MXPA99005432A - Preparation in form of a matrix material-auxiliary agent compound containing optionally an active substance - Google Patents

Abstract

Se describe un preparado en forma de un compuesto que contiene material de matriz, con una fase de auxiliar con cuando menos un auxiliar y/o una fase de ingrediente activo con cuando menos un ingrediente activo y una fase de material de matriz con cuando menos un polímero y/o lípido. La invención se caracteriza porque la fase de material de matriz del preparado es incoherente y porque la fase de auxiliar y/o ingrediente activo del preparado es coherente. Asimismo, se describe un procedimiento para la obtención del preparado de conformidad con la invención.Éste es adecuado para la elaboración según procedimientos conocidos de unidades de matriz mayores con propiedades de liberación controladas y, en especial, para la elaboración de tabletas mediante tableteado directo.

Description

PREPARED IN THE FORM OF AU COMPOSITE AUXILIARY-MATRIX MATERIAL THAT OPTATIVELY CONTAINS AN ACTIVE INGREDIENT FIELD OF THE INVENTION The invention relates to a preparation in the form of a compound, which has an auxiliary phase with at least one auxiliary and / or one phase of active ingredient with at least one active ingredient and one phase of a forming material. of matrix (hereinafter also referred to as matrix material), selected from polymers and / or lipids, that is to say, a polymer phase and / or a lipid phase with at least one polymer, or lipid, and thus with medicaments retardants containing polymers and / or lipids, processes for their preparation and their use, in particular for the manufacture of tablets or other larger matrix units.

BACKGROUND OF THE INVENTION This type of compounds are physical compounds of at least two starting substances and are used especially in the pharmaceutical field. It is known to achieve a controlled, delayed or independent release of physiological parameters, of active ingredients of a preparation, to process the starting substances in such a way, that the resulting preparations, or, the drugs made from these preparations, present a coating that controls the release (for example, of polymers such as polymethacrylates or organic molecules such as shellac or cellulose acetate phthalate), or, alternatively, a matrix system consisting of polymers. The matrix units for the controlled release using polymers, described in the specialized literature, are: 1. Polymeric particles (for example, pellets, grains of granulates, microparticles) 2. Larger matrix units (eg, tablets, dragee cores) and implants). The particles described below in more detail are characterized in that the active ingredient is integrated in the polymer phase in a molecularly dispersed or particular manner. The larger matrix units described below in more detail, usually must be elaborated by the expensive compression process after previous granulation.

