmaceutical composition is preferably present in the form of a powder and can be used directly in almost all known pharmaceutical formulations in which the active ingredient is incorporated as a powder instead of the active ingredient. In this way, for example, as in WO 01/68058 or WO 2005/046649, the neutral cores (without equal) can be coated with pharmaceutical compositions in the form of powder and a binder in the process of powder layers. Subsequently, the coated cores are formulated in finished dosage forms with additional excipients and polymer layers as prescribed in WO 01/68058 or WO 2005/046649. For the pharmaceutical form of particles multiple, the pharmaceutical composition in the form of a powder still without neutral core, can be processed with binders by rounding, compressing the active ingredient containing particles or pellets that can be provided by themselves with the correct polymeric coating layers to control the release of the ingredient active. The production of multi-particle dosage forms to give tablets by compression of a pharmaceutically customary binder with active ingredient containing particles is described in detail, for example in, Beckert et al., (1996), "Compression of enteric-coated pellets. for disintegrating tablets ", International Journal of Pharmaceutics 143, pp. 13-23 and in WO 96/01624. The film coatings in the pellets containing active ingredient are typically applied in fluidized bed systems. The film formers are typically mixed with plasticizers and release agents through a suitable process. In this process, film formers can be present as a solution or suspension. The excipients for film formation can likewise be dissolved or suspended. Solvents or organic or aqueous dispersants can be used. To stabilize the dispersion, the stabilizers can be used additionally (example: Tween 80 or other emulsifiers or stabilizers) suitable). Examples of release agents are glyceryl monostearate or other suitable fatty acid derivatives, silicon derivatives or talc. Examples of plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, and also other substances mentioned in the literature. A separating layer, which serves for the separation of the active ingredient and the coating material for the purposes of avoiding interactions, can be applied between the layer containing the active ingredient and a layer of intestinal juice soluble copolymer which is optionally present. This layer can consist of inert film formers (for example HPMC or HPC) or, for example, talc or other suitable pharmaceutical substances. It is also possible to use combinations of film formers and talc or similar substances. It is also possible to apply a separation layer composed of partially or completely neutralized copolymer dispersions, which can, for example, comprise anionic (meth) acrylate copolymers. Mixtures to produce coated particle tablets are prepared by mixing the pellets with suitable binders to make tablets, if necessary addition of disintegrating promoter substances and if the addition of a lubricant is necessary. The mixing can be carried out in suitable machines. Inadequate mixers are those that lead to damage to the coated particles, for example plow grinders. In order to achieve suitably short disintegration times, a specific sequence in the addition of the excipients to the coated particles may be required. The premix with coated particles comprises the lubricant or mold release agent of magnesium stearate which allows its surface to be hydrophobicised and thus prevent adhesion. Suitable blends for tabletting typically contain from 3 to 15% by weight of a disintegration assistant, for example Kollidon CL and for example, from 0.1 to 1% by weight of a lubricant and a mold release agent such as magnesium stearate. . The binder content is determined by the required proportion of coated particles. Typical binders are, for example, Cellactose®, microcrystalline cellulose, calcium phosphates, Ludipress®, lactose and other suitable sugars, calcium sulfates or starch derivatives. Preference is given to low volume density substances. Typical disintegration assistants (disintegrants) are crosslinked starch or derivatives of cellulose and also cross-linked polyvinylpyrrolidone. The cellulose derivatives are equally suitable. The selection of a suitable binder allows the use of