EP2897645A1 - Magnesium hydroxide carbonate as carrier material in active ingredient-containing preparations - Google Patents

Abstract

The present invention relates to solid formulations which contain at least one porous carrier and one or more functional substances in a stable mixture, and to the use thereof.

Description

 Magnesium hydroxide carbonate as a carrier material in active substance-containing preparations

The present invention relates to solid formulations containing at least one porous carrier and one or more functional substances, and to their use.

State of the art

Active ingredients (APIs) for use in pharmaceutical

Dosage forms must on the one hand have useful processing properties for the pharmaceutical practice, so that the active ingredient is at all suitable for the further processing of pharmaceuticals to the final dosage form. On the other hand, by judicious choice of an inert excipient, it is also possible to prepare problematic active components to be processed into patient-appropriate formulations, such as e.g. Transfer powder, granules, capsules or tablets. Depending on the problem and the active substance, the carriers used for such purposes must have special physical or chemical properties in order to compensate for the processing deficiencies of the API.

A special challenge is the galenic in cases

opposite, in which the application advantageously takes place in powder form, but the active ingredient is particularly fine-grained and / or must be used in low doses. In such cases, it is desirable to co-formulate the active ingredient with a suitable carrier.

Due to their biological properties, it is desirable to dilute in particular highly effective poorly soluble active ingredients with a powdered carrier so that the active ingredient can be made available at a constant dosage.

 In a first approach, it would be convenient to use the active ingredient simply with a commonly used for the production of tablets

To mix carrier material to submit a metered amount of powder can. However, a problem in this context is that the carrier material and the powdery active substance must not segregate for a permanently uniform dosage. This is special during storage and handling of the powder formulation, if the active ingredient is present in substantially smaller particles than that

Support material. In such mixtures, the active ingredient in the form of smaller particles tends to trickle down while the larger carrier particles apparently migrate upwards and remain there. In order to avoid this segregation effect, in the recent past attempts have been made to obtain appropriate formulations by granulation in the presence of suitable solvents

manufacture. However, this is associated with additional process steps and an increased energy expenditure. In addition, this method is also not suitable for those active ingredients which have instabilities due to necessary for their preparation and processing solution steps and drying processes. In itself, a wide variety of carrier and filling materials are known for the preparation of solid, active ingredient-containing formulations.

Frequently, microcrystalline cellulose is used, which is prepared from pulp or crude cellulose by heating with mineral acids and then brought into a finely particulate form by mechanical comminution of the cellulose aggregates. This cellulose shows plastic flow during compression and is one of the viscoelastic

 Substances. Microcrystalline cellulose is used as a filler and dry binder in direct tableting.

Another plastic carrier and filling material is starch, preferably water-soluble, directly tablettable starch which has both plastic and elastic (viscoelastic) deformation behavior.

 Corresponding starch products are found in direct tableting

 Application as filling and disintegrating agent.

Especially common are different forms of lactose

 Carriers for mixtures, granules, hard gelatin capsules and tablets used. Lactose can be used both as a monohydrate and in an anhydrous form. In addition, it lies, depending on

Manufacturing process, in various modifications, partly with amorphous Shares, before. For example, spray-dried lactose containing a high amorphous content can be prepared as directly tablettable

Tablettierhilfsmittel be used. Lactose variants are offered by the various suppliers in a variety of particle sizes and grain morphologies for a variety of applications.

In addition, in the recent past, sugar alcohols such as mannitol, sorbitol and xylitol have become increasingly important as tableting aids with the function of carriers and fillers. When

spray-dried, optionally granulated products they are directly tabletted.

However, not for any formulation, it is desirable to use organic carriers and fillers due to undesirable drug interactions or incompatibility with the user.

As an alternative, it has therefore been attempted to use inorganic salts for tableting, preferably those which are well tolerated and themselves show no side effects when used in the usual amounts.

