MXPA06000430A - Multiparticle pharmaceutical dosage form containing a mucoadhesively formulated peptide or protein active substances method for producing said pharmaceutical dosage form - Google Patents

Abstract

The invention relates to an oral, multiparticle pharmaceutical dosage form containing pellets, the size of which ranges from 50 to 2500µm and which essentially consist of:a) an inner matrix layer containing an active substance which is a peptide or a protein, including the derivatives or conjugates thereof, and which is embedded in a matrix consisting of a polymer with mucoadhesive effect, and b) an outer film coating essentially consisting of an anionic polymer or copolymer, which can be optionally formulated with pharmaceutically conventional adjuvants, more particularly softening agents.

Description

PHARMACEUTICAL DOSAGE FORM OF MULTIPLE PARTICLES WHICH CONTAINS A PEPTIDE FORMULATED MUCOADHESIVELY OR ACTIVE PROTEIN SUBSTANCES AND A METHOD TO PRODUCE THIS METHOD OF DOSAGE The invention relates to a multi-particle pharmaceutical form comprising a peptide formulated ucoadhesively and / or protein active substances and to a method for producing the pharmaceutical form. Prior art DE 1000 24 451 A1 describes the pharmaceutical dosage forms suitable for Parenteral use and comprises, in dissolved or dispersed form, peptides that are prone to aggregation. The peptides can, in this case, be present in various salt forms. The dosage forms comprise, in addition to free acids and, when appropriate, additional pharmaceutical excipients. WO 02/03955 discloses bioadhesive pharmaceutical forms, microspherically formulated for sublingual administration of the active substances. The microspheres have an average diameter of less than 50 μm and comprise the active substance, which may be, for example, a peptide, in a non-crystalline form in an icromatrix embedded in a bioadhesive polymer. The bioadhesive polymer can, among other things, be a cellulose, a chitosan or an acrylic copolymer. WO 02/64148 describes formulations comprising • a mucopolysaccharide and a method for its production. In this case a mucopolysaccharide, for example heparin, is formulated together with an adsorption enhancer, for example a chitosan, and then it is provided with a soluble coating in the intestinal juice, so that the active substance can be released in the middle segments. inferior of the small intestine. Examples of the soluble coatings in the intestinal juice are anionic acrylic copolymers of the Eudragit® L, S, L100-55 type. The formulations may include capsules, tablets and granules. WO 02/43767 describes the oral pharmaceutical compositions for the active substances of physiologically active peptide comprising the active substance that is coupled to a cell membrane translocator, an agent for lowering the pH and / or a protease inhibitor and a transport vehicle stable to the acid that protects the pharmaceutical composition when it passes through the patient's stomach and avoids contact with the protease present in the stomach. The transport vehicle can be capsules that are coated with acid resistant coatings composed of Eudragit® L30 D-55. WO 03/007913 describes oral pharmaceutical forms of multiple particles comprising the active substance in the form of a multiplicity called patches. A patch is a disc-shaped object made of a biocompatible material having a diameter from 500 μm to 5 mm and a weight of 100 to 1000 μm. The patch consists of two layers or sides, on one side having only low permeability for water or body fluids, for example made of ethylcellulose and on a second side comprising the active substance, for example, a peptide or protein, which can be present in a mixture with mucoadhesive polymers, for example chitosan, CMC, polyacrylic acid or pectin. The patches may be compressed to form a tablet or packaged in a capsule that is additionally provided with a coating soluble in the intestinal juice. The active substance preparations can also be combined with so-called enhancers such as fatty acids, fatty alcohols, esters, surface active substances and protease inhibitors. At the site of action, for example in a particular segment of the intestine, the capsule dissolves and releases the patches. The released patches can also adhere with their mucoadhesive side to the intestinal mucosa and thus deliver the active substance in a delayed manner and directly into the intestinal mucosa. The only slightly permeable side of the patches is intended to provide the active substance with a certain protection towards chemical or enzymatic inactivation from the side facing the intestinal lumen and also to prevent the active substance from escaping on this side. Problem and solution The solution offered by WO 03/007913 for the production of oral dosage forms, especially for active peptide or protein-based substances that are released in the intestinal lumen and that are intended to act there, is remarkable and must be recognized. One disadvantage of this solution is, among other things, the elaborate construction and the production of the two-layer patch structures. It appears to be particularly unfavorable, however, so that the dosage form can be provided as a capsule having a coating that is resistant to gastric juice and soluble in intestinal juice. The size distinctly of more than 2.5 mm results in this case in an inadequate therapeutic reproducibility. The time for the capsule to pass through the stomach can vary widely. In any case, a delayed insertion of action must be expected. In addition, the capsule itself can dissolve rapidly or slowly after partial dissolution of the coating. The two principles of the coating and the overlap of the capsule in an unfavorable manner, in this case, so that the release of the patches can generally be expected to be uncontrolled. The capsule can, in a situation where it is at least partially accessible to the intestinal juices, remain intact or substantially mechanically disintegrated, depending on the current intestinal contents or intestinal peristalsis. There may be on the one hand a sudden release of large amounts of patches, or on the other hand also an unwanted delay of release, depending on the disintegration of mechanical concentration in the structure of the initially coated capsule. Therefore, the delivery of an active substance that can usually be better controlled is desirable. It has been considered as one of the problems of the invention to provide a pharmaceutical form that is suitable for the targeted and efficient release of the active substances of proteins or peptides. The dosage form is intended to provide a high dose release and to be distributed well in the intestinal lumen after a rapid passage through the stomach. The active substances contained in proteins or peptides are even more intended to be substantially protected from physical, chemical or proteolytic inactivation and to be released at the defined site of action so that a large portion of the active substance can be absorbed by the body. The release site is intended to be adjusted in a variable and reliable manner depending on the therapeutic purpose. The problem is solved by a multiple particle oral dosage form comprising granules having a size in the range of 50 to 2500 μm, which are composed of a) an inner matrix layer comprising an active substance which is a peptide or a protein and which includes derivatives or conjugates thereof, and, is embedded in a matrix of a polymer having a mucoadhesive effect, wherein the matrix can, optionally, comprise the usual pharmaceutical excipients, b) an outer film coating consisting essentially of an anionic polymer or copolymer which can be optionally formulated with conventional pharmaceutical excipients, especially plasticizers, characterized in that, the multi-particle dosage form is formulated so that the contained granules are released in the pH range of the stomach, the outer coating is adjusted through the choice of anionic polymer or copolymer or its formulation with excipients and its layer thickness so that the coating dissolves in the pH ranges of 4.0 to 8.0 in the intestine in a period of 15 to 60 minutes, so that the mucoadhesive matrix layer containing the substance Active is exposed, and can adhere to the intestinal mucosa and release the active substance there, where the polymer having a mucoadhesive effect is chosen to exhibit a mucoadhesive effect at least of? = 150 to 1000 mPa »s and a water absorption of 10 to 750% in 15 minutes in a range of units of +/- 0.5 pH in relation to the pH at which the outer coating begins to dissolve, and the active substance content of the matrix layer is a maximum of 40% by weight of the content of the polymer having a mucoadhesive effect. Implementation of the invention The invention relates to an oral pharmaceutical form of multiple particles, in particular in the form of a tablet, mini-tablet, granules packed in capsules or sachets or reconstitutable powders, comprising granules having an average size or an average diameter. in the range of 50 to 2500, preferably 100 to 1000 um, which are composed of: a) an inner matrix layer comprising an active substance that is a peptide or a protein, including derivatives or conjugates thereof, and is embedded in a matrix of a polymer having a mucoadhesive effect, wherein the matrix may optionally or ordinarily comprise additional customary pharmaceutical excipients, b) an outer film coating consisting essentially of an anionic polymer or copolymer which may be optionally formulated with pharmaceutical excipients usual, especially plasticizers. The multi-particle pharmaceutical formula is formulated so that the contained granules are released in the range of the stomach's pH. The outer coating is adjusted through the choice of the anionic polymer or copolymer or its formulation with excipients and its layer thickness so that the coating dissolves at a pH in the range of 4.0 to 8.0, preferably 5.5 to 7.8, particularly preferred. from 5.8 to 7.5, in the intestine for 20 to 40 minutes, so that the mucoadh.esiva matrix layer containing the active substance is exposed, and can adhere to the intestinal mucosa and release the active substance there. The polymer or copolymer having a mucoadhesive effect is chosen so as to exhibit a mucoadhesive effect of. at least r | b = 150 to 1000, preferably 150 to 600, mPa »s and water absorption from 10 to 750, preferably from 10 to 250, particularly preferably from 10-160% in 15 minutes in a range of + / - 0.5, preferably +/- 0.3, units of pH in relation to the pH at which the outer coating begins to dissolve and the active substance content of the matrix layer is a minimum of 40, in particular 0.001 to 15 or 0.05 a 5% by weight of the content of the polymer having a mucoadhesive effect. Layer of the internal matrix The layer of the internal matrix acts as a carrier of active substance. The inner matrix layer additionally has the function of binding the active substance, by means of the contained mucoadhesive polymer, to the intestinal mucosa so that the active substance can enter the body from there. The internal matrix layer also has the function of protecting the active substance from physical, chemical or enzymatic inactivation. Formulations of active substances / active substance The matrix layer comprises an active substance which can be a protein or peptide, including derivatives or conjugates thereof, having an average molecular weight Mw from 300 to 1,000,000 (bulging). By derivatives is meant chemical or biochemical modifications of the primary or secondary structure. Examples are proteins or peptides that are derived from natural sources or that are completely synthetic or that have non-natural amino acid residues. Conjugates with covalent linkages of proteins or peptides to non-peptide compounds, for example proteins or peptides coupled to polyethylene glycol. Active substances The active substances used for the purposes of the invention are intended in particular for use on or in the human or animal body for the purpose of: 1. Curing, alleviating, preventing or diagnosing disorders, conditions, physical injuries or pathological symptoms; 2. Reveal the condition, condition or functions of the body or mental states; 3. Replace active substances or body fluids produced by the human or animal body. 4. Isolate, eliminate or render harmless pathogens, parasites or exogenous substances; or 5. Influence the condition, condition or functions of the body or mental state. The peptides and protein active substances can be used as free acids or bases. Examples of counterions that may be employed are physiologically acidic bases or alkaline earth metals or alkali metals or tolerated amines and, for example, acetate, adipate, ascorbate, alginate, benzoate, bensenosulfonate, bromide, carbonate, arboxymethylcellulose (free acid) ), citrate, chlorine, dibutyl phosphate, dihydrogen citrate, dioctyl phosphate, dihexadecyl phosphate, fumarate, gluconate, glucuronate, glutamate, hydrogen carbonate, hydrogen tartrate, hydrochloride, hydrogen citrate, iodine, lactate, alpha lipoate, malate, maleate, malonate, pamoate, palmitate, phosphate, salicylate, stearate, succinate, sulfate, tatrato, tannate, oleate, octyl phosphate. The active substance content of the matrix layer is a maximum of 40, in particular 0.001 to 15 or 0.05 to 5,% by weight of the content of the polymer having a mucoadhesive effect. Depending on the physical-chemical properties of the active substance, such as, for example, water-in-oil partition coefficient or isoelectric point, etc., the matrix layer may additionally comprise a carboxylic acid or Ce-a C2o fatty acid- preferably a carboxylic or fatty acid Cs_, Cι-, or C12- to C2o ~ and / or a C6- to C2o- / preferably C8-, C ?0-, or Ci0- to C2o ~ alcohol including its salts, ether, ester or derivatives of amine and / or a lipid and / or a phospholipid and / or a lipid-soluble vitamin and / or a protease inhibitor and / or a penetration promoter and / or an efflux pumping inhibitor, for example, ketoconazole or polyethylene 660 12-hydroxystearate (Slutol® HS15).