disintegrating assistants can be eliminated. Lubricants and mold release agents are magnesium stearates and other suitable salts of fatty acids or substances mentioned in the literature for this purpose (eg, lauric acid, calcium stearate, talc, etc.). When suitable machines are used (for example, presses for making tablets with external lubrication) or suitable formulations, the use of a lubricant and a mold release agent in the mixture can be eliminated. An excipient may be added to the mixture for flow improvement (eg, high dispersion silica derivatives, talc, etc.). The preparation of tablets can be carried out in customary presses for the manufacture of tablets, eccentric presses or rotary presses for the manufacture of tablets, with force pressures in the range of 5 to 40 kN, preferably 10-20 kN. The presses for making tablets can be equipped with systems for external lubrication. Excipients Excipients or additives may be added preferably in a manner known per se to the inventive composition in the course of production of granules, pellets or powder. All excipients used must, of course fundamentally not be controversial toxicologically and especially usable in medicines without risk for patients. The use of quantities and the use of customary additives in the coating of medicines are familiar to those skilled in the technology. Typical additives may, for example, be release agents, pigments, stabilizers, antioxidants, pore formers, penetration promoters, glitters, flavors or flavorings. These serve as excipients in the processing and must ensure a reliable and reproducible production process and good long-term storage stability, or that achieve additional advantageous properties in the pharmaceutical form. They are added to the polymer preparations before processing and can influence the permeability of the coatings that may be correct to be used as an additional control parameter. • Release Agents: Release agents, usually have lipophilic properties and are generally added to spray suspensions. These avoid the agglomeration of cores during the movie application. Preference is given to the use of talc, magnesium stearate, calcium stearate, earth silica, kaolin or non-ionic emulsifiers with a HLB value between 3 and 8. Typical amounts of use for release agents are between 0.5 to 100% by weight based on the sum of active ingredients, copolymer of Water-soluble (met) acrylate and water-insoluble polymer. • Pigments The pigments to be used can be non-toxic and suitable for pharmaceutical purposes. In this topic, see also, for example: Deutsche Prschungsgemeinschaft [German Research Institute], Farbstoffe für Lebensmittel [Dyes for Foods], Harald Boldt Verlag KC, Boppard (1978); Deutsche Lebensmittelrundschau 74, 4, pg. 156 (1978); German Law of Dyes for Medicines of 08.25.1980. Suitable pigments are, for example, pigments of aluminum oxide or orange yellow, cochineal red lake, chromatic pigments based on aluminum oxide or azo dyes, sulfonic acid dyes, Yellow Orange S (E110, C.I. 15985, FD &C Yellow 6), Carmine indigo (E132, C.I. 73015, FD &C Blue 2), Tartrazine (E 102, C.I. 19140, FD &C Yellow 5), Ponceau 4R (E 125, C.I. 16255, FD &C Red Cochineal A), Yellow Quinoline (E 104, C.I. 47005, FD &C Yellow 10), Erythrosine (E127, CI 45430, FD &C Red 3), Azorubin (E 123, CI 14720, FD &C Carmoisine), Amaranth (E 123, CI 16185, FD &C Red 2) ), Bright Acid Green (E 142, CI 44090, FD &C Green 8). The reported E numbers of the pigments are based on the EU numbering. In this topic, see also "Deutsche Forschungsgemeinschaft, Farbostoffe Für Lebensmittel, Harald Boldt Verlag KG, Boppard (1978), Deutsche Forschungsgemeinschaft, Farbstoffe für Lebensmittel, Harald Boldt Verlag KG, Boppard (1978), Deutsche Lebensmittelrundschau 74, 4, pg 156 (1978), German Drug Dyes Act of 25.08.1980 The FD &C numbers are based on the Food, Drug and Cosmetic Approval of the United States, Food and Drug Administration (FDA) described in: Food Administration and US Drugs, Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors, Code of Federal Regulations - Title 21 Color Additive Regulations, Part 82, List of Provisionally Related Certified Colors and Specifications (CFR 21 Part 82) • Plasticizers Additional additives can also be plasticizers, typical amounts are between 0 and 50% by weight, preferably between 5 to 20% by weight.