Medications for the controlled release using polymers: The controlling effect of the release of a preparation or medication like this, also known as "Controlled Relay" preparation (CR preparation), is controlled on the one hand by the properties of the polymer phase itself, as for example the wettability, the swelling or the crystallinity, and on the other, by the structure of the matrix formed by the polymer phase. This de-matrix structure, which may be configured homogeneously or heterogeneously, is either present in the preparation itself or is formed during processing in the preparation of the drug. As the properties of the polymer phase that influence the release, the solubility properties are mentioned here. Thus, the polymers, or the macromolecules, according to their solubility and / or swellable in aqueous solvents, are suitable for releasing the active ingredients which are integrated in a matrix of these polymers, through the pores of the matrix, or well, macromolecules. In addition, medicaments with polymeric substances are known, which, due to the solubility of the polymers in the "gastric or intestinal juices, constitute a preparation that controls the place of release." In these preparations that control the release of the active ingredient, In particular, two groups must be distinguished: On the one hand, the particles containing polymers are known, in a size range of approximately 0.01 to 2 millimeters, which are also referred to as microparticles (0.05 to 0.2 millimeters), grains of granules or pellets But also the microparticles, or micro-spherules, with a typical size of 50 to 200 micrometers, nanoparticles, nanopellets and nanospherules, known only recently, if they present a polymer phase, they can be classified in the group of particles that contain polymers. The particles are presented as independent release units in the form of a particular matrix, the preparation then presenting a matrix structure. On the other hand, the particles described in the present application can be joined to result in larger release units, or larger matrix units. This further processing is illustrated in detail below. As examples of particular matrices, whose particles form independent release units, the dispersion of microparticles can be cited to obtain parenteral injections, which allow a release Controlled analogues of LH-RH, as well as the filling of pellets in a gelatin capsule in commercial preparations, such as sympathomimetics. These are described by Müller, R.H., Hildebrand, G.E. (Editors) in "Pharmazeutische Technologie: Moderne Arzneiformen ", issenschaftliche Verlagsgesellschaft mbh Stuttgart, (1997), by Bauer, KH, Frómming, KH., Führer, C. in" Pharmazeutische Technologie ", Georg Thieme Verlag Stuttgart, New York, (1991), as well as by List, PH "Arzneiformenlehre", Wissenschaftliche Verlagsgesellschaft mbh Stuttgart, (1986) Further, European Patent 0 261 677 describes compositions containing polymers, which are supposed to allow a delayed release of the active ingredient. a spray drying process, so that using the disclosure of said document, particles with a size of at least 30 micrometers are obtained, which present the active ingredient with a homogeneous distribution. preparation of these preparations with particular matrix structure In the procedure according to the method of "solve nt evaporation "or" in-liquid-drying ", the polymer, or the matrix former is a substance soluble in an organic solvent (for example, polymers such as polylacids, polylactide / glycolide). The polymer is dissolved in an organic solvent, the active ingredient is also dissolved in the organic phase or dispersed, in the case of insoluble active ingredients. The solution of the polymer, or matrix former, containing the active ingredient is then placed in an aqueous surfactant solution and, by stirring, an oil / water emulsion is obtained. The organic solvent is removed and the matrix former precipitated. Pellets, or solid microparticles are obtained. According to the method to remove the solvent, there is a difference between the "solvent evaporation" method and the "in-liquid-drying" method. These procedures have been described by Speiser, P. in Müller, R.H. , Hildebrand, G.E. (Editors) "Pharmazeutische Technologie: Moderne Arzneiformen", Wissenschaftliche Verlagsgesellschaft mbh Stuttgart (1997), by Beck, L.R., Pope, V.Z., Cowsar, D.R., Lewis, D.H., Tice, T.R. in "Evolution of a new three-month injectable contraceptive microsphere systeme in primates (baboons)", Contracept. Deliv.1 Syst., 1, 79-80 (1980), by Beck, L.R., Flowers, CE., Pope, V.Z., Tice, T.R. Wilborn, W.H. in "Clinical evaluation of an improved injectable microcapsule contraceptive system" in Amer. J. Obstet. Gynecol. 147 (7), 815821 (1983) and by Beck, L.R., Pope, V.Z., Flowers, CE., Cowsar, D.R., Tice, T.R., Lewis, D.H., Dunn, R.L., Moore, A.B. , Gilley, R.M. in "Poly (d, I-lactide-coglycolide) / norethisterone microcapsules: An injectable biogradable contraceptive" in Biol. Reprod. 28, 186-195 (1983a). With these methods very fine particles can be obtained, in the range of a few micrometers. However, the great work with which the preparation methods are linked, as well as the loading of the particles with residual solvent, is disadvantageous. For this reason, there is no product in Germany that has been manufactured according to this method and meets the authorization criteria for a medicine. Alternatively, the solution of the polymer or of the matrix former which contains the active ingredient can be sprayed. Also, in this case, a residual content of organic solvents in the product can not be avoided due to the manufacturing process. The products manufactured according to this process, such as, for example, microparticles for the parenteral application of. bromocriptine, are described by Fahr, A., Kissel, T. in Müller, R.H., Hildebrand, G.E. (Editors), "Pharmazeutische Technologie: Moderne Arzneiformen", Wissenschaftliche Verlagsgesellschaft mbh Stuttgart, (1997). They are found in the pharmaceutical market. The problem of residual solvent content, however, it has only been eliminated because the release of the toxic solvent is also delayed and, therefore, occurs in smaller quantities. With the amount released per day from the matrix, it remains below the maximum daily tolerated value. All the processes mentioned so far are characterized in that the polymer phase, or the matrix former, is in a dissolved form as a molecule and is located in an organic solvent. Particular preparations are obtained, the polymer phase of which contains the active ingredient in a molecularly dispersed manner or in the form of fine particles. These preparations present a so-called heterogeneous matruz structure, as also described by Fahr, A., Kissel, T. in Müller, R.H., Hildebrand, G.E. (Editors), "Pharmazeutische Technologie: Moderne Arzneiformen", Wissenschaftliche Verlagsgesellschaft mbh Stuttgart, (1997). Another process for the preparation of a particular preparation with polymer phase, avoiding the use of organic solvents, is described in European Patent 0 361 677. The matrix former according to said water-soluble document, or, the polymer phase, is dissolved in water (for example, ethyl acrylate / methacrylate copolymer in ammonia solution), the active ingredient is also dissolved or dispersed and, unlike the "solvent evaporation" and "in-liquid drying" method, instead of a oil / water emulsion only a water / oil emulsion is obtained. Dispersing agents are organic solvents that do not mix with water, for example, liquid paraffin or methylene chloride. The matrix former can be dissolved in water or emulsified in the aqueous phase. In the second case, an emulsion is dispersed in an organic solvent that does not mix with water. By means of the expensive azeotropic distillation of water and organic solvent, polymer particles are precipitated, which include the active ingredient with a particular or molecular dispersion distribution. The particles are obtained by filtration separation and subsequent washing. In the US Patent US-A-5 043 280 a process for the preparation of a particular preparation by extraction in overcritical gases is described. In this, the matrix former, as in "solvent evaporation", is a substance soluble in organic solvents, such as, for example, a polymer. The polymer is dissolved in an organic solvent and the active ingredient is also dissolved or dispersed, in the case of insoluble active ingredients, in the organic phase. The solution of the matrix former containing the active ingredient is finely pulverized in an overcritical gas phase. Fine drops are distributed in the overcritical gas, which extracts the organic solvent from them. As a consequence, particles containing the active ingredient are precipitated. This method also leads to preparations which have the active ingredient integrated in the polymer phase in the form of a molecular dispersion, or in particular. By means of this inclusion of the active ingredient in the polymer phase due to the process, the external phase of the preparation mainly has a polymer, by means of which the relevant pharmaceutical properties are also established for eventual further processing. In addition, the aforementioned preparations have the disadvantage that they can only be produced at considerable cost and time. It is known the possibility of further processing of particular preparations containing polymers to obtain drugs having larger matrix units, such as, for example, tablets, dragee cores or implants. Thus, Müller, R.H., Hildebrand, G.E. (Editors), in "Pharmazeutische Technologie: Moderne Arzneiformen", Wissenschaftliche Verlagsgesellschaft mbh Stuttgart, (1997), describe the preparation of implants containing Lh-Rh analogs. The preparation of tablets is of particular relevance, because this form of medicine has many advantages, such as the possibility of processing almost all solid active ingredients, high dosage precision, easy ingestion and handling and good storage and transport capacity. The preparation of drug forms that constitute larger matrix units, and especially tablets, is normally carried out by compression. For this, for the processing of common preparations containing polymers, in the form of particular matrices, several procedural steps are required. First, the various ingredients are homogeneously mixed, for example, various active ingredients, auxiliaries and polymers. The mixture is then subjected to a wet granulation by adding binders, adhesives or solvents. The resulting granulate is dried to remove residual moisture. The compression to tablets, dragee cores or implants is then carried out with the dry granulate, adding additional auxiliaries, such as viscosity regulators, lubricants and mold release agents. It is disadvantageous that, during wet granulation, the active ingredient is exposed for a long time to the moisture of the binder, the adhesive or the solvent and, during the drying process, must necessarily be subjected to an elevated temperature. In addition, due to the various individual steps or the devices and apparatuses necessary for this, the procedure is linked to a relatively large time requirement, and thus, it is expensive. The direct tableting of preparations with polymeric components, which is frequently used for the manufacture of tablets without polymer phase, given the low costs and the rapid implementation, has not been possible until now due to the following difficulties. On the one hand, due to the mainly elastic deformation, the polymers present a poor compression behavior, since a compression is usually achieved mainly by plastic deformation. On the other hand, the tabletting mixture is prone to unwanted demixing between the sprayed and / or auxiliary active ingredients and the polymers, due to the different surface constitution and the different viscosity properties that result therefrom. For these reasons, direct tableting would result in strongly heterogeneous tablets due to the demixing of the tablet material. Another problem is the generally bad viscous behavior of the polymers. This has the consequence that a satisfactory retarding effect is not achieved by the limited mixing capacity of the polymers to the tableting mixture. In specialized literature, McGinity, J.W. , Cameron, C.G., Cuff, G.W. , in "Controlled-release teophylline tablet formulations containing acrylic resins, I. Dissolution properties of tablets", Drug Development and Industrial Pharmacy, (162), 57-68 (1983) and Cameron, C.G., McGinity, J.W. in "Controlled relay teophylline tablet formulations containing acrylic resins II Combination resin formulations" and "III Influence offiller excipient", a. to. O. 13 (8), 1409-1427 (1987), a. to. O. (13 (2), 303-318 (1987), describe in the case of acrylate polymers a maximum addition of usually 10-15% polymer in a tablet recipe for direct tableting. Delayed medicines are known in which lipids are used, In the case of these drugs for the controlled release using lipid, described in the specialized literature, it is essentially: 1. Suppositories 2. Vaginal globules 3. Pellets for the peroral application ( for example, Mucosalvan retard.) Compared to polymers, lipids offer the following advantages: 1. good compatibility in vivo, especially when they are made up of physiological fatty acids, 2. no toxicological waste from production (for example , catalyst residues), 3. control of the rate of decomposition through the chemical structure of lipids, 4. economic. Thus, they constitute auxiliaries that can be used in addition to polymers for the preparation of CR formulations.