So is distributed as tableting aids under the brand name Di-Cafos ^® Calciumhydrogenphosphat- dihydrate. It is made by reacting calcium hydroxide with phosphoric acid at temperatures below 40 ° C. This produces the monoclinic dihydrate, which occurs in nature as a brushite (Gmelin's Handbook of Inorganic

Chemie, 1961, 8th Ed. Calcium, Part B, 27, ed. Deutsche Chemische Gesellschaft, Verl. Chemie GmbH, Berlin, 321-329). It shows a brittle deformation behavior which is largely independent of the pressing speed (Rees, JE and P., J. Rue, "Time-dependent deformation of some direct compression excipients", J. of Pharmacy and Pharmacology 30 (10): 601- 7. (1978)). The primary particles are less elastic and of high hardness. Di-Cafos ^® is used as a filling and dry binders in the direct, as Flow regulator in capsule formulations and as abrasive component in toothpastes.

As Fujicalin ^® is anhydrous calcium hydrogen phosphate sold for the production of tablets. Calcium hydrogen phosphate is produced industrially by reacting calcium hydroxide with phosphoric acid at temperatures above 75 ° C (Toy ADF, Walsh EN in: "Phosphorus Chemistry in Everyday Living", 2nd Edition American Chemical Society, Washington, DC (1987)) Tableting finds

Anhydrous calcium hydrogen phosphate usually used as a filler and binder, as a Ca ²⁺ supplier in mineral preparations or as an abrasive in dentifrices. In the synthetic preparation of Fujicalin ^® crystal growth is limited (Takami K., Machimura is; H., Takado K .; Inagaki M .; Kawashima Y .; in "Novel preparation of free flowing spherically granulated dibasic calcium phosphate anhydrous for direct tabletting" , Chem. Pharm. Bull., 44 (4), 868-870 (1996)), thereby reducing the size of the crystallites as compared to other methods of preparation. Then, granulation by spray-drying (Takado K, Murakami T, Japanese Patent Application Kokai No. 298505 (1994), Takado K, Murakami T, Japanese Patent Application Kokai No. 18005 (1995)), whereby nearly spherical, extremely porous Particles are obtained. At 27 m ² / g, this product has a surface area 90 times larger than the Di-Cafos ^® .

As inorganic salts for the production of tablets are

 in particular carbonates of interest, which can be easily dissolved in water in the presence of acidic substances, whereby the active ingredient can be provided in an effervescent beverage. Usually, for the preparation of effervescent tablets

 Sodium carbonate, sodium bicarbonate, calcium carbonate or corresponding potassium carbonates used as well as acid components citric acid, tartaric acid or ascorbic acid.

However, under certain conditions it is desirable to

 to be able to provide corresponding tablets in which

inorganic salts are used, the magnesium salts instead of the calcium, Sodium or potassium salts as filler and carrier material included. This applies not only to the mentioned effervescent formulations but also to other mixtures, granules or conventional tablets.

Conventional powdered magnesium hydroxide can, however, because of its poor flow properties and lack of

Compressibility not without special additives or special

Pretreatment can be used as a carrier or tableted directly. It is basic magnesium hydroxide carbonate with the chemical composition 4MgC0 ₃ xMg (OH) ₂ x5H ₂ O. It is formed from aqueous solution only if it contains a lot of excess carbon dioxide. Magnesium carbonate can crystallize with 5, 3 and 1 mol of water of crystallization and gradually becomes basic when boiled with water

Magnesium carbonate decomposes. Corresponding methods for the production have long been known.

task

The present invention is based on the object, a

powdery carrier material, optionally also in a good

tablettable form, which in simple,

Inexpensive, the production of solid dosage forms allowed in which the active substance or substances are distributed as homogeneously as possible and protected against Entmenmenden tendencies.