Depending on the type (lipophilic or hydrophilic) and the amount added, plasticizers can influence the functionality of the polymer layer. By virtue of the physical interactions with the polymer, the plasticizers manage to lower the glass transition temperature, and depending on the amount added, they promote the addition of film. Suitable substances generally have a molecular weight between 100 and 20,000 and contain one or more hydrophilic groups in the molecule, for example, hydroxyl, ester or amino groups. Examples of suitable plasticizers are alkyl citrates, glyceryl esters, alkyl phthalates, 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 generally liquid at room temperature, such as citrates, phthalates, sebacates or castor oil. Preference is given to the use of citrus and sebaceous esters. The addition of plasticizers to the formulation can be committed in a known manner, directly in an aqueous solution or after thermal pretreatment or a mixture. It is also possible to use mixtures of plasticizers. Pharmaceutical Form The invention further relates to a pharmaceutical form comprising an inventive pharmaceutical composition. Use The invention further relates to the use of an inventive pharmaceutical composition for the production of a pharmaceutical form. The pharmaceutical composition can preferably be incorporated in the form of a powder instead of a pulverized active ingredient. In the inventive formulation, the powder has the property of releasing the active ingredient present in a buffered medium at pH 1.2 in dissolved form at a concentration which, after 2 hours at pH 1.2, corresponds to at least sixteen times the solubility value of the active ingredient only at pH 1.2. This makes it possible to introduce active ingredients that are moderately soluble by themselves in pharmaceutical forms of all types in a state of high solubility. Advantageous Effects of the Invention An advantageous effect of the inventive pharmaceutical composition is in particular that the moderately soluble active ingredients in water are converted to a state of higher solubility, this state, in demarcation of the prior technology (see Example 1), remains stable at a pH of 1.2 for a period of 120 minutes. The period of 120 minutes at a pH of 1, 2 simulates an average passage time in the stomach. In this way, it is possible, after the initial high solubility of the active ingredient, to reduce or even prevent its recrystallization during the time of residence in the stomach. This increases the bioavailability as a function of time and in particular considerably at the time of transfer in the intestinal tract. The environment similar to gastric juice represents a high test requirement, so it can be assumed that the high solubility state, when stability is obtained in the test with a pH of 1.2 after 120 minutes, no longer significantly changes disadvantageously yet after transfer in the intestine section with the highest pH values that exist there. Therefore, the inventive pharmaceutical composition is not only suitable for the active ingredients that are released in the stomach but virtually also for all other pharmaceutical forms and / or dosage forms with a retardant formulation that actually releases the active ingredient into the stomach. This is possible, in a better way than to date, also obtain the comparatively high blood levels therapeutically required even in the case of moderately soluble active ingredients in water and also to maintain them for prolonged periods. The pharmaceutical composition is preferably present in powder form and can be used virtually in all formulations in which the active ingredient is processed in powder form instead. Due to the high solubility, in principle new possible therapies are opened in this way. The advantageous effects of the invention can be explained, for example, with reference to the examples. Examples A) Polymers EUDRAGIT® E is a water-soluble copolymer of 25% by weight of methyl methacrylate, 25% by weight of butyl methacrylate and 50% by weight of dimethylaminoethyl methacrylate. EUDRAGIT® NE is a water-insoluble copolymer of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate. EUDRAGIT® RL is a water-insoluble copolymer with 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammonioethyl methacrylate chloride.