Drug forms for the controlled release using lipids - compound preparations: The elaboration of suppositories and vaginal globules is carried out, usually, by emptying the mixture containing the active ingredient (P.H. List, Arzneiformenlehre, Wissenschaftliche Verlagsgesellschaft 1976). The elaboration of suppositories is also possible by compressing a mixture of lipid particles and powder of active ingredient, however, a large-scale manufacture presents difficulties due to the often poor viscous capacity of these mixtures when filling in the molds Of compression. For this reason, this method is first described for the prescription-scale manufacture of a pharmacy (1. Münzel, J. Büchi, O.-E. Schultz, Galenisches Praktikum, Wissenschaftliche Verlagsgesellschaft Stuttgart, page 652, 1959). In this, only lipids are used that melt, or at least, soften at body temperature. The medicinal forms for peroral application are pellets, which are manufactured on a large industrial scale by extruding melted lipids with an extruder and a perforated disc (Voigt, Lehrbuch der Pharmazeutischen Technologie, Verlag Chemie, 1975). Disadvantages are, for example, the integration of the active ingredients in the lipid (for example, by dispersion or solution), the thermo-loading of the active ingredients in the extrusion and the need for the further processing of the pellets in an additional production step ( for example, filled in hard gelatin capsules).

OBJECTIVES AND ADVANTAGES OF THE INVENTION The object of the present invention is to provide a preparation in the form of a compound containing matrix material, such as delayed medicated preparations, having an auxiliary and / or active ingredient phase and a material phase of matrix. The preparation must have a sufficiently large portion of matrix material, so as to allow a controlled release of the active ingredient contained or subsequently added in the case of processing to larger matrix units. In addition, the preparation must be able to process through direct tabletting to larger matrix units. In addition, a process for the preparation of these preparations, or compounds, must be provided. The objective according to the invention is achieved by a delayed drug form containing matrix material, which is in the form of an auxiliary compound-matrix material, an active ingredient compound-matrix material and / or a compound of auxiliary active-auxiliary-matrix material, the matrix material being selected from among polymers and lipids, such that the compound has a polymeric phase and / or a lipid phase and an auxiliary phase and / or an active ingredient phase. A compound like this can be transformed by direct compression into its final drug form. Thus, the invention relates to preparations containing polymers or lipids, which are in the form of a compound, which has a polymeric, or lipid, phase with at least one polymer, or, lipid, a auxiliary phase with at least one auxiliary and / or one phase of active ingredient with at least one active ingredient. In accordance with the invention, it was recognized that the attainment of the objective is possible by the preparation described in claim 1, which a) has an auxiliary phase with at least one auxiliary and / or one active ingredient phase with at least one active ingredient and a polymer phase with at least one polymer, the polymer phase being coherent and the auxiliary and / or active ingredient phase coherent, or b) has a lipid phase with at least one lipid, an auxiliary phase with at least one auxiliary and / or an active ingredient phase, the lipid phase being coherent and the auxiliary and / or active ingredient phase coherent.