The active substance can be a protein or a peptide having an average molecular weight Mw of less than 3000 Da. Examples of these peptides are in particular abarelix, angiotensin II, anidulafungin, antide, argipressin, azaline and azaline B, bombesin antagonist, bradykinin, buserelin, cetrorelix, cyclosporin A, desmopressin, detirelix, encephalitis (Leu-, Met) ganirelix , gonadorelin, goserelin, growth hormone secretagogue, micafugin, nafrerelin, leuprolide, leuprorelin, octreotide, orntido, oxytocin, ramorelix, secretin, somatotropin, terlipressin, tetracosáctide, teverelix, triptorelin, tiroliberin, thyrotropin, vasopressin. It is preferred in this case that the matrix layer further comprises a carboxylic acid or C6- to C2o-f fatty acid, preferably C3-, Cio- or C1Z- to C2o- optionally to a carboxylic or fatty acid Co_ and / or C6- to C20 -, preferably C8-, Cio- or C? 2- to C2O ~? optionally up to C3o- alcohol, including its. salts and / or a phospholipid and / or a lipid soluble vitamin and / or an efflux pump inhibitor. The addition has the advantage that the solubility, stability and absorption of the active substance can be improved in this way. Suitable examples are fatty acid esters such as glycerol trimyristate, glycerol monostearate, glycerol tristereate, glycerol tripalmitate, glyceryl genic acid ester and fatty acid amides, aliphatic long chain carboxylic acids such as palmitic acid, stearic acid, acid lauric, cetyl alcohol and waxes such as carnauba wax, beeswax and phospholipids such as egg lecithin, soy lecithin and vitamins such as vitamin E. The active substance can be a protein or a peptide having an average molecular weight Mw from 3000 to 10,000 Da. Examples as proteins or peptides are in particular calcitonin, corticotrophin, endorphins, epithelial growth factor, glucagon, insulin, novilin, parathyroid hormone, por-somatostatin, salmon secretin. If the active substance is a protein or a peptide having an average molecular weight Mw from 3000 to 10 000, the matrix layer preferably comprises a carboxylic acid or fatty acid C6- a C2ct > preferably C8-, Cio- O CI2- a C2o ~ r when it is correct to alcohol Co-, including its salts, ether, ester or amide derivatives and / or a lipid and / or a phospholipid and / or a lipid-soluble vitamin and / or a protease inhibitor. The active substances of proteins or peptides having an average molecular weight Mw from 3000 to 10 000 are frequently particularly sensitive to enzymatic degradation through proteases, so that the addition of the protease inhibitors is particularly advantageous by itself, in addition to the stabilization of the active substance. Examples of pharmaceutically suitable protease inhibitors are antidolor, aprotinin, acitrazine, idina benzene, bestatin, captopril, ki ostatin, chicken ovoinhibitor, Na2 EDTA, chitosan-EDTA conjugates, Na glycocholates, leupeptin, pepstatin, trypsin inhibitors, soybean, thiorfan, tos-lis chloromethyl ketone, potato carboxypeptidase inhibitor. The active substance can be a protein or a peptide having an average molecular weight M w of more than 10,000. Examples of these proteins or peptides are in particular interferons (alpha, beta, gamma), interleukins (IL1, IL2), somatotropin, erythroproietin, tumor necrosis factor (TNF alpha, beta), relaxin, endorphin, alpha domase, follicle stimulating hormone (FSH), chorion gonadotropin (HCG), growth hormone release factor human (HgRF), luteinizing hormone (LH) or epidermal growth factor. If the active substance is a protein or a peptide having an average molecular weight Mw of more than 10 000 Da, the matrix layer preferably further comprises a carboxylic or C6- to C20- fatty acid, preferably C8-, C- or C- ? 2- to C20-, where it is correct to a C3or alcohol including its saltsamide, ether, ester or derivatives of amide and / or a lipid and / or a phospholipid and / or a lipid soluble vitamin and / or a protease inhibitor and (or a penetration promoter) The addition of a penetration promoter is advantageous because the absorption of the active substance having a high average molecular weight Mw of more than 10 000 is comparatively favored by this The suitable penetration promoters are in particular plasticizers such as, for example, triethyl citrate, triethyl citrate acetyl , diethyl debate, dibutyl sebacate, polymers such as carbomer, chitosan, chitosan-cysteine, sodium camoxymethylcellulose, N-trimethylated chitosan, polycarbophil cysteines, long-chain fatty acids, their esters (eg, mono and diglycerides) and their salts such as lauric acid, laurinosulfonic acid, palmitic acid, caprylic acid, caprylic acid, oleic acid, acylcarnitines, chelating agents such as EDTA, asilicilatos, cyclodextins, acid two polyacrylates, bile acids such as coic acid, coliltaurin, colilsarcosine, kenodeoxycholic acid, and their salts such as Na cholate, Na glycolate, Na taurocholate, Na taurodihydrofusidate, Na glycidihydrofusidate, surfactants and emulsifiers such as, in particular polyethylene 12-hydroxystearate 660 (Solutol ® HS15) (Solutol HS15), polysorbate 80 (Tween 80), polyethoxylated castor oil (Cremophor EL), polyoxyethylene-polyoxypropylene glycol (Pluronic® F68), the toxin of zonula toxin (ZOT) and vitamins such as vitamin E ( tocopherol) or vitamin B12. If the active substance is a protein or a peptide having an average molecular weight Mw of more than 10 000 Da, the matrix layer preferably comprises an efflux pumping inhibitor such as, in particular, ketoconazole or polyethylene 12-hydroxystearate 660 ( Slutol HS15). Polymers that have a mucoadhesive effect The matrix layer further comprises polymers that have a uco-adhesive effect. Suitable polymers that have a mucoadhesive effect are in particular a chitosan (chitosan and derivatives, chitosan), copolymers of (meth) acrylate consisting of 20-45% by weight of methyl methacrylate and 55 to 80% by weight of methacrylic acid, celluloses, especially methyl celluloses such as carboxymethylcellulose Na (for example Blanose® or Metocel®). The polymer having a mucoadhesive effect is chosen to exhibit an absorption of water from 10 to 750, preferably from 10 to 250, particularly preferably from 10 to 160% in 15 minutes in a range of +/- 0.5, preferably + / - 0.3 pH units in relation to the pH at which the outer coating begins to dissolve. Measurement of mucoadhesive properties A suitable measurement method for characteristic mucoadhesive properties is contained in Hassan and Gallo (1990) (see Hassan EE and Gallo JM? A Simple Rheological Method for the in Vitro Assessment of Mucin-Polymer Bioadhesive Bond Strength "' ("A Simple Rheological Method for the In Vitro Evaluation of the Bioadhesive Bond Concentration of the Mucin Polymer" Phrma Res. 7 (5), 491 (1990).) The method is based on the hypothesis that the viscosity (? dynamic viscosity or viscosity coefficient) of a mixture of polymers with mucin is different from the total viscosities of the individual components.

The mixture of polymer with mucin represents the difference. A? B means higher mucoadhesive properties. The individual components are initially measured by their viscosity using a rotary viscometer. A concentration of 0.5% is used (w / w) of aqueous solution of the mucoadhesive polymer and 15% resistance of a solution of porcine gastric mucin. To determine the mucoadhesive properties β, the mucin and polymer are measured alone and mixed at the concentrations mentioned. The polymer having a mucoadhesive effect is chosen to exhibit a mucoadhesive effect measured as viscosity? B from 150 to 1000, preferably from 150 to 600 mPa * s in a range of +/- 0.5, preferably +/- 0.3 pH units in relation to the pH at which the outer coating begins to dissolve. Hydration and water absorption The hydration of polymers is based on the affinity of the polymer to absorb water. The polymers swell due to their absorption of water. This is due to a lack of balance between the chemical potential of the water in the polymer and the water in the surrounding medium. the water is absorbed, due to the osmotic pressure of the polymer, until a balance is established between the interior and exterior phases. The polymer is then hydrated at 100%. The polymers having a low average molecular weight are then in the form of a solution. A gel is produced with polymers having a higher molecular weight or cross-linked polymers. The absorption of water up to equilibrium is established and can add, for example, up to 10 times the inherent weight, corresponding to 1000% of the weight of the polymer. Measurement of water percentage absorption The measurement of water absorption percentage is known to the authorized worker. A suitable method is described in the Lehrbuch der phar azeutischen Technologie / Rudolf Voigt, Basis: Verlag Chemie, 5th edition completely revised, 1984, page 151, 7.7.6 under "Aufsaugvermógen". The method makes use of the so-called Enslin apparatus, in which a glass suction filter funnel is connected by a tube to a graduated pipette. The pipette is mounted exactly horizontally in such a way that it is on the same level as the porous glass washer. A water absorption of 100% is defined in the present case as a water absorption of 1 ml of water per 1 g of polymer having a mucoadhesive effect in 15 minutes. The comparatively fast water absorption or hydration and the high degree of hydration, same time as the outer coating begins to dissolve, ensure a rapid protection of the active substance and a direct agglomeration to the intestinal mucosa. The agglomeration of the active substance in the mucoadhesive matrix should only be small, so that the active substance can pass directly from the intestinal mucosa into the body. Control of the pH of the matrix The mucoadhesive effect is dependent on the pH by many ucoadhesive polymers »The pH in the matrix can only be controlled in a specific way through the addition of an acid, a base or a buffer system. The inner matrix comprises as a polymer having a mucoadhesive effect, for example, a chitosan which is used together with an acetate buffer system. The acetate / acetate acetate NO, for example, adjusted to a pH of 5.0 to 5.5, can be present as an additive in the matrix or applied to a core in which the matrix is applied. It is thus possible to use a chitosan also in combination with film coatings that begin to dissolve at higher pH values, for example, pH from 6.0 to 8.0. Despite the high surrounding pH, the low pH is maintained in the matrix's micro-environment. In this way it is possible to use the mucoadhesive properties of the polymer in a pH range in which otherwise it would not have had a mucoadhesive effect or not in this measurement. This has the advantage that some protection can be achieved against proteases whose optimum pH is in the higher pH ranges. The same principle can also be applied inversely by raising the pH of the matrix by adding a base, and combining it with a film coating that dissolves at lower pH values. Examples of the selection of suitable mucoadhesive polymers The selection of suitable mucoadhesive polymers is based on their mucoadhesive properties and their water absorption capacity. The polymers must have a mucoadhesive effect of at least? B = 150 to 1000 mPa * s and an absorption of water from 10 to 750% in 15 minutes in the respective pH range. The following table presents a list by way of example. Chitosan is suitable, for example, for use in a surrounding pH region of 5.5 (duodenum) or in another pH of a surrounding region (ileus or colon) as long as the pH region of the matrix is adjusted, for example with the help of a buffer system, for the region around pH 5.5. The (meth) acrylate copolymer listed in the table is more suitable for a pH region with a pH of 7.2 than for a pH region around pH 5.5. Alginate Na is suitable for the pH region around a pH of 5.5 but not for a pH of 7.2. The carboxymethylcellulose Na and the crosslinked polyacrylic acid are suitable over a wide pH range from 5.5 to 7.2.