Kollicoat® SR is a water-insoluble polymer (a polyvinyl acetate copolymer). Kollicoat® IR (a glycol block copolymer of ethylene vinyl acetate) which is a water soluble polymer. PEG 6000: polyethylene glycol 6000 (water soluble polymer). B. Production of extrusions for Examples 1 to 14 The examples are produced by melt extrusion in a twin screw extruder (Leistritz MICRO 18 GL 40 D Pharma). The temperature was selected so that at least one zone is above the melting point of the active ingredient. The extrusion was carried out in the range between 70-170 ° C. Felodipine, water soluble (meth) acrylate copolymer EUDRAGIT® E and, if correct, the "second" polymer is measured by means of solid or liquid measuring devices, mixed in the extruder, melted and extruded. In the inventive examples, the "second" polymer is insoluble in water and is present in an inventive ratio with the active ingredient at a maximum of 3.5: 1. The speed was 200 to 250 rpm. The resulting melt is removed by means of a band for cooled air and then exchanged with a chain granulator. Subsequently, the granule is milled at 6000 1 / minute in a Retsch ultra-centrifugal mill with an insert 250 μm screen and then sieve. Composition of individual extrudates in% by weight Table 1 Inventive: Examples 2 - 4, 7 - 10 Non-Inventive: Examples 1, 5, 6, 11 - 14 Examples 1 to 14 Release of the active ingredient felodipine from the ground granules: The release of the active ingredient from ground granules was carried out in a pallet apparatus (DT 700 Dissolution Tester, Erweka) USP 26 method 2. The examples were weighed in correspondence between each case for fluid sine pancreatin, USP) pH 1.2 (37 ° C ± 0.5) where it was used as a medium and the agitator speed was 100 rpm. Samples of 5 ml were taken at certain intervals, filtered through a membrane filter (Rezist® 30 / 0.45 μm PTFE, Schleicher &Schüll), and diluted 1: 1 with methanol. The first 2 ml were discarded. The volume removed was replaced with fresh medium with controlled temperature. The amount of felodipine released was detected by means of HPLC. (Column used: RP 18 (Lichrospher 100.5 μm, 125 x 4, Merck), eluent: acetonitrile: methanol: phosphate buffer pH 3, flow rate: 1 ml / min, wavelength: 362 nm).

Determination of solubility of felodipine with pH 1.2: Felodipine has a solubility in water of < 1 mg / 1 (0.0001 g / 1). The solubility for felodipine was determined for comparison in a buffered medium at pH 1.2 (SGPsp pH 1.2). For this purpose, 10 mg were kept moving at 37 ° C on an orbital shaker in 20 ml of medium for 24 hours. The concentration was determined by means of HPLC. For felodipine alone, without the inventive formulation, a solubility of 0.5 mg / 1 was determined. The tables for Examples 1 to 14 reproduce the solubility values of felodipine at pH 1.2 as a function of time. Three parallel experiments were carried out (containers 1 to 3). Example 1 (non-inventive): Compound extrusion of 90/10 EUDRAGIT® E and felodipine (non-inventive) The maximum solubility here is obtained after 5 minutes, but then fails significantly.

Example 2: Extruded compound of 9.5 / 85.7 / 4.8 Felodipine, EUDRAGIT0 E and EUDRAGIT® NE Example 3: Extruded compound of 9.1 / 81.8 / 9.1 felodipine, EUDRAGIT® E and EUDRAGIT® NE Example 4: Extruded composite of 8.3 / 75 16.7 felodipine, EUDRAGIT® E Example 5 (non-inventive) Extruded compound of 7.14 / 64.28 / 28.58 felodipine, EUDRAGIT® E and EUDRAGIT® NE Example 6 (non-inventive) Extruded compound of 6.25 / 56.25 / 37.5 felodipine, Example 7: Extruded compound of 9.1 / 81.8 / 9.1 felodipine, EUDRAGIT® E and Kollicoat® SR Example 8: Extruded composite of 8.3 / 75 / 16.7 felodipine, EUDRAGIT® E and Kollicoat® SR Example 9: Extruded comprising 9.1 / 81.8 / 9.1 felodipine, EUDRAGIT® E and EUDRAGIT® RL Example 10: Extruded comprising 8.3 / 75 / 16.7 felodipine, EUDRAGIT® E and EUDRAGIT® RL Example 11 (non-inventive) The extrudate comprises 9.1 / 81.8 / 9.1 felodipine, EUDRAGIT® E and PEG 6000 Example 12 (non-inventive) The extrudate comprises 8.3 / 75 / 16.7 felodipine, EUDRAGIT® E and PEG 6000 Example 13 (non-inventive) The extrudate comprises 9.1 / 81.8 / 9.1 felodipine, EUDRAGIT® E and Kollicoat® IR Example 14 (non-inventive) The extrudate comprises 8.3 / 75 / 16.7 felodipine, EUDRAGIT® E and Kollicoat® IR Summary of Examples 1 to 14 in relation to the increase in solubility of felodipine at pH 1.2 after 120 minutes The results are compiled in Table 2 below. Table 2 *) Relation to the "second" polymer reported, which is, however, soluble in water in Examples 11-14.