 Furthermore, it is the object of the present invention to provide corresponding formulations in solid form, wherein the optionally very low-dose or very fine particulate

(micronized) active ingredient is homogeneously distributed. It is beyond that

Object of the present invention, a directly tablettable,

To provide drug-containing product with good flowability, which allows the production of pharmaceutical application forms with homogeneous drug distribution. Solution of the task

According to the present invention, the object is surprisingly achieved by solid formulations which are characterized in that they

 a) comprise at least one porous support consisting of

 Magnesium hydroxide carbonate,

 and

 b) one or more functional substances.

Corresponding formulations comprise ordered mixtures consisting of 50 to 99.9% by weight of magnesium hydroxide carbonate and 50 to 0.1% by weight of at least one micronized functional component. Preferably, it is included

Magnesium hydroxide carbonate to a material having a BET surface area in the range 25 to 70 m ² / g, preferably greater 44 n 7g, and a

Bulk density in the range of 0.40 to 0.60 g / ml, and a ramming density in the range of 0.50 to 0.80 g / ml. Surprisingly good properties have formulations in which a directly compressible

Magnesium hydroxide with a particle diameter (laser, D ₅₀ ) in the range between 10 and 60 pm, preferably between 20 and 60 pm, and at least one functional component in the form of a micronized substance having a particle size (laser, D ₅₀ ) of 1-20pm , especially 1-1 Opm.

According to the invention, corresponding formulations may contain at least one functional component from the pharmaceutical field

Active ingredients, diagnostics, dietary supplements, cosmetics, herbicides, fungicides, reagents, dyes, minerals or catalysts also contain enzymes or microorganisms.

Surprisingly, these formulations are ordered mixtures containing from 50 to 99.9% by weight

 Magnesium hydroxide carbonate exist, and the itself under

 mechanical stress, by a pronounced homogeneity and

Distinguishing stability. According to the invention, these formulations contain, apart from at least one functional component, active ingredients and excipients selected from the group consisting of flow improvers, binders, lubricants, sweeteners and polymers. Unexpectedly, these mixtures may be formulated as a powder or tablet. The ordered mixture is resistant to long-term powder and retains its homogeneous distribution of active ingredients even after mechanical stress, such as by transport or in required processing steps, even if the pharmaceutical agent is low doses in it.

The formulations according to the invention are distinguished by the fact that the porous magnesium hydroxide carbonate contained as carrier together with one or more functional substances form a stable ordered mixture with particularly good homogeneity, which have particularly low separation tendencies.

According to the present invention, the present object is also achieved by the use of the described formulations for the preparation of mixtures in solid, semisolid and liquid form, which are used, for example, for the preparation of active ingredient-containing tablets, capsules, powders, ointments, creams, suspensions, dispersions. According to the invention, they can also be advantageously used for the preparation of pharmaceutical formulations for oral or dermal application. The formulations are also well suited for the production of cosmetic, agricultural and technical formulations or food preparations and formulations for food supplementation.

The object of the invention is also achieved in particular by a process for the preparation of the described formulations, wherein at least one porous carrier consisting of

Magnesium hydroxide carbonate, and at least one functional substance in the form of a micronized powder in a mixer selected from the group of tumble mixer, screw-cone mixer, compulsory mixer, agitator, high-speed mixer and fluidized bed mixer are mixed thoroughly. Detailed description of the invention

In the production of tablets, there are several problems that have to be solved by the galenic. On the one hand, the

various introduced starting products are formed together to form a stable tablet body. On the other hand, everyone must

Tablets containing the active ingredient (s) always in the same concentration. But that's not all. The active ingredient must also be evenly distributed in each individual tablet, so that the user, when dividing the tablet, the same in each part of the tablet

Drug concentration finds and can dose accurately. Depending on the physical properties of the active ingredient or the active ingredients that are to be formulated as tablets, this results in different requirements, especially when low-dose tablets are to be formulated.

1. For example, if the active ingredient is in liquid form, e.g. as an oil, dissolved in aqueous or organic solvents or as a dispersion or emulsion, it must be in a solid state before being used

 Dosage form first be converted into a powder, which can be further processed.