In particular, the polymeric or lipid phase can contain auxiliaries and / or active ingredients or be free of them. In the preparation according to the invention, the portion of polymeric or lipid phase, referred to the total amount of auxiliary phase and / or active ingredient and polymeric phase, or lipid phase, can be of input 1 and 98%. In particular, the preparation can have a polymer / lipid phase portion of 10 to 95%. In addition, the polymer / lipid phase portion in the preparation can be more than 15% and maximum 90%. However, it is particularly advantageous for the embodiment of the present invention, that the polymer / lipid phase is a portion of 40 to 70% based on the total amount of auxiliary phase and / or active ingredient and polymer / lipid phase. The preparation according to the invention can in principle have any type of active ingredient or be exempt therefrom. In addition, the active ingredient can be subsequently added to the preparation, for example, before further processing to larger matrix units. In general, the preparation may contain the following active ingredient groups: hydroxylated hydrocarbons, carbonyl compounds, such as ketones (for example, haloperidol), monosaccharides, disaccharides and amino sugars, carboxylic acids, such as aliphatic carboxylic acids, carboxylic acid esters aliphatics and aromatics, esters basically substituted for aliphatic and aromatic carboxylic acids (eg, atropine, scopolamine), lactones (e.g., erythromycin), amides and imides of aliphatic carboxylic acids, amino acids, aliphatic aminocarboxylic acids, peptides (e.g., cyclosporine) ), polypeptides, jß-lactam derivatives, penicillins, cephalosporins, aromatic carboxylic acids (for example, acetylsalicylic acid), aromatic carboxylic acid amides, vinylogous carboxylic acids and vinyl carboxylic acid esters, - carbonic acid derivatives, such as urethanes and thiourethanes, urea and urea derivatives, guanidine derivatives, hydantoin, acid derivatives barbiturates and thiobarbituric acid derivatives, - nitro compounds, such as aromatic nitro compounds and nitro heteroaromatic compounds, - amines, such as aliphatic amines, aminoglycosides, phenylalkylamines, eferdirine derivatives, hydroxyphenylethanolamines, adrenaline derivatives, amphetamine derivatives, amines aromatics and derivatives, quaternary ammonium compounds, sulfur-containing compounds, such as thiols and disulfanes, sulfones, sulphonic acid esters and sulfonic acid amides, polycarboxyclics, such as tetracycline, steroids with aromatic ring A, steroids with carbonyl function alpha, beta-unsaturated in ring A and alpha group. cetol (or methyl-methyl group) at C-17, steroids with a butenolide ring at C-17, steroids with a pentadienolide ring at C-17 and dry-steroids, - heterocycles containing O, as chroman derivatives (eg, acid) chromoglycine), - N-containing heterocycles, such as pyrazole derivatives (e.g., propifenazone, phenylbutazone), - imidazole derivatives (e.g., histamine, picocarpine), pyridine derivatives (e.g., pyridoxine, nicotinic acid), pyrimidine (e.g., trimethoprim), indole derivatives (e.g., indomethacin), lysergic acid derivatives (e.g., ergotamine), yohimban derivatives, pyrrolidine derivatives, purine derivatives (e.g., allopurinol), xanthine derivatives , 8-hydroxyquinoline derivatives, amino-hydroxy-alkylated quinolines, aminoquinolines, isoquinoline derivatives (eg, morphine, codeine), quinazole derivatives, benzopyridazine derivatives, pteridine derivatives (e.g. example, methotrexate), 1,4-benzodiazepine derivatives, tricyclic heterocycles containing N, acridine derivatives (e.g., ethacridine), and dibenzazein derivatives (e.g., trimipramine), - heterocycles containing S, as thioxanthene derivatives (for example, chlorprothixene), heterocycles containing N, 0 and N, S, as monocyclic heterocycles containing N, 0, monocyclic heterocycles containing N, S, thiadiazine derivatives, bicyclic heterocycles containing NS, benzothiadiazine derivatives, tricyclic heterocycles containing N, S and phenothiazine derivatives, - heterocycles containing 0, P, N (for example, cyclophosphamide). The following medicinal substances (such as salts, esters, ethers or in free form) are suitable, for example, for incorporation: Analgesics / anneurotic BTM bases, such as morphine, codeine, piritamide, fentanyl and fentanyl derivatives, levomethadone, tramadol, diclofenac, ibuprofen, indometacin, naproxen, piroxicam, penicillamine, antiallergics, feniramine, dimetidene, terfenadine, astemizole, loratidine, doxylamine, meclozine, bamipine, clemastine, ^ antibiotics / chemotherapy agents. Of them: polypeptide antibiotics, such as colistin, polymyxin B, tepicplanin, vancomycin; antimalarial agents, such as quinine, halofantrine, mefloquine, 5-chloroquine; static for viruses, such as ganciclovir, foscarnet, zidovudine, acyclovir and others, such as dapsone, fosfomycin, fusafungin, t imethoprim, ^ Antiepileptics Phenytoin, mesuximide, ethosuximide, primidon, 10 phenobarbital, valproic acid, carbamazipine, clonazepam, Antimycotics a) internal: nystatin, natamycin, amphotericin B, flucytosine, ^ miconazole, fluconazole, itraconazole, 15 b) external, in addition: clotrimazole, econazole, thioconazole, fenticonazole, bifonazole, oxiconazole, ketoconazole, iscoconazole, tolnaftate, Corticosteroids (internal) Aldosteron, fludrocor isone, betamethasone, 20 dexamethasone, triamcinolone, fluocortolone, hydroxycortisone, prednisolone, prednilidene, cloprednol, methylpredinsolone, Dermatics a) Antibiotics: Tetracycline, erythromycin, neomycin, gentamicin, clindamycin, framcetin, thyrothricin, chlortetracycline, miniprocin, fusidinic acid, b) Static viruses as mentioned above, in addition: Podofilotoxin, vidarabine, tromantadine, c) Cor as mentioned above, in addition: Amcinonide, fluprednidene, alclometasone, clobetasol, diflorasone, halcinonide, fluocinolone, chlorcortolone, flumetasone, diflucortolone, fludroxicortid, halometasone, deoximetasone, fluocinolid, fluocortinbutyl, fluprednidene, prednicarbate, desonid, Diagnostic agents a) Radioactive isotopes , such as Te99m, Inll or 1131, covalently bound to lipids or lipoids or other molecules or in complexes, b) highly substituted iodine-containing compounds, such as lipids, Hemetoflexes / antihemorrhages Blood coagulation factors VIII, IX Hypnotics , sedatives Cyclobarbital, pentobarbital, phenobarbital, metaqualone (BTM), benzodiazepine (flurazepam, midazolam, nitrazepam, lormetazepam, flunitrazepam, triazolam, brotizolam, temazepam, loprazolam), Hyposphysical hormones, hypothalamus, regulatory peptides and their inhibitors Coricotrophin, tetracosactid, coriongonadotropin , urofollitropin, urogonadot ropina, somatropin, metergoline, bromocriptine, terlipressin, desmopressin, oxytocin, argipressin, ornipressin, leuprorelin, triptorelin, gonadorelin, buserelin, nafarelin, goselerin, somatostatin, immunotherapeutic agents and cytokines Dimepranol-4-acetamidobenzoate, thymus, a-interferon, characterized in that β-interferon, β-interferon, filgrastim, interleukins, azathioprine, cyclosporine, Internal local anesthetics: Butanilicain, mepicacaine, bupivacaine, etidocaine, lidocaine, articaine, prilocaine, external additions: Propipocaine, oxybuprocaine, tetracaine, benzocaine, Proxibarbal anti-migraine agents, lisurid, metisergid, dihydroergotamine, clonidine, ergotamine, pizotifen, Metohexital narcotic agents, propofol, etomidate, ketamine, alfentanil, thiopental, droperidol, fentanyl, lateral thyroid gland hormone, calcium metabolism regulators Dihydrotaquisterol, calcitonin, clodronic acid, etidronic acid , Ophthalmic agents Atropine, cyclodrine, cyclopentolate, homatropine, tropicamide, scopolamine, foledrine, edoxudin, idouridin, tromantadine, acyclovir, acetazolamide, diclofenamide, carteolol, timolol, metipranolol, betaxolol, pindolol, befunolol, bupranolol, levobununol, carbachol, pilocarpine, clonidine, neostimgina, Psychotropic drugs Benzodiazepines (lorazepam, diazepam), clomethiazole Therapeutic agents for the thyroid gland 1-thyroxine, carbimazole, thiamazole, propylthiouracil Serums, immunoglobulin, vaccines a) Immunoglobulins in general and specific, such as hepatitis, rubella, cytomegaly, rabies, FSME, varicella, tetanus, Rhesus factors, b) Immunosueros, such as botulism antitoxin, diphtheria, "gas burns, poison of viper, scorpion venom, c) Vaccines, such as influenza, tuberculosis, cholera, diphtheria, types of hepatitis, FSME, rubella, Haemophilus influenzae, measles, neisseria, mumps, poliomyelitis, tetanus, rabies, typhoid, sex hormones and their inhibitors Anabolics, androgens, aniandrogens, gestagens, estrogens, anostrogens (tamoxifen, etc.) Cytostatic and inhibitors of metastases a) Alkylans, such as nimustine, melphalan, carmustine, lomustine, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, busulfan, treosulfan, prednimustine, thiotepa , b) Antimetabolites, such as cytarabine, fluorouracil, methotrexat, mercaptopurine, thioguanine, c) Alkaloids, such as vinblastine, vincristine, vindesine, d) Antibiotics, such as aclarubicin, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, plicamycin, e) Complexes of the elements of secondary groups (for