* - Copolymer of (meth) acrylate of 30% by weight of methyl methacrylate and 70% by weight of methacrylic acid. The outer coating of copolymers of anionic (meth) acrylate The outer coating of anionic polymers or copolymers serves as a coating resistant to gastric juice in order to protect the inner matrix layer of gastric juices. The outer coating additionally acts to protect the active substance from the proteolytic enzymes until the moment in which the coating reaches a section of intestine (duodenum, jejunum, ileum or colon) where it begins to dissolve. The outer coating in this case serves in particular for the so-called "gastrointestinal target", for example, the intended release of the inner matrix layer in the sections of the intestine determined by the prevailing pH therein, so that there is no impediment to the When the internal matrix layer is delivered, the (meth) acrylate copolymer of the outer coating must exhibit minimal or only slight interactions with the active substance or with the mucoadhesive polymer of the inner matrix layer, suitable anionic polymers or copolymers are glycolate cellulose (Duodcell®), cellulose acetate phthalate (CAP, Cellulosi acetates, PhEur, cellulose acetate phthalates, NF, Aquateric®), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), Hydroxypropylmethylcellulose phthalate (HPMCP, PH50, PH55), hydroxypropylmethylcellulose acetate succinate (HPMCAS-LF, -MF, -HF), polyvinyl acetate phthalate (PVAP, Suret eric®), vinyl acetate-vinylpyrrolidone copolymer (PVAc, Kollidon®, VA64), vinyl acetate: protonic acid 9: 1 copolymer (VAC: CRA, Kollicoat® VAC) and / or lacquer. These polymers and copolymers can in many cases be formulated in a perfectly satisfactory manner to allow the specific pH solution to be achieved. The outer film coating consists preferably in particular essentially of (meth) acrylate copolymers having a content of monomers having anionic groups of 5 to 60% by weight, which can optionally be formulated with usual pharmaceutical excipients, especially plasticizers. Compared to the polymers mentioned at the beginning, these copolymers of Anionic (meth) acrylates make it possible within the scope of the invention in many cases to adjust the specific pH of the pH solution to adjust even more precisely and with reproducibility. Management and application is also usually considered less elaborate. The (meth) acrylate copolymer for the outer coating preferably consists of from 40 to 95, preferably from 45 to 90, in particular 30% by weight, polymerized C 1 to C free radical acrylic or polymeric methacrylic acid esters and can comprise from 5 to 60, preferably from 8 to 40, in particular from 20 to 35% by weight of (meth) acrylate monomers having an anionic group. The proportions mentioned normally add up to 100% by weight. However, it is possible in sum, without this leading to an inability or alteration of the essential properties, for small amounts in the region of 0 to 10, for example 1 to 5% by weight of additional monomers with vinyl copolymerization capacity, as for example, that hydroxyethyl methacrylate or hydroxyethyl acrylate is present. The alkyl esters of acrylic or methacrylic acid C 1 -C 4 are in particular methyl methacrylate, ethyl methacrylate, butyl methylacrylate, methyl acrylate, ethyl acrylate and butyl acrylate. A (meth) acrylate monomer having an anionic group may, for example, be an acrylic acid, but preferably a methacrylic acid. Also suitable are copolymers of (meth) acrylate anionic compounds of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate (Eudragit @ L or Eudragit® Ll00-55). Eudragir®L is a copolymer of 50% by weight of methyl methacrylate and 50% by weight of methacrylic acid. Eudragit® L 30D is a dispersion comprising 30% by weight of Eudragit®L. This (meth) acrylate copolymer is particularly suitable for dissolution in the pH ranges of around pH 6.0 to 6.5 (jejunum).

Eudragit® L100-55 is a copolymer of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid. Eudragit® L 30-55 is a dispersion comprising 30% by weight of Eudragit® L 100-55. This (meth) acrylate copolymer is particularly suitable for dissolution in pH ranges of about pH 5 to 6.0 (duodenum). Equally suitable are the copolymers of anionic (meth) acrylate from 20 to 40% by weight of methacrylic acid and from 80 to 60% by weight of methyl methacrylate (type Eudragit® S). This (meth) acrylate copolymer is particularly suitable for dissolution in pH ranges of around pH 6.5 to 7.0 (jejunum and ileum). Particularly suitable are (meth) acrylate copolymers consisting of 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid. Eudragit® FS is a copolymer of 25% by weight of methyl methacrylate, 65% by weight of methyl acrylate and 10% by weight of methacrylic acid. Eudragit® FS 30D is a dispersion comprising 30% by weight of Eudragit® FS. This (meth) acrylate copolymer is particularly suitable for dissolution in the pH ranges of about pH 7.0 to 7.8 (ileus and colon). Additionally suitable is a copolymer composed of 20 to 34% by weight of methacrylic acid and / or acrylic acid, 20 to 69% by weight of methyl acrylate and 0 to 40% by weight of ethyl acrylate and / or where correct 0 10% by weight of additional monomers with vinyl copolymerization capacity. with the assumption that the transition temperature of the copolymer with respect to ISO 11357-2, subsection 3.3.3, is not more than 60 ° C. This (meth) acrylate copolymer is particularly suitable, due to its good elongation to the breaking properties, for compression of granules to tablets. Additionally suitable are copolymers composed of 20 to 33% by weight of methacrylic acid and / or acrylic acid 5 to 30% by weight of methyl acrylate and 20 to 40% by weight of ethyl acrylate and more than 10 to 30% by weight. weight of butyl methacrylate and where it is correct 0 to 10% by weight of additional monomers with vinyl copolymerization capacity, where the proportions of the monomers add up to 100% by weight, with the assumption that the glass transition temperature of the copolymer of According to ISO 11357-2, subsection 3.3.3 (midpoint temperature Tm), it is 55 to 70 ° C. Copolymers of this type are particularly suitable, due to their good mechanical properties, for compressing granules to tablets. The aforementioned copolymer is in particular composed of free radical polymerized units of from 20 to 33, preferably from 25 to 32, particularly preferably from 28 to 31% by weight of methacrylic acid or acrylic acid, preferably of methacrylic acid, from 5 to 30, preferably from 10 to 28, particularly preferably from 15 to 25,% by weight of methyl acrylate, 20 to 40, preferably from 25 to 35, particularly preferably from 18 to 22% by weight of ethyl acrylate, and more than 10 to 30 , preferably from 15 to 25, particularly preferably from 18 to 22% by weight of butyl methacrylate, wherein the monomer composition is chosen such that the glass transition temperature of the copolymer is 55 to 70 ° C, preferably 59 to 66, particularly preferably 60 to 65 ° C.

It is also possible to use mixtures of the said copolymers in order to adjust specific release profiles or release sites. The glass transition temperature means in this particular connection the mean temperature point Tmg according to ISO 11357-2, subsection 3.3.3. The measurement is carried out without added plasticizers, with residual monomer contents (REMO) of less than 100 ppm, with a heating rate of 10 ° C / min and under a nitrogen atmosphere. The copolymer consists essentially of exclusively 90, 95 or 99 to 100% by weight of the methacrylic acid monomers, methyl acrylate, ethyl acrylate and butyl methacrylate in the ranges of the amounts indicated above. However, it is possible, without this necessarily leading to an inability of the essential properties, for small quantities in the range of 0 to 10, for example 1 to 5% by weight of additional monomers with vinyl copolymerization capacity to be present additionally, such as, for example, methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinylpyrrolidone, vinylmalonic acid, styrene, vinyl alcohol, vinyl acetate and / or derivatives thereof. The copolymers are obtained in a manner known per se by free radical polymerization, bulk material, solution, beads or emulsion. Before processing, these must be brought to the range of the particle size of the invention through suitable grinding, drying or spraying processes. This can be carried out by simple grinding of extruded and cooled or hot-cut granules. The use of powders can be advantageous especially in the mixture with other powders or liquids. Apparatus suitable for producing powders are familiar to skilled workers, for example air jet mills, perforated disk mills, magazine mills. It is possible, where it is correct to include the correct cutting steps. A suitable laminator for large industrial quantities is for example an opposite jet laminator (Multi No. 4200) which is operated with an overpressure of 6 bars. Preparation of the Copolymer The (meth) acrylate copolymers can be obtained by free radical polymerization of the monomers (see, for example, EP 0 704 207 A2 and EP 0 704 208 A2). The copolymers can be prepared in a known manner by free-radical emulsion polymerization in the aqueous phase in the presence of, preferably, emulsifiers, for example through the process described in DE-C 2 135 073. Organic solution These (meth) copolymers ) acrylate can be provided in the form of an organic solution, for example, in a concentration of 10 to 30% by weight. Examples of the solvents that can be used are acetone, isopropanol or ethanol or the mixture thereof, which can, when correct, comprise water in proportions of up to about 10% by weight. However, aqueous dispersions are preferred. Dispersions The (meth) acrylate copolymers can be produced and used as emulsion polymers, preferably in the form of an aqueous dispersion with a concentration of 10 to 50 percent by weight, in particular at a concentration of 20 to 40 percent. The partial neutralization of methacrylic acid units can be dispatched for processing; however, it is possible, for example, to a certain extent up to 5 or 10 mol%, if a stabilization or thickening of the dispersion of the coating composition is desired. The average weight size of the latex particles is ordinarily 40 to 100 nm, preferably 50 to 70 nm, thus ensuring a viscosity below 1000 mPa »s, which is favorable for processing.

With higher degrees of neutralization, for example 10 to 50 mol% or complete neutralization, it is possible for the copolymer to be converted to a dissolved state. In order to make an anionic copolymer solution, it is usually necessary to neutralize the acid groups partially or completely. The anionic copolymer can, for example, be stirred gradually in water in a final concentration or from 1 to 40% by weight and at the same time be partially or completely neutralized by adding a basic substance such as, for example, NaOH, KOH, ammonium hydroxide, or organic bases such as, for example, triethanolamine. It is also possible to use a copolymer powder to which a base has been added during its preparation, for example NaOH, for the purpose of (partial) neutralization, so that the powder is a polymer that is already (partially) neutralized. The pH of the solution usually above 4, for example, in the range of 4 to about 7. The dispersion may, for example, also be sprayed, dried or frozen frozen in a manner known per se and provided in the form of a re-dispersed powder (see, for example, EP-A 0 262 326). The alternative processes are dried by freezing or coagulation or squeezed out of the water in an extruder with subsequent granulation (see for example EP-A 0 638 028). Surprisingly it has been found that spray copolymer- or freeze-drying dispersions and dispersing powders again exhibit increased shear stability. This is advantageous in particular in the case of spray application. This advantage is particularly evident when the copolymer present in the dispersion is partially neutralized to the extent of 2 to 10 mol% (based on acid groups present in the copolymer). Partial neutralization is preferred when adding NaOH for this purpose. An anionic emulsifier is preferably present in an amount from 0.1 to 2% by weight. Sodium lauryl sulfate is particularly preferred as an emulsifier. Thicknesses of the layer The thickness of the outer coating layer is preferably in the range of 20 to 200, preferably 50 to 150 μm. Production of a multi-particle dosage form The invention further relates to a process for producing a multi-particle dosage form through a) producing an inner matrix layer comprising an active substance, which is a peptide or protein, and a polymer having a mucoadhesive effect and, where appropriate, additional conventional pharmaceutical excipients by means of spray application in a core or through rotating agglomeration, precipitation or dew processes without a core, and subsequently b) application of an outer film coating consisting essentially of an anionic polymer, which optionally can be formulated with usual pharmaceutical excipients, especially plasticizers, by means of spray application so that the wrapped granules containing active substance are obtained, and c) processing of the resulting granules by means of pharmaceutical excipients In a manner known per se as a pharmaceutical form of multiple particles, in particular tablets containing granules, minitablets, capsules, sachets or reconstitutable powders, which are formulated so that the contained granules are released in the pH range of the stomach. Production of pre-granules and granules The granulation can be done in pearls free of active substance (colored tablets), or free core granules that can be produced. First, the internal matrix layer with or without a core is produced. This rounded layer still uncovered is referred to as a pre-granule (granule core).