2. If the drug is to be dosed very low, have special

 Measures may be taken, whereby the uniform distribution in the solid pharmaceutical dosage form can be ensured. The same applies if the active ingredient in such a small

 Grain size is present that it can not be sufficiently stable mixed for further tabletting with the other ingredients of the formulation. So tend some drugs because of their

 Particle size and particle morphology to segregations.

3. Also problematic are electrostatic phenomena, which can cause an insufficient active substance distribution. As a rule, corresponding problems can be solved by applying the problematic drug to a porous carrier prior to its further processing into a tablet. This can be done in different ways. Usually this is done in an additional granulation step.

The magnesium hydroxide carbonate described in WO 2011/095269 is distinguished by a special particle morphology, combined with a particularly large BET surface area and a high pore volume.

The magnesium hydroxide carbonate thus characterized is easily soluble in an acidic and aqueous environment such as gastric juice due to its porous structure and releases CO2 gas. Depending on the size of a tablet made therefrom, this magnesium hydroxide carbonate can be used as a carrier material or filler, which quickly disintegrate when administered in the mouth or for the preparation of active ingredient-containing

Fizzy drinks.

Through experiments it has now been found that this porous

Magnesium hydroxide carbonate large amounts of finely particulate

can bind pharmaceutical agents.

Surprisingly, the production of suitable

 Dosage forms consisting predominantly of porous magnesium hydroxide carbonate as a carrier, in the absence of solvents by simple intensive mixing, when the sparingly soluble active ingredient is present as ultrafine powder.

The special particle properties lead to the fact that the very fine particulate active ingredients already by intensive mixing at the

 Surface of Magnesiumhydroxidcarbonatpartikel be bound by adsorptive interactions and thus a demixing can be prevented, so that the drug equal distribution in the tableted, but especially in the powdered

Dosage form can be guaranteed. Further experiments with liquid, optionally present as oil active ingredients have shown that they can be applied by a strong adsorption on the surface as such but also in a dissolved liquid preparation on the Magnesiumhydroxidcarbonatpartikel and can be converted into free-flowing powder, which, if desired , can be compressed into tablets.

By the mentioned intensive mixing of the functional

Component or components with the coarser, more porous

Magnesium hydroxide carbonate particles becomes a so-called stable

"Ordered mixture" of porous magnesium hydroxide carbonate as a carrier and at least one functional component, which means that the very dilute component present in the mixture can be uniformly dosed so that variations in the weight of the formulation result in smaller variations in dosage under these conditions as if the functional component

undiluted. This effect is especially for

single-dose pharmaceutical dosage forms of considerable importance, such as: in the filling of sacchets with powders or in the filling of the matrices of tableting machines with the mixture to be tableted.

Dosage forms are to be understood as meaning all forms which are used for

Use as a medicament, in particular for oral administration, as well as dietary supplements but also cosmetics,

 Plant treatment agents such as herbicides or fungicides, reagents, diagnostics and feed and also as dyes, minerals or catalysts are suitable. These include, for example, tablets of any shape, pellets or granules and powder mixtures.

The special properties of the magnesium hydroxide carbonate described in WO 2011/095669 gives the galenic in the

 pharmaceutical industry and the formulator in the

Food industry or in other areas, the ability to bring even galenically problematic drugs or materials in a more workable form. As it is used in the Magnesium hydroxide carbonate is a substance listed in all pharmacopoeias, no additional requirements have to be met with regard to the registration of the filling and carrier material. Although the magnesium hydroxide used in the invention is directly tablettierbar, can in the active ingredient-containing solid

Formulations in addition to the active ingredient and the porous

Magnesium hydroxide carbonate as carrier according to the invention may be included. This may include, among others

Flavor enhancers, Tablettierhilfen, such as lubricants and lubricants, and the like can act. Possible additions are, for example

thermoplastic polymers, lipids, sugar alcohols,

Sugar alcohol derivatives, solubilizers, lubricants, and others.