example, Ti, Zr, V, Nb, Ta, Mo, W, Ru, Pt), such as carboplatin, cisplatin and metallocene compounds, such as titanocene dichloride, f) Amsacrine, dacarbazine, estramustine, etoposid, hydroxycarbamide, mitoxantron , procarbazine, temiposid, g) Alkylamidophospholipids (described in JM Zeidelr, F. Emling, W. Zimmermann und HJ Roth, Archiv der Pharmazie, 324 (1991), 687), h) Eterlipids, such as hexadecylphosphocholine, ilmofosin and the like, described in R. Zeisig, D. Arndt und H. Brachwitz, Pharmazie 45 (1990), 809-818. Special mention should be made of cyclosporins, such as cyclosporin A, and cyclosporin derivatives, as well as paclitaxel. As the polymer, the preparation according to the invention can have common polymers, such as, for example, polyacrylates or polymethacrylates (eudragit E, L, F), celluloses and cellulose derivatives (methylhydroxypropylcellulose, ethylcellulose, hydroxypropylcellulose acetate succinate (Aquoat®)) or natural polymers (shellac, waxes, beeswax, glitter waxes). By choosing the polymer, the release property of the preparation or of the larger matrix units made with it can be controlled. Thus, using methylhydroxypropylcellulose only a slightly delayed release of the active ingredient can be achieved compared to non-retarded tablets. The use of eudragit E as a polymer leads to a delayed release of the active ingredient already in the stomach. If the preparation presents eudragit L or F as a polymer, a controlled release of the active ingredient is only possible in the intestinal area. The preparation according to the invention can contain as lipid the conventional lipids, for example, natural, semi-synthetic and synthetic triglycerides or their mixtures, mono and diglycerides alone or in a mixture with each other or with, for example, triglycerides, natural and synthetic waxes. , fatty alcohols including their esters and ethers, as well as lipid peptides. Synthetic mono, di and triglycerides are particularly suitable as isolated or mixed substances (for example, rigid fat), esters of glycerintrigraphic acid (for example, trilaurate, myristate, palmitate, stearate and glycerin behenate) and waxes, for example , cetylpalmitate and Cera alba (bleached wax, DAB9), beeswax (for example, Apifil, Apifac). Other lipids in part with additional emulsifying properties (SE = self emulsifying) are glycerin behenate (e.g., compritol 888 ATO), glycerin tribehenate (compritol 888), palmitoate stearates, such as, for example, glycerin-palmitate stearate (eg example, Biogapress Vegetable ATO BM 297, Precirol Ato 5, Geleol), diethylene glycol palmito stearate, propylene glycol, ethylene glycol, polyglycol and propylene glycol, stearates such as glycerin stearate (eg, Precirol WL 2155 Ato) and polyglycol stearate, isostearate, polyalcohol fatty acid esters (eg, Compritol WL 3284), behenate of PEG (e.g., Compritol HD5 ATO), cetylpalmitate (e.g., Precifac Ato), sucrose esters, such as monodistearate and sucrose monopalmitate (e.g., Serum-Ester WE15), sucrose distearate (e.g. Ester WE 7), polyglycerin esters, such as polyglycerol isostearate (Lafil WL 3254) and ploglycerin palmito-stearate, polyglycolized glycerides (for example, Gelucire, Labrafil, Suppocire), self-emulsifying polyglyclic stearate (for example, Superpolystate), polyglycol palmito-stearate (for example, Tefose Series), glycerides of fatty acids with 12 to 18 carbon atoms (for example, Lipocire), as well as their mixtures of two or more lipids. By choosing the lipid, the release property of the preparation or of the larger matrix units made with it can be controlled. Thus, using lipids of good decomposition in the intestine, the release can be accelerated, because in addition to the release by diffusion, the release also occurs by erosion of the same. With slower decomposing lipids or lipids that can not be broken down in the stomach-intestine tract, the release occurs delayed. As a relatively rapid decomposition lipid by pancreatic lipase / colipase, Dynasan 114 is described, the decomposition of Dynasan 118 is slower (C Olbrich, RH Müller, Proceed.Institute Symp.Controlled Reí. Bioact. Mater., Stockholm, 921 -922, 1997). As auxiliaries, the following groups of substances can be used in particular: Fillers in the area of sugars, for example, disaccharides (lactose, saccharose), monosaccharides (glucose, fructose) or polysaccharides (starches, corn or potato starch, cellulose, natural cellulose powder, microcrystalline cellulose), saccharine alcohols, such as, for example, sorbitol or mannitol, or calcium phosphates. Binders such as polyvinylpyrrolidone (PVP, collidon CL), gelatin, starch paste, celluloses, cellulose ethers or sugar. According to the invention, it was observed that a preparation is obtained in the form of a compound containing polymers / lipids, which has an auxiliary phase with at least one auxiliary and / or one phase of active ingredient with at least one active ingredient and a polymeric / lipid phase with at least one polymer / lipid, the polymer / lipid phase of the preparation being incoherent and the phase of auxiliary and / or active ingredient, coherent, when the various phases of the preparation are suspended together in a liquid or suspended and they dissolve, the polymer / lipid phase not being soluble in the liquid, and then this suspension is dried by spray drying. In this way, a preparation is obtained in particular whose polymer / lipid phase is free of auxiliary phase and / or active ingredient. It is also possible to dry the suspension in a fluidized bed or turbulent bed dryer. For this, the phases of the preparation are also suspended together in a liquid or suspended and dissolved, the polymer / lipid phase not being soluble in the liquid, and this suspension is then dried in a fluidized or turbulent bed dryer. For carrying out the process according to the invention, the corresponding quantities of polymer / lipid and auxiliary and / or active ingredient are suspended, or suspended and dissolved, in a liquid with the help of a high-speed stirrer or a disperser, wherein the polymer / lipid, unlike the known processes with polymer processing, is not soluble in the liquid, but is found as solid particles. Depending on the polymer / lipid to be suspended, it must be observed that no excessive shear forces or temperatures appear in the dispersion, which lead to an aggregate, or a confluence of the polymer / lipid particles. The liquid used is in particular demineralized water or an aqueous or organic dispersion or suspension agent. The respectively desired viscosity of the suspension to be sprayed in the spray dryer, the fluidized or turbulent bed dryer, is controlled through the percentage portion of solid. There are additional possibilities of regulation in the case of water-soluble auxiliaries, through their concentrations and chemical nature (for example, lactose, auxiliaries with marked viscosity increase effect). Another advantageous configuration is the addition to the suspension of crosslinking agents and / or binders and / or plasticizers (for example, triethyl citrate, propylene glycol and others). Suitable binders are, in particular, polyvinylpyrrolidone, gelatin, starch pastes, cellulose, cellulose ethers or sugar. Increase the mechanical resistance of the preparation. The plasticizer allows an action capable of validating on the plasticity, deformability and laminating capacity of the polymer / lipid and thus allows the control of the release of the active ingredient in addition to the delay effect itself of the polymer / lipid. As plasticizers, triethylcitrate and propylene glycol can be used in particular. However, other internal and external plasticizers, which are known as common additives for polymers / lipids, are suitable for controlling the release of the active ingredient. Then, at spray pressures normally of more than 20 bar, with the help of nozzles of one and several suitable substances, in the spray tower, with suitable exhaust air temperatures, depending on the sensitivity of the active ingredient and auxiliaries , as well as the apparatus conditions of the spray tower and its periphery, the suspension is dried by spray or in the fluidized or turbulent bed dryer. The preparation obtained, if necessary, can be subsequently subjected to further drying. For this, further drying and / or further agglomeration of the preparation in fluidized or turbulent bed dryers is possible. Due to the drying process in the spray dryer, fluidized or turbulent bed, the preparation obtained has an approximately spherical shape. In accordance with the invention it was recognized that the described preparation, which has an incoherent polymeric / lipid phase and an auxiliary phase and / or coherent active ingredient, is suitable for use in the preparation of larger matrix units with controlled release properties. . For this, all known methods can be used, so that larger matrix units of any shape are obtained, such as, for example, tablets, pellets or cylindrical rods. In the same way, with the preparation according to the invention, the known processes for the production of extrusion or spherification pellets or for the filling of the preparation in capsules can be carried out.