It is possible by means of a fluidized bed to be processed to apply the liquid to the placebo granules or to other suitable carrier materials, with evaporation of the solvent or suspending agent. You can follow a drying step to the production process. The active substance of peptide or protein is introduced with the polymer having a mucoadhesive effect in an organic solvent or in water and mixed. In order to ensure a satisfactory spray process of the mixture, it is usually necessary to formulate a low viscosity mixture. It may be beneficial for this purpose to employ the polymer having a mucoadhesive effect at comparatively low concentrations, for example, from 1 to a maximum of 10, preferably from 2 to 5% by weight. The addition of a detergent, for example Tween, in concentrations of 0.1 to 20, preferably 0.5 to 10% by weight may be even more advantageous for reducing the surface tension. They can, in addition to the active substance, comprise additional pharmaceutical excipients: binders such as cellulose and derivatives thereof, polyvinylpyrrolidone (PVP), humectants, disintegration promoters, lubricants, disintegrants, (meth) acrylates, starch and derivatives thereof, sugar solubilizers or others.

The correct application processes are revealed, for example in Bauer, Lehmann, Osterwald, Rothgang "Überzogene Arzneiformen" Wissenschaftliche Berlagsgesellschaft mbH Stuttgart, chapter 7, page 165-196. The details are further revealed for the authorized worker in textbooks, for example see: - Voigt, R. (1984): Lehrbuch der pharmazeutischen Technologie; Verlag Chemie Weinheim - Beerfield Beach / Florida - Basel. Sicker, H., Guchs, O., Speiser, P .: Pharmazeutische Technologie, Georg Thieme Verlag Stuttgart (1991), especially chapters 15 and 16, page 626-642. - Gennaro, A.R. (publisher), Remington's Pharmaceutical Sciences, Mack Publishing, Co., Easton Pennsylvania (1985), Chapter 88, page 1567-1573. List, P.H. (1982): Arzneiformenlehre, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart. The inner matrix can also be produced without the assistance of an inert nucleus (colored tablets).

The ingredients of the internal matrix can in this case be rounded so that the uncovered granules (pre-granules) of defined size, for example, 50 to 1000 μ,. through processes such as agglomeration by rotation, precipitation or spray processes, especially ultrasound fluidized spray processes. This has the advantage that the entire core volume is available to be loaded with active substance. The loading with the active substance can, in this way, be increased in addition to being additionally compared with the embodiment which has an inert core. After the production of the inner matrix (or of the pre-granules), these can be provided in exchange, preferably in the spray process, with the outer coating, to result in the finished granules. The granules are produced by spray application of the organic solution, or preferably by aqueous dispersions. It is decisive that uniform, pore-free coatings are produced for the implementation in this case. Top layer The granules can additionally be provided with pigmented coatings which, however, should not influence the pH of the solution. Suitable examples are coatings composed of pigmented hydroxypropylmethylcellulose and other polymers that are soluble in water or rapidly disintegrate in water. Usual pharmaceutical excipients Common excipients or additives can be added to these formulations of the invention during production.

It is, of course, always necessary for all substances used that are acceptable or toxicologically utilizable, particularly in medicines without a risk to patients. The amounts used and the use of usual additives in coatings or layers of medicines are familiar to be used by skilled workers. Possible examples of customary additives are plasticizers, release agents, pigments, stabilizers, antioxidants, pore formers, penetration promoters, gloss agents, flavoring substances, detergents, lubricants or flavorings. These serve as a processing aid and are intended to ensure a reliable and reproducible production process as well as good long-term storage stability, or they can 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, it being possible to use this when appropriate as an additional control parameter. • Release agents Release agents usually have lipophilic properties and are usually added to spray suspensions. These avoid the agglomeration of the cores during the film coating. Preference is given to using talc, Mg stearate or Ca stearate, ground silica, kaolin or nonionic emulsifiers having an HLB of between 3 and 8. The usual amounts of release agent used in the coating agents or binders of the invention they are between 0.5 and 100% by weight based on the copolymer. • Pigments: Pigments incompatible with the coating agent are in particular pigments that, if they are added directly to the dispersion of the (meth) acrylate copolymer, for example by stirring, in the usual amounts used, for example, 20 to 400% by weight on the dry weight basis of the copolymer of (meth) acrylate, lead to destabilization of the dispersion, coagulation, for signs of inhomogeneity or similar undesired effects. The pigments to be used are still, of course, non-toxic and suitable for pharmaceutical purposes. Regarding this, see also, for example: Deutsche Forschungsgemeinschaft, Farbstoffe für Lebensmi ttel, Harald Boldt, Verlag KG, Boppard (1978); Deutsche Lebensmittelrundschau 74, No. 4 page 156 (1978): Arzneimittelfarbstoffverordnung AmFarbV of 25.08.1980.

The pigments incompatible with the coating agent can be, for example, alumina pigments. Examples of incompatible pigments are orange yellow, red cochineal carmine lake, alumina-based color pigments or azo dyes, sulfonic acid dyes, orange yellow S (E110, CI 15985, Yellow 6 FD &C), indigo carmine (E132, CI 73015, Blue 2 FD &C), tartrazine (E 102, CI 19140, Yellow 5 FD &C), 4R punch (E 125, CI 16255, Red Carmine Cochineal A FD &C), yellow quinoline (E 104, CI 47005, Yellow 10 FD &C), erythrosine (E127, CI 45430, Red 3 FD &C), azorubine (E 122, CI 14720, Carmoisine FC &C), amaranth (E 123, CI 16185, Red 2 FD &C), bright green acid (E 142, CI 44090, Green S FD &C). The numbering with E is indicated for the pigments related to the numbering of the United States. Concerning this, see also "Deutsche Forschungsgemeinschaft, Farbstoffe, für Lebensmittel, Harald Boldt Verlag Kg, Boppard (1978), Deutsche Lebensmittelrundschau 74, No. 4, page 156 (1978), Arsneimittelfarbstoffverordnung AmBarbV dated 08.25.1980. C are related to the Food, Drug and Cosmetic approval of the Food and Drug Administration (FDA) of the United States described in: Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors: Code of Federal Regulations -Title 21 Part 82 of Color Additive Regulations, List of Colors and Specifications Provisionally Listed Certificates (CFR 21 Part 82) • Plasticizers Other additives may also be plasticizers.The usual amounts are between 0 and 50, preferably from 2 to 20, in particular from 5 to 10% by weight Plasticizers can influence the functional d 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 glass and promote the formation of film, depending on the amount added. Suitable substances usually have a molecular weight of between 100 and 20,000 and comprise one or more hydrophilic groups in the molecule, for example, hydroxyl, ester or amino groups. Examples of additional plasticizers with alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters, SORBITAN esters, diethyl sebacate, dibutyl sebacate and polyethylene glycols 200 to 12 000. The preferred plasticizers they are triethyl citrate (TEC) and acetyl triethyl citrate (ATEC). Special mention should be made of esters that are usually liquid at room temperature, such as citrates, phthalates, sebacates or castor oil. The esters of citric acid and sebacic acid are preferably used. The addition of plasticizers to the formulation can be carried out in a known manner, directly, in an aqueous solution or after the thermal pre-treatment of the mixture. It is also possible to use mixtures of plasticizers. Production of multiple particle pharmaceutical forms Coated granules containing active substance can be processed by conventional pharmaceutical excipients and in a manner known per se for multi-particle pharmaceutical forms, in particular for tablets containing granules, minitablets, capsules, sachets or powders for reconstitution, which are formulated in such a way that the contained granules are released in the pH range of the stomach. The preparation as a pharmaceutical form of multiple particles puts the reliability of a high dose that offers the advantage of a good distribution of the granules in the intestinal lumen. The multi-particle dosage form of the invention may additionally also comprise different types of granules with different active substances and / or different granule structure. Compressed Tablets The production of multiple particle dosage forms by compression of a conventional pharmaceutical binder with particles containing an active ingredient is described, for example, in Beckert et al. (1996), "Compression of entric-coated pellets to disintegrating tablets," International Joumal of Pharmaceutics 143 r page 13-23 r and in WO 96/01624. Film coatings in granules containing active substances are normally applied in fluidized bed apparatus. The formulation examples are mentioned in this application. Film formers are usually mixed with plasticizers and release agents through the proper process. It is possible in this case for film formers to be in the form of a solution or suspension. The excipients for film formation can likewise be dissolved or suspended. Organic or aqueous solvents or dispersing agents can be used. The stabilizers can be used additionally to stabilize the dispersion (example: Tween 80 or other suitable emulsifiers or stabilizers). Examples of release agents are glycerol monostearate and other suitable fatty acid derivatives, silicon derivatives or talc. Examples of plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, and other substances mentioned in the literature. Examples of release agents are glycerol monostearate or other suitable fatty acid derivatives, silica or talc derivatives. Examples of plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates and other substances mentioned in the literature. A separation layer can be applied between the copolymer layer containing active substance and the soluble copolymer layer in the intestine to separate the active substance and the coating material for the purpose of avoiding interactions. This layer may consist of inert film formers (e.g., HPMC, HPC or (meth) acrylic acid copolymers) or for example, talc and other suitable pharmaceutical substances. It is also possible to use combinations of film and talc formers or similar substances. It is also possible to apply a separating layer composed of partially or completely neutralized (meth) acrylate copolymer dispersions. The separation layer may also consist of the same mucoadhesive polymer or a different one as in the underlying matrix layer. The possible interactions or incompatibilities of the active substance or the mucoadhesive polymer with the layer of (meth) acrylate copolymer forming the film can be counteracted in this way. Blends for producing tablets composed of coated particles are prepared by mixing the granules with suitable binders to make tablets, if necessary add disintegrating substances and if necessary lubricants are added. The mixing can be carried out in suitable machines. Inadequate mixers are those that cause damage to coated particles, for example plowshare mixers. In order to achieve adequate short disintegration times it may be necessary to add the excipients to the coated particles in a specific sequence. It is possible through premixing with the particle coated with the lubricant or the magnesium stearate mold release agent for this surface to become hydrophobic and in this way adhesion is prevented. Suitable blends for tabletting typically comprise from 3 to 15% by weight of a disintegration assistant, for example, Kollidon CL and, for example, 0.1 to 1% by weight of a lubricant and mold release agent such as magnesium stearate. The proportion of the binder is determined by the required proportion of the coated particles. Examples of typical binders with Cellactose®, microcrystalline cellulose, calcium phosphates, Ludipress®, lactose and other suitable sugars, calcium sulfates or starch derivatives. Bulk low density substances are preferred. The typical disintegration assistants (disintegrants) are crosslinked starch derivatives or cellulose derivatives, and crosslinked polyvinylpyrrolidone.

The cellulose derivatives are equally suitable.