Suitable thermoplastic polymers are, for example

Polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone and vinyl acetate or vinyl propionate, copolymers of vinyl acetate and crotonic acid, partially saponified polyvinyl acetate, polyvinyl alcohol,

Polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates and polymethacrylates (Eudragit types), copolymers of methyl methacrylate and acrylic acid, polyethylene glycols, alkyl celluloses, in particular

Methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose (HPC), hydroxyalkyl-alkylcelluloses, in particular hydroxypropylmethylcellulose (HPMC), cellulose esters such as

Cellulose phthalates, in particular cellulose acetate phthalate,

 Hydroxypropylmethylcellulose phthalate and

 Hydroxypropylmethylcellulose acetate succinate (HPMCAS). The skilled worker is familiar with such thermoplastic polymers. He can choose depending on the desired properties of the tablets to be produced between the commercially available for this purpose thermoplastic polymers.

But even low molecular weight substances may be included as additional carriers and fillers in the active ingredient-containing formulations.

These can be sugars such as sucrose, glucose, maltose, xylose, Fructose, ribose, arabinose, galactose, trehalose, but also

Sugar alcohols. Suitable sugar alcohols are sorbitol, xylitol, mannitol, maltitol; a suitable sugar alcohol derivative is also isomalt. These

Additives can be commercially available in different qualities

various trade names are obtained.

Suitable lipids are fatty acids, such as stearic acid; Fatty alcohols, such as cetyl or stearyl alcohol; Fats, such as animal or vegetable fats;

Waxes, such as carnauba wax; or mono- and / or diglycerides or phosphatides, especially lecithin. The fats preferably have a melting point of at least 50 ° C. Preferred are triglycerides of C ₂ -, CM-, C 16- and cis-fatty acids.

In addition, conventional galenic adjuvants whose total amount may amount to up to 20% by weight, preferably less than 10% by weight, in particular less than 5% by weight, based on the dosage form,

be used. Which includes:

 Extenders or fillers, such as lactose, cellulose, silicates or

silica;

 Lubricants, such as magnesium and calcium stearate,

sodium stearyl;

 plasticizers;

 Dyes, such as azo dyes, organic or inorganic pigments or dyes of natural origin;

 Stabilizers, such as antioxidants, light stabilizers, hydroperoxide killers, radical scavengers, preservatives and microbial attack stabilizers;

Flavors and odors;

Anti adhesive;

disintegrating auxiliaries (disintegrants)

and retarding agents.

 For the purposes of the invention, active substances are to be understood as meaning all substances having a desired physiological action on the human or animal body or plants. It is about

in particular pharmaceutical active substances. The amount of active ingredient per Dose can vary within wide limits. It is usually chosen so that it is sufficient to achieve the desired effect. Also drug combinations can be used. Active substances in the sense of

Invention are also vitamins and minerals. The vitamins include the vitamins of the A group, the B group, which in addition to Bi, B ₂ , B ₆ and B12, in a broader sense also nicotinic acid and nicotinamide are understood, as well as biotin, folic acid, but also compounds with vitamin-like Properties such. Adenine, choline, pantothenic acid,

Adenylic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-inositol and lipoic acid, as well as vitamin C, vitamins of the D group, E group, K group. Active substances within the meaning of the invention also include peptide therapeutics and proteins.