It was also recognized that the preparation according to the invention is suitable in particular for the preparation of larger matrix units and / or tablets with controlled release properties, by means of direct tableting. The above is possible despite the high polymer / lipid portion, since thanks to the process according to the invention, among other things, a very good viscosity property and an improved compression performance of the preparation are achieved. It is particularly advantageous to prepare tablets by direct tableting, from a preparation free of active ingredient, which is mixed with at least one active ingredient and, if necessary, with other auxiliaries, as well as from a preparation that it contains an active ingredient, which can optionally be further mixed with at least one active ingredient and, if required, with other auxiliaries. In addition to the usual tablets, they can be obtained by direct tableting or direct compression, in particular also dragee cores, cores of coated or coated tablets or cylindrical canes. Likewise, the preparation according to the invention can be used for the preparation of larger matrix units, which have various active ingredients or the same active ingredient in different dosages (for example, layered tablets), each active ingredient or each dose a moment of self-release, independent of the other active ingredients or the other doses. For this, a preparation according to the invention, which contains active ingredient, and which can also additionally have at least one auxiliary, is mixed with at least one or the same active ingredient, if required, by adding auxiliaries, such as, for example, fillers, release agents or binders. Subsequently, the mixture is processed to larger matrix units by direct tableting or according to other known methods. The foregoing is advantageous especially in the case of incompatible active ingredients, since this process leads to a physical separation of the active ingredients in the medicated form. With the use of the preparation according to the invention in a process for the production of larger matrix units, modifications of the release profile are possible, since the active ingredient (s) in the larger matrix unit are incorporated differently as a function of the amount of polymer / lipid, and thus, they are released with different speed. The use according to the invention of the preparation for direct tableting has, in particular, the advantage that the active and / or auxiliary ingredients, by the drying process used, are exposed only for a short time to humidity, compared to the usual wet granulation, which was necessary so far as a preliminary stage of the compression of preparations containing polymer. In the aforementioned drying process, the temperature load can be controlled and even eliminated if it is dried in the air jet at room temperature. For the production of larger matrix units according to known methods, for example, the production of pellets is indicated. For this, the preparation according to the invention, by adding suitable auxiliaries, is extruded with a conventional extruder for the production of pellets, and through a subsequent spheronization, it is transformed into small spheres the size of pellets. Alternatively, the processing can be carried out using a perforated roller compactor with a connected pellet container. The possible devices are Spheronizer® and Marumizer®. Likewise, these pellets can be made from the preparation described using a disc to make pellets. These pellets, like the preparation itself, can be filled, for example, in capsules, or compressed into larger units.