It is possible to dispatch them with the use of disintegration assistants through the selection of the appropriate binder. Typical lubricants and mold releasing agents are magnesium stearates or other suitable salts of fatty acids or substances detailed in the literature for this purpose (eg, lauric acid, calcium stearate, talc, etc.). It is possible to dispense with the use of a lubricant and a mold release agent in the mixture or use suitable machines (eg tablet press with external lubrication) or suitable formulations. It is possible, where it is correct to add an assistant to the mixture to improve the flow (for example, derivatives of silica, talc, etc.). The manufacture of tablets can be carried out in conventional tablet presses, eccentric or rotary tablet presses, with compression forces in the range of 5 to 40 kN, preferably of 10-20 nK. The tablet presses can be equipped with systems for external lubrication. Special systems for filling temp, which prevent the filling of dye by means of propeller blades, are used where it is correct. Additional Multi-Particulate Pharmaceutical Forms As an alternative for compressing tablets or mini-tablets, it is also possible that the coated granules containing active substances are processed into another multiple-particle pharmaceutical form administered orally. The coated granules can, for example, be packaged in capsules, for example gelatin capsules, or formulated for reconstitutable sachets or powders. Advantageous effects of the invention The pharmaceutical form of the invention is suitable for efficiently directing and releasing the active substances of proteins and peptides. The dosage form exhibits a high dose of reliability and is well distributed in the intestinal lumen. The active substance of protein or peptides is substantially protected from physical or proteolytic inactivation and can be released at the defined site of action such that a high proportion of the active substance can be taken by the body. Therefore, the pharmaceutical form is made with less active substance, because only a little of this active substance is lost. The risk of side effects is usually reduced through the intended delivery. The site of action can be adjusted in a variable manner depending on the therapeutic assistant. The timing of the absorption of the active substance can be better controlled. Because the pharmaceutical form is for oral use, it is generally better accepted by patients (patient compliance) compared to other forms of administration. A large number of peptide or protein active substances may, therefore, be advisable for oral use for the first time and the risk of administration is often less than with the Parenteral administration in particular. Administration costs can also be kept low because a qualified staff is not necessary for administration. An accelerated release, at the same time, with an increase in bioavailability can be achieved from the matrix systems in which the proportion of the polymer has a mucoadhesive effect in a percentage by weight of 3 times, preferably of 1000 times higher than the proportion of the active substance. Lipophilic matrix A special aspect of the invention arises when the active substance has been embedded in a lipophilic matrix having a melting point above 37 ° C, preferably above 45 ° C, particularly preferably above 55 ° C, and the lipophilic matrix containing active substance has been embedded in the composite matrix of the polymer having a mucoadhesive effect. The purpose of the formulation in the lipophilic matrix is to improve the solubility and bioavailability of the active substance, preferably the slightly or slightly soluble active substances (as defined in DAB 10, 2003). A lipophilic matrix means in the context of the invention, a substance or a mixture of substances in which the active substance can be dissolved, suspended or emulsified. The substance or substances of the lipophilic matrix are different from the usual pharmaceutical excipients and the polymer having a mucoadhesive effect. The substance or substances of the lipophilic matrix preferably have a hydrophobic or amphiphilic character. The lipophilic matrix can also refer to an amphiphilic matrix or lipoidal matrix. The lipophilic matrix can consist of a simple substance, for example a lipid or a mixture of substances, for example of a mixture of lipids. In the case of mixtures, the properties described hereinafter for solubilities in water according to DAB 10, the partition coefficients and / or the HLB values are calculated in each case from the arithmetic element of the parts by weight and from the values of the substances of the mixture. The substances used must not be toxic. The active substance and the substance or substances forming the lipophilic matrix preferably differ in their solubility in steeping water with DAB 10 and not more than +/- 50%, preferably do not differ by more than +/- 25%, and / or they differ in their partition coefficient in accordance with Annex V of guideline 67/548 / EEC, A.8 not more than +/- 60%, preferably not more than +/- 30%, and / or differ in their HLB , if a HLB can be assigned to the substances, measured by the Marszall method, no more than +/- 80%, preferably no more than +/- 40%. A greater agreement of the active substance with the lipophilic matrix is at least one, preferably two or all three of the properties, meaning a greater favoring of the solubility and bioavailability of the active substance in the pharmaceutical form. Solubility in water The solubility in water for the active substance and the substance or substances forming the lipophilic matrix can be defined as specified in D7AB 10 (Deutsches Arzneibuch, 10th edition with 3rd supplement 1994, Deutscher Apothekerverlag, Stuttgart und Govi Verlag, Frankfurt / Main, 2nd supplement (1993), IV Allgemeine Vorschriften, pages 5-6, "Lóslichkeit und Lósungsmittel"; see also Ph. Eur 4.07, 2004). Solubility is defined by the number of parts by volume of the solvent for 1 part by weight of the substance or drug. The definition of "slightly soluble" includes substances that require 30 to 100 parts by volume of the solvent for 1 part by weight of the substance or drug, and the definition of "poorly soluble" includes substances that require 100 to 1000 parts by volume of the solvent for 1 part by weight of the substance or drug. Partition coefficients. The partition coefficients for the active substance and the substance or substances forming the lipophilic matrix can be determined in accordance with Annex V for guideline 67/548 / EEC, A.8, "partition coefficient". HLB HLB is a measure, introduced by Griffin in 1950, of the hydrophilicity or lipophilicity of non-ionic surfactants. It can be determined experimentally by a method of titration of phenol from Marszall; cf, "Parfümerie, Kos etik", volume 60, 1979, pages 444-448; additional references in Rdmpp, Chemie-Lexikon, 8th edition, 1983, page 1750. See also, for example, US 4 795 643 (Seth)). An HLB (hydrophilic / lipophilic balance) can be determined precisely only by non-ionic substances. With ammonia substances it is possible to determine this value through calculation, but it is virtually always above or well above 14. The HLB values for the active substance and the substance or substances that make up the lipophilic matrix can in most cases be determined at . through the Marszall method, taken from tables of pharmaceutical or chemical reference works or textbooks or, in the case of ionic substances, determined by calculation. Active substances in the lipophilic matrix The pharmaceutical form preferably comprises in the lipophilic matrix an active substance having a solubility in water according to DAB 10 of at least 30, in particular from 30 to 100 or from 100 to 1000 parts by volume of water on the one hand by weight of active substance. The active substance is preferably correspondingly light or even slightly soluble according to the definition of DAB 10. The active substance formulated in the lipophilic matrix can be selected, for example, from the group of peptides, antibiotics, in suppressors, LHRH, antagonists, and immunomodulators. The active substance formulated in the lipophilic matrix can be for example abarelix, angiotensin II, anidulafungin, antide, argipressin, azaline and azaline B, bombesin antagonist, bradykinin, buserelin, cetrorelix, cyclosporin, cyclosporin A, desmopressin, detirelix, enkephalins (Leu). -, Met) ganirelix, gonadorelin, goserelin, growth hormone secretagogue, insulin, interferon (alpha, beta, gamma), interleukins (IL1, IL2), micafungin, nafarelin, leuprolide, leuprorelin, octreotide, orntido, oxytocin, paratyphoid hormone,. ramorelix, secretin, somatotropin, terlipressin, tetracosáctide, teverelix, triptorelin, tiroliberin, tumor necrosis factor thyrotropin (TNF alpha, beta), or vasopressin. Polymers / lipophilic matrix having a mucoadhesive effect In a preferred embodiment, the possible interactions of the lipophilic matrix with the polymer having a mucoadhesive effect are taken into account. In order to avoid uncontrollable interactions, the substance or substances that make up the lipophilic matrix, and the polymer having a mucoadhesive effect, must preferably have the same ionic properties, that is, both must have an anionic character accordingly. In the case that substances having opposite ionic properties are selected, the polymer having a mucoadhesive effect should preferably be present in at least 50, particularly preferably 100% in neutralized form. The neutralization can be carried out by adding acid or base in a known manner. Substance or substances to assemble the lipophilic matrix The lipophilic matrix preferably consists of 80 to 100, preferably 90 to 100, particularly preferably 100% by weight of a substance or a mixture of substances having an HLB (average) from 0 to 15, preferably consists of 2 to 10. The lipophilic matrix may comprise 0 to 20, preferably 0 to 10% by weight of the usual pharmaceutical excipients, especially stabilizers, thickeners or absorbers. It is particularly preferred that the usual pharmaceutical excipients are not present. The substance or substances forming the lipophilic matrix can for example belong to the group of oils, fats, mono-, di- or triglycerides, fatty acids, fatty alcohols, especially C6 to C2o fatty acids and / or a C6 to C20 alcohol including their salts, ether, ester or amide derivatives, phospholipids, lecithins, emulsifiers, lipids, vitamins or lipid-soluble surfactants. The lipophilic matrix may comprise for example one of the following lipid preparations: (Imwitor 308) glyceryl monocaprylates having a monoester content of >80% (Imwitor 312) glyceryl monolaurates having a monoester content of > 90%, (Imwitor 491) glycerol monostearate (Cie + Cie) having a monoester content of > 90%, (Imwitor 900 P) glycerol monostearate having a monoester content of 40-55% and a Cie content of 40-60%, (Imwitor 900 K) glycerol monostearate, which has a monoester content of 40-55% and a Cie content of 60-80%, (I witor 742) C8 and Cio glycerides with medium chain length having a content of monoester of 45-55%, (Imwitor 928) partial glycerides of Cío-Cie fatty acids of saturated vegetables with a main content of Ci2 and having a content of monoester of 34-36% of glycerides C8 and Cio, caprylate Na or capriato Na The lipophilic matrix may comprise, for example, one of the following preparations: fats such as mono-, di-, triglycerides of saturated and unsaturated fatty acids and mixtures thereof. In particular glycerol stearic acid ester, glycerol palmitic acid ester, glycerol myristic acid ester, glycerolpalmitic acid stearic ester, glycerol lauric acid ester, glycerol caprylic acid ester, glycerol oleic acid ester glycerol, examples of these esters are Imwitor® -308, -312, -491, -742, -900, -928, -988, and Gelucire® 44/14, -50/13, Sulele, Co pritol E ATO, Dynasan 114, Softisan, Witepsol, Dynacet 212, coconut fat. Oils such as, for example, castor oil, sesame oil, sunflower seed oil, cottonseed oil, corn oil, almond oil, peanut oil, olive oil, coconut oil, carrot oil, wheat germinated oil, walnut oil. Neutral oils such as isopropyl myristate, isopropyl palmitate, isopropyl stearate, medium chain triglycerides (Miglyol®). Short chain aliphatic and aromatic carboxylic esters with, for example, dibutyl phthalate, diethyl sebacate, dibutyl sebacate, tributyl citrate, acetyl tributyl citrate, glycerol triacetate. Waxes such as, for example, carnauba wax, beeswax, wool wax, glycerol behenic acid ester.