Inventive Examples 2-4, 9-10: In all the examples, an increase in solubility was found after 120 minutes with a pH of 1.2 of at least 16 times the value of felodipine alone with a pH of 1.2.

Non-Inventive Examples 1, 5, 11-14: Example 1: If the inventive addition of a water-insoluble polymer, the good solubility initially (after 5 minutes, see individual heats of Example 1) falls by the factor 7.4 after 120 minutes. Examples 5 and 6: When the water-insoluble polymer is used, based on the active ingredient, in a ratio of more than 3.5 to 1 part by weight, the solubility improvement is below 16 times that of the active ingredient alone. . Examples 11 to 14: When, instead of the water-insoluble polymer, a water-soluble polymer is used, the solubility improvement is below 16 times that of the active ingredient alone.

Claims (16)

1. CLAIMS 1. A pharmaceutical composition comprising a mixture of at least one water soluble (meth) acrylate copolymer, at least one polymer insoluble in water and at least one active ingredient, with a solubility in demineralized water of 3.3 g / 1 or less, characterized in that the water insoluble polymer and the active ingredient are present in a ratio of at most 3.5 to 1 part by weight, and the pharmaceutical composition has the property of releasing the active ingredient present in a buffered medium with a pH of 1.2 in dissolved form in a concentration which, after 2 hours with a pH of 1.2, corresponds to at least sixteen times the solubility value of the active ingredient only with a pH of 1.2.
2. 2. The pharmaceutical composition according to claim 1, characterized in that the copolymer or copolymers of water-soluble (meth) acrylate and the water-insoluble polymer or polymers are present in a relative relation to each other of 40:60 to 99: 1 parts by weight. The pharmaceutical composition according to one or more claims 1 or 2, characterized in that the water-soluble cationic (meth) acrylate copolymer is partially or completely composed of alkyl acrylates and / or alkyl methacrylates with a tertiary amino group in the alkyl radical. The pharmaceutical composition according to Claim 3, characterized in that the water-soluble cationic (meth) acrylate copolymer is an addition polymer composed of 30 to 80% by weight alkyl esters Ci to C4 of alkyl esters of acrylic acid or of methacrylic acid and 70 to 20% by weight of monomers of (meth) acrylate with a tertiary amino group in the alkyl radical 5. The pharmaceutical composition according to claim 3 or 4, characterized in that the water-soluble (meth) acrylate copolymer is an addition of polymer composed of 20- 30% by weight of methyl methacrylate, 20-30% by weight of butyl methacrylate and 60-40% by weight of dimethylaminoethyl methacrylate. The pharmaceutical composition according to one or more of Claims 1 to 5, characterized in that the water insoluble polymer is a copolymer composed of 20 to 40% by weight of ethyl acrylate and 60 to 80% by weight of methacrylate of methyl and 0 or less than 5% by weight of acrylic acid and / or methacrylic acid. 7. A pharmaceutical composition according to one or more of Claims 1 to 5, characterized in that the water insoluble polymer is an addition of polymer composed of 98 to 88% by weight of Ci to C4 alkyl esters of acrylic acid or methacrylic acid and 2 to 12% by weight of (meth) acrylate monomers having a quaternary amino group. 8. A pharmaceutical composition according to one or more Claims 1 to 5, characterized in that the water-insoluble polymer is a polyvinyl acetate, a polyvinyl acetate copolymer, an ethylcellulose or a methylcellulose. Pharmaceutical composition according to one or more of Claims 1 to 8, characterized in that the active ingredient is selected from the group of BCS classes II and IV (biopharmaceutical classification system according to Prof. Amidon) and / p from the group of antiandrogens, antidepressants, antidiabetics, antirheumatics, flucocorticoids, cytostatics, migraine drugs, neuroleptics, antiobiotics, estrogens, vitamins, psychotropic drugs, ACE inhibitors, ß-blockers, calcium channel blockers, diuretics, cardiac glycosides, antiepileptics, diuretics , antiglaucoma, urioscostáticos, H2 receptor blockers and virostatic. 