BRIEF DESCRIPTION OF THE DRAWINGS Next, the invention is illustrated in more detail with the help of exemplary embodiments and figures. All percentage data refer to weight.

DETAILED DESCRIPTION OF THE INVENTION Examples 1. Preparation of a lactose-ethylcellulose preparation (50:50): Both components are dispersed in demineralised water with the aid of a stirrer. The dispersion, with a solids content of up to 50 percent and a spray pump pressure of 30-50 bar, is sprayed in a laboratory spray tower, at exhaust air temperatures of between 70 and 100 degrees centigrade. The result is a spray agglomerate with good viscosity, which consists of lactose and ethylcellulose with a grain size distribution of between 1 and 630 micrometers, with the main portion being 50-80% between 63 and 400 micrometers. The preparation obtained in this way, in particular due to its property that the polymer phase is incoherent and the phase of auxiliary and / or active ingredient is coherent, as well as its approximately spherical shape and its surface constitution (cavities, lactose), It is characterized as having very good mixing and loading capacity with the active ingredient. In the case of lipophilic active ingredients, the duration of release of the active ingredients with a direct mixture of the preparation can be prolonged up to a factor of three with respect to non-retarded tablets. The duration of release can be varied, in turn, by modifying the polymer portion in the rattle mass, for example, by mixing a filling of the starch and lactose types. 2. Obtaining a preparation of lactose-ethylcellulose that presents acetylsalicylic acid (ASS): The preparation is carried out as described in 1., the mixture of the components lactose: ethylcellulose: ASS is carried out with a weight ratio of 45: 45:10. 3. Preparation of a tablet from a preparation sue presents acetylsalicylic acid (ASS): The preparation of lactose-ethylcellulose free of active ingredient, obtained in 1., is mixed with ASS in a ratio of 90:10, to the mixture is added 0.5% aerosil and 1% magnesium stearate and tablets directly. 4. Preparation of a tablet from a preparation that presents acetylsalicylic acid (ASS): To the lactose-ethylcellulose preparation loaded with ASS, obtained in 2., 0.5% of aerosil and 1% of magnesium stearate are added and tableted directly.

. Obtaining a preparation of paracetamol-lactose-etllcelulosa (20:40:40): All the components are dispersed in demineralized water and adjusted to a desired viscosity according to the pumping and pressure. The pulverization is carried out according to the procedure described above. The preparation obtained in this way, due to its spray properties, is suitable for use in direct tapping, the release of the active ingredient in the desired range being delayed by the variable variable portions of polymer, mixing other auxiliaries, hardness of variable tablet. 6. Preparation of a compritol-trehalose compound: Compritol 888 ATO was melted, poured into hot water after adding 1.2% Poloxamer 188 and dispersed by a high-revolutions Ultra-Turrax. After cooling, trehalose was dissolved in the aqueous dispersion of lipid particles, so that 10% lipid and 3% trehalose were obtained in the final concentration. This mixture was spray-dried in a Mini-Büchi (inlet temperature: 110 ° C, outlet temperature: 50 ° C, spray flow: 600 standard liters). A granulated lipid-auxiliary compound was obtained. 7. Preparation of a tablet from the compound with 1% paracetamol: 9 parts of the lipid-trehalose compound described in Example 1 were compressed directly in a Korsch eccentric press, adding 0.1 part of paracetamol and mixing 0.5% of aerosil 200 and 0.5% of magnesium stearate. Theoretical weight of the tablets 505 milligrams. 8. Preparation of a tablet from the compound with 10% paracetamol: 13 parts of the lipid-trehalose compound described in Example 6 were mixed with 3 parts of trehalose; To this mixture was added 10% paracetamol and compressed directly in a Korsch eccentric press, adding 0.5% aerosil 200 and 0.5% magnesium stearate. Theoretical weight of the tablets 505 milligrams. 9. Release of a tablet of the compound with 10% paracetamol: The release of paracetamol from the tablet made in Example 8 was determined with the Paddle method according to the United States Pharmacopeia, release medium: water, temperature 37 ° C The curves of release obtained are shown in Figures 5 and 6.

Brief illustration of the figures Figure 1: Figure 1 shows the preparation of a preparation according to the invention through a compound, according to the process according to the invention: the matrix former (for example, polymer particles) / lipid) is dispersed in water, the auxiliary and / or the active ingredient also dissolves, or disperses in the water phase and the suspension is pulverized, the water being removed by drying. A preparation is obtained which is composed of small polymer / lipid particles, the intermediate spaces being filled with the auxiliary (left) or with the auxiliary and the active ingredient (right). The preparation has an incoherent polymeric / lipid phase and a phase of auxiliary and / or coherent active ingredient.