Fatty acid amides, such as, for example, stearamide, palmitamide, lauramide. Long-chain aliphatic carboxylic acids, such as, for example, stearic acid, palmitic acid, lauric acid, myristic acid, oleic acid, caprylic acid, linoleic acid. And, for example, its salts of NA, Al and Mg. Fatty alcohols such as, for example, stearyl alcohol, lauryl alcohol, cetyl alcohol, myristin alcohol, formal glycerol. W / O emulsifiers, such as cholesterol, glycerol monostearate, ethylene glycol monostearate, sorbitan monooleate, (Span® 80), sorbitan monostearate (Span® 60), sorbitan trioleate (Span® 85), sorbitan sorbate (Span® 65), sorbitan sesquioleates (Arlacel® 83), Ca stearate, Al, Mg, polyoxyethylene sorbitan sorbate (Tween® 65), polyoxyethylene sorbitan trioleate (Tween ® 85). Nonionic O / W emulsifiers, for example, macrogol 400 stearate (Chremophor® A), macrogol lauryl ether, polyethylene glycol 20 sorbitan monolaurate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monooleate, triricinoleate macrogol 1500 glycerol, macrogol glycerol hydroxystearate (Cremophor® RH), macrogol 1000 glycerol monolaurate, monostearate, monooleate, sucrose monostearate. Polysorbate 60 (Tween® 60), polyoxyethylene monostearate (Myrj 49), polysorbate 80 (Tween® 20), poloxalene 407 (Lutrol® F 127), poloxalene 188 (Lutrol® F 68), polyoxyethylene ricinoleate (Cremophor® EL) , polyoxyethylene stearyl stearate. O / W ionic emulsifiers, such as, for example, cetylstearyl sulfate (Lanette® E), Na lauryl sulfate (Texapon® Z), Na glycocholate, hederagenin. Amphiphilic emulsifiers, such as, for example, egg phosphate-dicholine (egg lecithin), soy phosphate-dichiloline (soy lecithin), betaine, sulfobetaines, ceramides (sphingomyelin). Vitamins such as, for example, retinol (vitamin A), cholecalciferol (vitamin D), alpha-tocopherol and alpha-tocopherol acetate (vitamin E), phylloquinone (vitamin K). Additional excipients are galactolipids as, for example, monogalactosyl diacylglycerol, digalactosyl diacylglycerol, trigalactosyl diacyl glycerol, and aromatic oils such as, for example, anise oil, citronella oil, eucalyptus oil, fennel oil, chamomile oil, cardamom oil, pine needle oil, cumin oil, dwarf pine oil, lavender oil, peppermint oil, muscatel oil, clove oil, peppermint oil, rosemary oil, sage oil, and terpenes, such as menthol, linalool, 1,4-cineol, pyrethrin, borneol, eudesmol, phytol, manool, azadirachtin, nimbin. The active substance is preferably at least 10%, particularly preferably at least 20%, especially at least 50%, soluble in the lipophilic matrix. The content of the lipid matrix containing active substance in the bale of the inner matrix a) can be from 1 to 50, preferably from 10 to 20% by weight. The lipophilic matrix preferably comprises at least 50% by weight of glycerol monocaprylate, up to 10% by weight of Na cholate, up to 10% by weight of tocopherol succinate, 1 to 5% by weight of efflux pump inhibitor in the case where the active ingredient is a PgP efflux pump substrate, for example, Solutol HS 15, a triglyceride, in particular tristearate, with components that add up to 100%. This lipophilic matrix can be incorporated directly into the mucoadhesive polymer or be emulsified in water and incorporated into the mucoadhesive polymer. In the latter case, the aqueous phase may comprise a weak acid such as, for example, citric acid. In the case of active substances that are slightly or even less soluble (according to DAB 10) that has a molecular weight of >; 3000, a protease inhibitor such as, for example, soy trisine inhibitor present in the aqueous phase. Process The invention also relates to a process for producing a multi-particle dosage form with the steps of: a) production of the lipophilic matrix containing active substance by suspending and / or dissolving the active substance with the substance (s) ) which forms the lipophilic matrix and, where appropriate, also conventional pharmaceutical excipients, by vigorously mixing or melting the ingredients; b) production of pre-granules (granule cores) by spraying the mucoadhesive polymer mixed with the lipophilic matrix containing active substance in a core or through agglomeration processes with rotation, precipitation or dew without a core; c) production of granules through spray application of an anionic polymer or copolymer coating, which may optionally comprise mixtures of conventional pharmaceutical excipients, especially plasticizers and libration agents, of an organic dispersion or solution in the pre-granules of the step b); d) production of a multi-particle pharmaceutical form by filling or incorporating the granules of step c) in a manner known per se, where appropriate with the use of customary pharmaceutical excipients, in particular through tablet processing with Content of granules, mini-tablets, capsules, sachets or reconstitutable powders. Preference process Steps a) and b) of the process are preferably carried out in the following manner: a) production of the inner matrix layer through preparing an emulsion, dispersion or solution of the active substance with the (s) substance (s) for the lipophilic matrix, and when appropriate, also conventional pharmaceutical excipients by vigorously mixing the ingredients in water and producing an oil-in-water preparation having an average particle size of not more than 60, preferably not more than 20 μm; b) production of pre-granules through spray application of the oil-in-water preparation of step a) in the mucoadhesive polymer which may optionally comprise additional mixtures of usual pharmaceutical excipients, where the ingredients are in the form of a micronized powder , for example, with an average particle size of 10 to 100 μm, through agglomeration by rotation, extrusion or granulation.

EXAMPLES The production of the granules comprises mucoadhesive formulated peptides and protein active substances. Example 1 First coating (pre-granules): 20 g of carboxymethylcellulose Na (Blanose 7LF, Hercules-Aualon) = 10% based on the granules (water absorption of Blanose 7LF: about 50% in 15 minutes with a pH of 7.2 in phosphate buffer, the mucoadhesion with a pH of 7.2 in measurement through the method of Hassan &Gallo:? b = around 250 mPa »s) are dissolved together with 1.25 g of Aerosol 200 (microcrystalline cellulose) = 6.25% based on Blanose in 378.8 g of ineralized water through agitation with a propulsion stirrer. 0.72 g of polysorbate 80 (33% concentration) = 40% based on glycerol monostearate (GMS) are dissolved by stirring in 10 g of water. Addition of 0.6 g of GMS = 3% based on Blanose and demineralized water ad 20 g is followed by heating of the dispersion at 80 ° C. the dispersion is cooled to 30 ° C and then homogenized with an Ultraturrax mixer for 10 minutes and subsequently added to the Blanose solution with stirring. Subsequently, 139.4 g of desmopressin acetate (Mw = 1067) = 0.062% in the formulation is dissolved in 30 g of demineralized water and added to the Blanose solution. 200 g of granules (colored tablets) 850-1000 μm are placed in a minifluidised bed apparatus (Glatt's MiniGlatt, Binzen) and coated with Desmopressin-Blanose solution. Spray parameters: Spray nozzle 0.5 mm Spray rate 1-1.26 g / minutes Spray pressure 0.8 bars Inlet air pressure 1 bar Inlet air temperature 45 ° C Product temperature 41.5 - 43 ° C Rear drying in MiniGlatt 10 minutes at 40 ° C Dew time: around 2 to 6 hours Drying overnight at RT Layer thickness (REM): 12-18 μm Table 1: Release (USP method XXC) of desmopressin in phosphate buffer with a pH of 7.2; 100 min-1; paleteo; 1 hour; 100 rmp; 37 ° C; n = 4; (first layer) .

The released desmopressin is detected using a 220 nm spectrometer.

Example 2 Second coating (granules): 66.7 g of Eudragit® FS30DF (30% concentration dispersion comprising a copolymer of 25% by weight of methyl methacrylate, 65% by weight of methyl acrylate and 10% by weight of methacrylic acid , Rohm GMBH &Co.

KG, Darmstadt) and mixed with 1 g of triethyl citrate (TEC) = 5% based on CDM (dry matter coating) in a 150 ml glass beaker. 2.2 g of polysorbate 80 (33% concentration) = 40% based on GMS are dissolved by stirring in 46 g of demineralized water. 1.8 g of GMS = 9% based on CDM and demineralized water are added followed by heating the dispersion to 80 ° C. The dispersion is cooled to 30 ° C and then homogenized with Utraturrax for 10 minutes and subsequently added with stirring to the Eudragit® FS30D dispersion. After stirring for 30 minutes, 100 g of the desmopressin-Blanose coated granules of Example 2 are introduced into a MiniGlatt and coated with the Eudragit® FS30D dispersion. Spray parameters: Spray nozzle 0.5 mm Spray rate 0. 6 - 0.9 g / minutes Spray pressure 0.7 bars Inlet air pressure 0.7 bar Inlet air temperature 30 ° C Product temperature 29-30 ° C Rear drying in MiniGlatt 10 minutes at 40 ° C Drying overnight at RT Dew time: around 1 to 2.5 hours Layer thickness (REM): 40-45 μm Table 2: Release of desmopressin from granules coated with Eudragit® FS30D , 2 hours in 0.1 M HCl, 1 hour in phosphate buffer with pH 7.2; 100 rpm; paleteo; 37 ° C; n = 4 (second coating) Example 3 First coating (pre-granules) 20 g of Blanose 7LF = 20% based on the granules (absorption of water: around 50% in 15 minutes with a pH of 6.0 in phosphate buffer, mucoadhesion with a pH of 6. 0 in phosphate buffer measured by Hassan & Rooster: = around 270 mPa * s) dissolve untos with 1.1 g of Aerosol 200 = 5.5% based on Blanose and 1. 52 g of polysorbate 80 (33% concentration) 2.5% based on Blanose in 727.4 g of demineralized water through agitation with a propulsion stirrer. 139.4 mg of desmopressin acetate = 0.062% in the formulation are then dissolved in 50 g of demineralized water and added to the Blanose solution with stirring. 200 g of neutral cores (colored tablets) 850-1000 μm are placed in a minifluidised bed apparatus (MiniGlatt, Glatt, Binzen) and coated with the desmopressin-Blanose solution. Spray parameters: Spray nozzle 0.5 mm Spray rate 1.4-2.0 g / minutes Spray pressure 1 bar Inlet air pressure 1.2 bar Inlet air temperature 45 - 47 ° C Product Temperature 41-42 ° C spray: around 2 to 6 hours Subsequent drying in MiniGlatt 10 minutes at 44 ° C Drying overnight at RT Layer thickness (REM): 10-12 μm Example 4 Second coating (granules): 66.7 g of copolymer dispersion from (meth) acrylate (30% dispersion concentration comprising a copolymer of methyl acrylate / butyl, methacrylate / ethyl, acrylate / methacrylic acid in the ratio of 20/20/30/30, Rohm GMBH &Co. KG, Darmstadt) are placed in a 250 ml glass beaker. 2.4 g of polysorbate 80 (33% concentration) = 40% based on GMS are dissolved by stirring in 81 g of demineralized water. Addition of 2.0 g of GMS = 10% based on the dry coating material that is followed by heating the dispersion to 80 ° C. The dispersion is cooled to 30 ° C and then homogenized with an Ultraturrax for 10 minutes and subsequently to the dispersion product 4154 D is added with stirring. After stirring for 30 minutes, 100g of the desmopressin-Blanose coated granules of Example 3 they are introduced there in a MiniGlatt and are coated with dispersion. Spray parameters: Spray nozzle 0.5 mm Spray rate 0.6 - 0.9 g / minutes Spray pressure 0.5 bars Inlet air pressure 0.7 bar Inlet air temperature 35-37 ° C Product temperature 32-33 ° C spray: around 1 to 2 hours After drying in MiniGlatt 10 minutes at 40 ° C Drying overnight at RT Layer thickness (REM): 40-45 μm Table 4: Release of desmopressin in the granules coated with the copolymer before mentioned, 2 hours in 1 M HCl, 1 hour in phosphate buffer with a pH of 6.0; 100 rpm; paleteo; 37 ° C; n = 4 (second coating) Example 5 First coating (pre-granules) 15 g of low MW kitosan (Fluka) = 10% based on the granules (water absorption of chitosan: about 140% in 15 minutes with a pH of 5.5 in acetate buffer, mucoadhesion with pH of 5.5 measured by the Hassan &Gallo method: eta-b = around 220 mPa »s) are dispersed together with 0.825 g of Aerosol 299 = 5.5% based on chitosan in 1122 g of demineralized water and 1.36 g of polysorbate 80 (33% concentration) = 3% based on chitosan by agitation with a propulsion stirrer. The chitosan is then dissolved by adding 60 g of acetic acid while stirring is continued for 1 hour. 104.6 mg of desmopressin acetate = 0.063% in the formulation dissolved in 50 g of demineralized water and added to the chitosan solution. 150 g of colored pellets granules 850 -1000 μm are placed in a MiniGlatt (Glatt, Binzen) and coated with the desmopressin-chitosan solution. Spray parameters: Spray nozzle 0.5 mm Spray rate 0.8 - 2.5 g / minutes Spray pressure 1.5 - 1.8 bars Inlet air pressure 1.1-1.2 bar Inlet air temperature 60-69 ° C Product temperature 59-62 ° C Subsequent drying in MiniGlatt 10 minutes at 50 ° C Dew time: around 3-8 hours Drying overnight at RT Layer thickness (REM): 12 μm Table 5: Release of desmopressin in a phosphate buffer with a pH of 5.5; 100 min "-1"; paleteo; 1 hour; 100 rpm; 37 ° C; n = 4 (first layer) Example 6 Second coating (granules) : 66.7 g of Eudragit® L30D-55 (30% dispersion concentration comprising a (meth) acrylate copolymer composed of 50% by weight of methacrylic acid and 50% by weight of ethyl acrylate) are mixed with 2 g of triethyl citrate (TEC) = 10% based on CDM (dry matter coating) in a 150 ml glass beaker. 0.73 g of polysorbate 80 (33% concentration) = 4% based on MSG are dissolved with stirring in 46 g of demineralized water. 0.6 g of GMS = 3% based on CDM and demineralized water are added followed by heating the dispersion to 80 ° C. The dispersion is cooled to 30 ° C and then homogenized with an Ultraturrax for 10 minutes and subsequently added with stirring to the dispersion of Eudragit® L30D-55. Then stir for 30 minutes, 100g of the desmopressin-chitosan coated granules of Example 5 are introduced there into a MiniGlatt and coated with the Eudragit® dispersion L30d-55.