10. The pharmaceutical composition according to one or more of Claims 1 to 9, characterized in that the active ingredient is bicalutamide, anastrozole, albendazole, amitriptyline, artometer, chlorpromazine, ciprofloxacin, clofaximin, dapsone, diloxanide, efevirenz, folic acid, furosemide, glibenclamide, griseofulvin, haloperidol, iver ectin, ibuprofen, idinavir, lopinavir, lumefantriña, mebendazole, mefloquine, niclosamide, nelfinavir, nifedipine, nitrofurantoin, phenytoin, purantel, puremetamine, retinol, ritonavir, spironolactone, sulfadiazine, sulfasalazine, sulfamethoxaxol, triclabendazole, trimethoprim, valproic acid, verapamil, warfarin, nalidixic acid, nevirapine, praziquantel, rifampin, glimipiride, nilutamide, bromocriptine, ketotifen, letrozole, naratriptan, ganciclovir, orlistat, misoprostol, granistron, pioglitazone, lamivudine, rosiglitazone, zidovudine, enalapril, atenolol, nadolol, felodipine, bepridil, digoxin, digitoxin, carbamazepine, acetazolamide, allopurinol, cimetidine, ranitidine or oxacarbazepine. 11. The pharmaceutical composition according to one or more of Claims 1 to 10, characterized in that it is present in the form of a powder. The process for making a pharmaceutical composition according to one or more of Claims 1 to 11 in the form of a milled granulate or extrudate with the property of releasing the ingredient active present in a buffered medium with a pH of 1.2 in dissolved form in a concentration which, after 2 hours with a pH of 1.2, corresponds at least to sixteen times the solubility value of the active ingredient only with a pH of 1.2, characterized in that the water soluble cationic (meth) acrylate copolymer, the active ingredient and the water insoluble polymer is mixed and extruded by melting at a temperature in the range of 60 to 220 ° C, and the extrudate is exchanged or grind to a granule. The process for preparing a pharmaceutical composition according to one or more of Claims 1 to 11 in the solid form with the property of releasing the active ingredient present in a buffered medium with a pH of 1.2 in dissolved form in a concentration that , after 2 hours with a pH of 1.2, corresponds at least to sixteen times the solubility value of the active ingredient only at a pH of 1.2, characterized in that a solution in an organic solvent or a mixture of solvent composed of cationic copolymer of Water-soluble (met) acrylate, first the active ingredient and the water-insoluble polymer are obtained, the organic solvent is removed, for example, by evaporation or by applying reduced pressure, which allows a solid with the mentioned properties. 14. The process for producing a pharmaceutical form comprises a pharmaceutical composition according to one or more Claims 1 to 11, characterized in that a pharmaceutical composition prepared according to Claims 12 or 13 is further processed into granules, pellets or powders, if formulated correctly by means of pharmaceutically customary excipients and processed in a manner known per se, for example by mixing, compressing, laminating and / or encapsulating a pharmaceutical form, for example in tablets, or preferably in a multi-particle pharmaceutical form, especially in tablets containing pellets, mini-tablets, capsules, sachets or reconstitutable powders. 15. The pharmaceutical form comprising a pharmaceutical composition according to one or more Claims 1 to 11. The use of a pharmaceutical composition according to one or more of Claims 1 to 11 to produce a pharmaceutical form.