Figure 2: Figure 2 shows an example of the use of the preparation according to the invention to produce larger matrix units. The preparation free of active ingredient (for example, polymer and lactose, or of spray-dried lipid and lactose with Flowlac 100, Co. Meggle, Germany) is mixed with the active ingredient (pulverized), optionally, if required , rattleting aids are added and the mixture is tapped directly.

Figure 3a: Oil / water emulsion process known from the prior art: in this case a drop of an organic solvent is dispersed with the matrix former (for example, polymer) dissolved therein, in a water phase (oil emulsion / water), the active ingredient being dissolved in the organic phase (left) or, in the case of an insoluble active ingredient, dispersed (right). For more explanations, see the text.

Figure 3b: Water / oil emulsion process known from the prior art: in this case a drop of water is dispersed with the matrix former (for example, water-soluble polymer) dissolved therein, in an organic phase (water emulsion) / oil), the active ingredient being dissolved in the aqueous phase (left) or, in the case of an insoluble active ingredient, dispersed (right). For more explanations, see the text.

Figure: Figure 4 shows the method according to the invention for obtaining the preparation according to the invention. The polymer / lipid phase is not dissolved, but dispersed, or suspended in drops of water, which are distributed by spraying in a gas phase. An auxiliary (for example, lactose, left) or an auxiliary and an active ingredient (right) are also dissolved or dispersed, or suspended in the drop of water. After removing the water, an auxiliary polymer / lipid preparation free of active ingredient (left) or an active ingredient-auxiliary-polymer / lipid preparation (right, the polymer / lipid phase in both cases being incoherent) is obtained.

Figures 5 and 6: Release of paracetamol from a tablet when using the preparation according to the invention (Example 4). Quantity released as a function of time (Figure 5) and as a function of the root of time (Figure 6).

Claims (18)

NOVELTY OF THE INVENTION Having described the above invention, it is considered as a novelty, and therefore, the content of the following is claimed as property: CLAIMS

1. A preparation in the form of a compound containing matrix material, with an auxiliary phase with at least one auxiliary and / or active ingredient phase with at least one active ingredient, characterized in that the matrix material is selected from among polymers, wherein, in the case of cellulose materials, these are cellulose derivatives, and lipids, the polymer phase and / or the lipid phase of the preparation are incoherent and the phase of auxiliary and / or active ingredient of the preparation are coherent.

2. A preparation in the form of a compound containing matrix material, with an auxiliary phase with at least one auxiliary and / or active ingredient phase with at least one active ingredient, characterized in that the matrix material is selected from among polymers, wherein, in the case of cellulose, the portion of the matrix material phase of the preparation is from 70 to 98%, and lipids, the polymer phase and / or the lipid phase of the preparation are incoherent and the auxiliary phase and / or the active ingredient of the preparation are coherent.

3. A preparation according to claim 1 or 2, characterized in that the matrix material phase of the preparation contains auxiliaries and / or active ingredients or is free of them.

4. A preparation according to claim 1 in any of claims 1 to 3, characterized in that the portion of the matrix material phase of the preparation is from 1 to 98%.

5. A preparation according to claim 1 in any of claims 1 to 4, characterized in that the portion of the matrix material phase of the preparation is from 10 to 95%.

6. A preparation according to claim 1 in any of claims 1 to 5, characterized in that the portion of the matrix material phase of the preparation is more than 15% and maximum 90%.

7. A preparation according to claim 1 in any of claims 1 to 6, characterized in that the portion of the matrix material phase of the preparation is from 40 to 70%.

8. A preparation according to claim 1, characterized in that the polymer phase contains a polyacrylate and / or a polymethacrylate and / or the lipid phase contains natural, semi-synthetic and synthetic triglycerides, or mixtures thereof, mono and diglycerides alone or in admixture with each other or with triglycerides, natural and synthetic waxes, fatty alcohols including their esters and ethers, as well as lipid peptides, in particular mono, di and synthetic triglycerides as isolated or mixed substances, especially rigid fat , ester of glycerintrigraphic acid, especially trilaurate, thromistratoi, tripamitate, tristearate and tribehenate of glycerin, and waxes, especially cetylpalmitate and Cera alba) bleached wax, DAB9), beeswax.

9. A preparation according to claim 1 in any of claims 1 to 8, characterized in that the polymer phase contains a polyacrylate and / or a polymethacrylate, a cellulose derivative or a natural polymer and / or the lipid phase contains natural lipid.

10. A preparation according to claim 1 in any of claims 1 to 9, characterized in that it contains at least one active ingredient.

11. A preparation according to claim 1, characterized in that the auxiliary phase has at least one filler, especially selected from monosaccharides, disaccharides, polysaccharides, saccharine alcohols and calcium phosphate, and / or at least one binder, especially selected from polyvinylpyrrolidone, gelatin, starch pastes, celluloses, cellulose ethers and sugars.

12. A preparation according to claim as claimed in any of the preceding claims, characterized in that it is in the form of a compressed piece that can be manufactured by direct compression.

13. A process for obtaining a preparation in the form of a compound containing matrix material, according to claim 1, characterized in that the phases of the preparation are suspended, or suspended and dissolved, together in a liquid, the phase of matrix material in the liquid being not soluble, and then this suspension is spray dried.

14. A process for obtaining a preparation in the form of a compound containing matrix material, in accordance with claim 1, characterized in that the phases of the preparation are suspended, or suspended and dissolved, together in a liquid, the phase of matrix material in the liquid being not soluble, and then this suspension is dried in a fluidized or turbulent bed dryer.

15. A method according to claim 13 or 14, characterized in that the liquid is an aqueous or organic suspension agent.

16. A method according to claim 13, characterized in that at least one binder and / or at least one crosslinker and / or at least one plasticizer is added to the suspension.

17. The use of the preparation in the form of a compound containing matrix material, according to claim 1 of claim 1, for the production according to known methods of larger matrix units with controlled release properties.

18. The use of the preparation in the form of a compound containing matrix material, in accordance with that claimed in any of claims 1 to 12, for the manufacture by direct tableting of tablets and / or larger matrix units with properties of controlled release.