Example 7: Sprayability Table 7: Probing of roceability (yes / no) of dispersions / or polymer solutions at various concentrations. * = 30% (meth) acrylate copolymer by weight of methyl methacrylate and 70% by weight of methacrylic acid Example 8: Formulation examples for a targeted release of the active substance in various sections of the intestine (see Table 8). The particle size after coating, the finished formulation using colored pellets granules 850-1000 as carrier material μm - > 900-1050 μm.

Table 8: Polymer formulations and properties *** Measurement of mucoadhesive property by the method of Hassan and Gallo EXAMPLES OF EMBODIMENTS WHICH HAVE A LIPOPHILIC MATRIX CONTAINING LEAD ACTIVE SUBSTANCE EXAMPLE: FORMULATION OF A FORMULATION FOR Slightly Soluble Proteins (Erythropoetin alfa), Water solubility in accordance with DAB of at least 500 parts of water per 1 part of active substance, equivalent to 2 g / 1). a) Preparation of the l ± pofílica phase 100 g of Inwitor 312 (melting point 55-60 ° C) is melted in a water bath at 65 ° C and 50 g of In itor 308 (melting point 30 30-34 ° C) are slowly stirred in the melt. The water bath is cooled to 50 ° C, and 7.5 g of tocopherol acetate, 2 and 3.5 g of Na glycocolate are added while stirring. The temperature of the bath can, in this way, be reduced by an additional 5 ° C without the resolidification of the fat. The resulting lipophilic matrix has a melting point of 38-41 ° C and a solubility in water, calculated from the individual components, in accordance with D7U3 10 of at least 400 parts of water for 1 part of matrix lipophilic; equivalent to 2.5 g / 1). 330 mg of erythropoetin alga (around 40 million U.I.) are added to this solution while stirring. b) Preparation of an emulsion 750 ml of distilled water is initially heated to 45 ° C, and 15 g of Na coating as an emulsifier (2%) is added. This solution is then adjusted to a pH of about 7 by adding citric acid. Thereafter, 1.5 g of soybean trypsin inhibitor (serine peptidase inhibitor) and 1.5 g of bacitracin (aminopeptidase inhibitor) are added to this solution while stirring. The lipophilic phase is then emulsified in this solution by vigorous stirring. The emulsion process can be terminated when a lipophilic drip greater than 50-60 μm is evident after microscopic investigation. c) Production of mucous nuclei 350 g of alginate powder Na, 145 of microcrystalline cellulose and 5 g of citric acid are mixed therein in a GPCG1 with rotor insert. The emulsion described in b) is sprayed as a binder in a rotary agglomeration process at a spray rate of about 90 g / min. The rotor is set at 1700 - 1800 rpm, the air inlet at 42 m3 / hour and the air temperature at 30 ° C. Under these conditions it is possible to produce mucoadhesive nuclei between 250 and 600 um with a production of up to 80%. A therapeutic dose of 240 μm is present in 0.5 g of granule nuclei. d) Production of coated granules The granule cores of c) ARE COATED WITH Eudragit® FS30D by means of conventional fluidized bed processes. The application of the polymer amounts to 40% by weight based on the weight of the core. The dispersion / suspension for coating consists of: Eudragit® FS30D 44.65% Triethyl Citrate 0.67% Polysorbate 80 0.26% Glycerol Monostearate 0.67% Water 52.75% Granules obtained in this way can be compressed to one tablet using conventional pharmaceutical processes and excipients or packed in capsules. 2nd Example: Formulation of a formulation for poorly soluble peptides (cetrorelix acetate, solubility in water according to DAB 10 at least 1000 parts of water per 1 part of active substance, equivalent to 1 g / 1). a) Preparation of the lipophilic phase 13 g of Imwitor 312 (melting point 55-60 ° C) are melted with 4 g of Poloza er 407 (Lutrol F127, melting point 50-55 ° C) in a 65 ° C water bath. Then 1 g of caprylic acid, 1 g of Na caprylate and 1 g of tocopherol acetate are added while stirring. The lipophilic matrix resulting from this form has a melting point of 40-48 ° C and a water solubility, calculated from the individual components, according to DAB 10 of at least 700 parts of water per 1 part of lipophilic matrix ( equivalent to 1.5 g / 1). After the solution is cooled to 45 ° C, 3.0 g of cetrorelix acetate is stirred in a lipophilic phase while stirring at high speed and cooled. b) Production of an emulsion The resulting dispersion of a) is dispersed using an Ultraturrax (20,000 rpm) with the chitosan citrate dispersion of b) while further cooling in an ice bath at 10 ° C for a minimum of 10 minutes. minutes The emulsification process can be terminated when lipophilic drops greater than 50-60 μm are not evident after microscopic examination. c) Production of mucoadhesive cores 20 g of chitosan are dispersed in 1000 g of water and then, while stirring at a very high speed, 20 g of citric acid. 2 g of Na dodecanate are added to the resulting light yellowish viscous solution while stirring at high speed, and stirring is continued for 1 hour. The emulsion of b) is sprayed using a GPGC1 (Glatt) at a dew rate of 10-12 g / min / kg in 250 g of neutral granules 400-600 μm at an inlet air temperature of 30 ° C and the Air intake is in this case adjusted to 45-50 m3 / h. The production in this case is 90%. d) Production of coated sheets The granules obtained in this way are coated with Eudragit® L12.5 by means of conventional fluidized bed processes. The application of the polymer sum 40% by weight based on the weight of the core. The coating suspension consists of: Eudragit® L12.5 53.3% Triethyl Citrate 1.33% Isopropanol 38.3% Talcum 2.0% Water 5.0% Granules obtained in this way can be compressed to a tablet using conventional pharmaceutical processes and excipients, or packaged in capsules 3rd Example: Formulation of a formulation for a poorly soluble protein (human beta-interferon, solubility in water according to DAB 10 at least 600 parts of water per 1 part of active substance, equivalent to 2 g / 1) ) Preparation of the lípofílica phase 400 g of Imiteor 312 (melting point 55-60 ° C) and 200 g of Dinasan 114 (melting point 55-58 ° C) are fused with 30 g of tocopherol acetate at 65 ° C and put in a granulator (Bohle). 20 g of Na caprylate are added thereto with stirring. The mixture is cooled to 45 ° C and 100 g of interferon-beta are dissolved there. The lipophilic matrix resulting from this form has a melting point of 39-46 ° C and a water solubility, calculated from the individual components, according to DAB 10 of at least 840 parts of water per 1 part of lipophilic matrix. The lipophilic matrix is milled while cooling to a particle size below 50 μm. b) Production of a buffer solution 1 g of Na citrate and 1 g of citric acid are dissolved in 500 g of water. While stirring at high speed, 0.5 g of Na cholate and 100 mg of soybean trypsin inhibitor are added. c) Granulation The lipophilic matrix containing a ground active substance of a) is mixed in a granulator with 1500 g of Blanose 7LF. The aqueous buffer solution of b) is then used for granulation to result in particles of 0.2 to 0.5 mm in size, which are rounded in a spheronizer. The resulting wet cores are dried under light conditions of 30 to 25 ° C in a fluidized bed dryer. d) Production of the coated granules In this way the nuclei of c) are coated with. Eudragit® FS30D using conventional fluidized bed processes. The application of the polymer adds 40% by weight based on the weight of the core. The dispersion / suspension for the coating consists of: Eudragit® FS30D 44.65% Triethyl Citrate 0.67% Polysorbate 80 0.26% Glycerol Monostearate 0.67% Water 53.75% Granules obtained in this way can be compressed to tablets using conventional pharmaceutical excipients and processes, or packed in capsules.

Claims (29)

1. KEGVINDICATIONS 1. An oral pharmaceutical form of particles comprising granules having a size in the range of 50 to 2500 μm, which are substantially composed of a) an internal matrix layer comprising an active substance that is a peptide or a protein, including derivatives or conjugates thereof, and is embedded in a matrix of a polymer having a mucoadhesive effect, wherein the matrix can optionally comprise additional customary pharmaceutical excipients, b) an outer film coating consisting essentially of an anionic polymer or copolymer which can optionally be formulated with usual pharmaceutical excipients, especially plasticizers, characterized in that the multi-particle dosage form is formulated in such a way that the contained granules are released in the pH range of the stomach, the outer coating is adjusted through the choice of the polymer or anionic copolymer or its f formulation with excipients and its layer thickness in such a way that the coating dissolves in pH ranges between 4.0 to 8.0 in the intestine in a period of 15 to 60 minutes, so that the mucoadhesive matrix layer containing active substance is exposed and can adhere to the intestinal mucosa and release the active substance there, where the polymer has a mucoadhesive effect of? b = 15 'at 1000 mPa * s and an absorption of water from 10 to 750% in 15 minutes in a range of + / - 0.5 pH units relative to the pH at which the outer coating to be dissolved begins, and the active substance content of the matrix layer is a maximum of 40% by weight of the polymer content having a mucoadhesive effect.
2. 2. The pharmaceutical form as described in claim 1, characterized in that the outer film coating is a cellulose glycolate (Duodcell® =, cellulose acetate phthalate (CAP, Cellulosi acetates, PhEur, cellulose acetate phthalates, NF, Aquaterie®), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), Hydroxypropylmethylcellulose phthalate (HPMCP, HP50, HP55), hydroxypropylmethylcellulose acetate succinate (HPMCAS-LF, -MF, -HF), polyvinyl acetate phthalate (PVAP, Sureteric®), vinyl acetate vinylpyrrolidone copolymer (PVAc, Kollidon®, VA64), vinyl acetate: protonic acid 9: 1 copolymer (VAC: CRA, Kollicoat® VAC) and / or lacquer.
3. 3. The pharmaceutical form "described in claim 1, characterized in that the coating of the outer film consists of a (meth) acrylate copolymer having a monomer content having anionic groups from 5 to 60% by weight. pharmaceutical form as described in one or more of Claims 1 to 3, characterized in that the thickness of the outer coating layer is in the range of 20 to 200 μm 5. The pharmaceutical form as described in one or more of the Claims 1 to 4, characterized in that the inner matrix comprises a C6-a fatty acid C2o ~ and / or a C6 to C20 alcohol including its salts, ether, ester or amide derivatives and / or a lipid and / or a phospholipid and / or a lipid soluble vitamin and / or a protease inhibitor and / or a penetration promoter 6. The pharmaceutical form as described in one or more of Claims 1 to 5, characterized in that the polymer has a mucoadhesive effect It's a k itosan, a (meth) acrylate copolymer consisting of 20-40% by weight of methyl methacrylate and 60 to 80% by weight of methacrylic acid and / or a cellulose, especially Na carboxymethylcellulose, a crosslinked polyacrylic acid and / or without crosslinking, a lectin, an alginate Na and / or a pectin. 7. The pharmaceutical form as described in Claim 6, characterized in that the inner matrix comprises as a polymer having a mucoadhesive effect a chitosan which is used together with an acid or a buffer system, which is located in the matrix or in a core in which the matrix is applied. 8. The pharmaceutical form as described in Claim 7, characterized in that the inner matrix layer comprises chitosan and is adjusted to a pH of 5.0 to 5.5 by means of an acid or a buffer system, and is combined with an outer film coating that begins to dissolve in the pH range of 6.0 to 8.0. The pharmaceutical form as described in one or more of Claims 1 to 8, characterized in that the active substance is a protein or a peptide having an average molecular weight Mw of less than 3000. 10. The pharmaceutical form as described in Claim 9, characterized in that the active substance is abarelix, angiotensin II, anidulafungin, antide, argipressin, azaline and azaline B, bombesin antagonist, bradykinin, buserelin, cetrorelix, cyclosporin A, desmopressin, detirelix, enkephalins (Leu-, Met-) of ganirelix, gonadorelin, goserelin, growth hormone secretagogue, micafungin, nafarelin, leuprolide, luprorelin, octreotide, oryntide, oxytocin, ramorelix, secretin, somatotropin, terlipressin, tetracosactide, teverelix, triptorelin, tiroliberin, thyrotropin, vasopressin. 11. The pharmaceutical form as described in Claim 10, characterized in that the matrix layer additionally comprises a C6- to C20 fatty acid and / or Ce ~, C20 alcohol including its salts, ether, ester or amide derivatives and / or or lipid and / or phospholipid and / or lipid-soluble vitamin. 12. A pharmaceutical form as described in one or more of Claims 1 to 8, because the active substance is a protein or a peptide having an average molecular weight Mw from 3000 to 10,000. 13. The pharmaceutical form as described in Claim 12, characterized in that the active substance is calcitonin, corticotrophin, endorphins, epithelial growth factor, glucagon, insulin, novoin, paratyphoid hormone, relaxin, por-somatostatin or salmon secretin. 14. The pharmaceutical form as described in claim 12 or 13, characterized in that the matrix layer comprises an alcohol e- to C20- including its salts, ether, ester or amide derivatives and / or a lipid and / or a phospholipid and / or a soluble vitamin in a lipid and / or a protease inhibitor. 15. The pharmaceutical form as described in one or more of Claims 1 to 9, characterized in that the active substance is a protein or a peptide having an average molecular weight Mw of more than 10,000. 16. The pharmaceutical form as described in Claim 15, characterized in that the active substance is interferon (alpha, beta, gamma), interleukins (111, IL2), somatotropin, erythropoietin, tumor necrosis factor (TNF alpha, beta) , relaxin, endorphin, dornase alfa, follicle stimulating hormone (FSH), human chorion gonadotropin (JCG), human growth hormone releasing factor (hGRF), luteinizing hormone (LH) or epidermal growth factor. 17. The pharmaceutical form as described in claim 15. or 16, characterized in that the matrix layer comprises a C6 to C2o fatty acid and / or a Ce-C2o alcohol including its salts, ether, ester or amide derivatives and / or lipid soluble vitamin and / or a protease inhibitor and / or a penetration promoter. 18. The pharmaceutical form as described in one or more of Claims 1 to 17, characterized in that a separating layer is applied between the matrix layer containing an active substance and the outer film coating layer. A process for producing a multi-particle dosage form as described in one or more of Claims 1 to 18, through a) producing an inner matrix layer comprising an active substance, which is a peptide or protein, and a polymer having a mucoadhesive effect and, where appropriate, additional conventional pharmaceutical excipients by means of spray application in a core or through rotating agglomeration, precipitation or dew processes without a core, and subsequently b) application of a coating of outer film essentially consisting of an anionic polymer, which optionally can be formulated with usual pharmaceutical excipients, especially plasticizers, by means of spray application so as to obtain the wrapped granules containing active substance, and c) processing of the resulting granules by means of usual pharmaceutical excipients in a manner known per se my sma as a multi-particulate pharmaceutical form, in particular tablets containing granules, minitablets, capsules, sachets or reconstitutable powders, which are formulated so that the contained granules are released in the pH range of the stomach. The pharmaceutical form as described in one or more of Claims 1 to 18, characterized in that the active substance is embedded in a lipophilic matrix having a melting point above 37 ° C., and the lipophilic matrix containing active substance is embedded in the composite matrix of the polymer having a mucoadhesive effect. The pharmaceutical form as described in one or more of Claims 20, characterized in that the active substance and the substance or substances forming a lipophilic matrix differ in their solubility in water according to DAB 10 and not more than +/- 50%, and / or differs in its partition coefficient in accordance with Annex V of guideline 67/548 / EEC, A.8 by not more than +/- 60% and / or differs in its HLB measured by the method of Marszall no more than +/- 80%. The pharmaceutical form as described in one or more of Claim 20 or 21, characterized in that an active substance having a solubility in water according to DAB 10 of at least 30 parts by volume of water for one part by weight of the active substance is present. 23. The dosage form as described in one or more of Claim 22, characterized in that the active substance is selected from the group of peptides, antibiotics, immunosuppressants, LHRH antagonists, immunomodulators. The pharmaceutical form as described in one or more of Claim 22, characterized in that the active substance is abarelix, angiotensin II, anidulafungin, antido, argipressin, azaline and azaline B, bombesin antagonist, bradykinin, buserelin, cetrorelix, cyclosporin A, desmopressin, detirelix, erythropoietin, enkephalins (Leu-, Met) ganirelix, gonadorelin, goserelin, growth hormone secretagogue, insulin, interferon (alpha, beta, gamma), interleukins (IL1, IL2), micafugin, nafahrelin, leuprolide , leuprorelin, octreotide, orntido, oxytocin, ramorelix, secretin, somatotropin, terlipressin, tetracostactide, teverelix, triptorelin, tiroliberin, thyrotropin, tumor necrosis factor (TNF alpha, beta) or vasopressin. 25. The pharmaceutical form as described in one or more of Claims 20 to 24, characterized in that the substance or substances forming the lipophilic matrix, and the polymer having a mucoadhesive effect have the same ionic property or, in the case of opposite ionic properties, the polymer has a mucoadhesive effect present in at least 50% of the neutralized form. 26. The pharmaceutical form as described in one or more of Claims 20 to 25, characterized in that the lipophilic matrix consists of 80 to 100% by weight of a substance having an HLB from 0 to 15 or a mixture of substances that they have an average HLB from 0 to 15, and can comprise from 0 to 20% by weight of usual pharmaceutical excipients, especially stabilizers, thickeners or adsorbents. 27. The pharmaceutical form as described in one or more of Claims 20 to 26, characterized in that the substance or substances forming the lipophilic matrix belong to the group of oils, fats, mono-, di- or triglycerides, fatty acids, fatty alcohols, especially Cs_ to C2o fatty acids and / or a Ce to C2o alcohol including its salts, ether, ester or amide derivatives. phospholipids, lecithins, emulsifiers, lipoids, lipid soluble vitamins or surfactants. 28. The pharmaceutical form as described in one or more of Claims 20 to 26, characterized in that the lipophilic matrix comprises one or more of the following lipid preparations: (Imor 308) glyceryl monocaprylates having a monoester content of >; 80%, (Imwitor 312) glyceryl monolaurates having a monoester content of > 90%, (Imwitor 491) glycerol monostearate (Cie + Ciß) having a monoester content of > 90%, (Imor 900 P) glycerol monostearate having a monoester content of 40-55% and a CIS with content of 40-60%, (Imwitor 900 K) glycerol monostearate, having a monoester content of 40-55% and a CIE with content of 60-80%, (Imwitor 742) of medium chain C8 and Cio glycerides that have a monoester content of 45-55%, (Imiteor 928) Partial fatty acid glycerides Cio - C? 8 of saturated vegetables with a main content of C12 and having a monoester content of 34-36% "of C8 and Cio glycerides, Na caprylate or Na capriate 29. The pharmaceutical form as described in one or more of Claims 20 to 29, characterized in that the content of the lipophilic matrix containing an active substance in the inner matrix layer a) is from 5 to 50% by weight 31. A process for producing a multi-particle pharmaceutical form as described in one or more of Claims 20 to 30, with the steps of: a) production of the lipophilic matrix containing active substance by suspending and / or dissolving the active substance with the substance (s) forming the lipophilic matrix and, where appropriate, also conventional pharmaceutical excipients, by vigorously mixing or melt the ingredients; b) production of pre-granules (granule cores) by spraying the mucoadhesive polymer mixed with the lipophilic matrix containing active substance in a core or through agglomeration processes with rotation, precipitation or dew without a core; c) production of granules through spray application of an anionic polymer or copolymer coating, which may optionally comprise mixtures of conventional pharmaceutical excipients, especially plasticizers and libration agents, of an organic dispersion or solution in the pre-granules of the step b); d) production of a multi-particle pharmaceutical form by filling or incorporating the granules of step c) in a manner known per se, where appropriate with the use of customary pharmaceutical excipients, in particular through tablet processing with Content of granules, mini-tablets, capsules, sachets or reconstitutable powders. 32. The process for producing a multi-particle dosage form as described in Claim 31, characterized by steps a) and b) are carried out in the following manner: a) production of the inner matrix layer through preparation an emulsion, dispersion or solution of the active substance with the substance (s) for the lipophilic matrix, and when appropriate, also conventional pharmaceutical excipients by vigorously mixing the ingredients in water and producing an oil-in-water preparation having an average particle size of not more than 60 μm; b) production of pre-granules through spray application of the oil-in-water preparation of step a) in the mucoadhesive polymer which may optionally comprise additional mixtures of usual pharmaceutical excipients, where the ingredients are in the form of a micronized powder , for example, by agglomeration by rotation, extrusion or granulation.