According to the invention, that described in WO 2011/095669

Magnesium hydroxide carbonate, for example, be used for processing the following active ingredients in a suitable method:

Acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, albrazolam,

Alfacalcidol, allantoin, allopurinol, ambroxol, A-mikacin, amiloride,

Aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin,

Ampicillin, ascorbic acid, aspartame, astemizole, atenolol, beclomethasone, benserazide, benzalkonium hydrochloride, benzocaine, benzoic acid,

Betamethasone, bezafibrate, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin, cefatroxil, cefazolin, cefixime, cefotaxime, ceftazidime, ceftriaxone, Cefuroxime, celediline, chloramphenicol, chlorhexidine, chloropheniramine, chlorthalidone, choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clavulanic acid, clomibramine,

 Clonazepam, clonidine, clotrimazole, codeine, cholestyramine,

 Cromoglycinic acid, cyanocobalamin, cyproterone, desogestrel,

 Dexamethasone, dexpanthenol, dextromethorphan, dextropropoxiphene, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine,

Dihydroergotoxine, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone, dopamine, doxycycline, enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, Ethinyl estradiol, etoposide, eucalyptus globulus, famotidine, felodipine, fenofibrate, fenofibric acid, fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil, gemfibrozil, gentamicin, gingko biloba, glibenclamide, glipizide, clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen, imipenem, indomethacin, insulin, lohexol, lopamidol, isosorbide dinitrate, isosorbide mononitrate,

Isotretinoin, Ketotifen, Ketoconazole, Ketoprofen, Ketorolac, Labatalon, Lactulose, Lecithin, Levocamitin, Levodopa, Levoglutamide, Levonorgestrel, Levothyroxine, Lidocaine, Lipase, Lipramine, Lisinopril, Loperamide,

Lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures or combinations and mineral salts, N-methylephedrine, naftidrofuryl, naproxen, neomycin, Nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol,

Pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, phenoxifylline, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone-iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, promocriptine, propafenone, propranolol, proxyphylline, pseudoephedrine , Pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur, teprenone , Terazosin, terbutaline, terfenadine, tetracycline,

Theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone acetonide, triamterene, trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, valine, zidovudine.

In addition, other difficult to dose, finely particulate active ingredients can be incorporated using magnesium hydroxide carbonate in a formulation and, if desired, be tabletted. For the preparation of solid dosage forms, the carrier and the active ingredients are mixed intensively with one another in an appropriate quantitative ratio, preferably in a suitable mixer. The active ingredients are, if they are not already present as a super fine powder before the

Milled to a very feinteiiigen powder, ie the active ingredient is micronized and then has average particle sizes of a few micrometers, or in the nanometer range. The active compounds are preferably used as functional components in the form of micronized substances having an average particle size (laser, D ₅₀ ) in the range from 1 to 20 μm, preferably in the range from 1 to 10 μm.

The magnesium hydroxide carbonate which can be used according to the invention is a porous material having a BET surface area in the range from 25 to 70 m ² / g, preferably greater than 44 m ² / g, particularly preferably greater than 50 m ² / g, and a bulk density in the range from 0.40 to 0.60 g / ml, and a tamped density in the range of 0.50 to 0.80 g / ml, which can be obtained as described in WO 2011/095669.

Depending on the physical properties of the active ingredient powder, powdered magnesium hydroxide carbonate as a carrier and the finely divided active ingredient are initially introduced in a suitable quantitative ratio and mixed thoroughly with one another. But it is also possible to gradually meter in the active ingredient during mixing, in order to achieve in this way a uniform distribution of the active ingredient on the carrier. The mixing of the two components can be carried out in devices that are known to those skilled in the art for this purpose. Preferably, the mixing takes place under mild conditions in a tumble mixer; Screw-cone mixer, compulsory mixer, high-speed mixer,

 Propeller mixer or in a fluidized bed mixer. These also make it possible to evenly mix liquid active ingredients with the solid carrier material.

For the preparation of the desired "drug-carrier adduct", based on the total amount, 50 to 99.9% by weight

Magnesium hydroxide carbonate and 50 to 0.1 wt .-% of a micronized functional component or a liquid functional component submitted and mixed together in a suitable manner. The directly compressible, porous used for this purpose

Magnesium hydroxide carbonate preferably has particle diameters (laser, D ₅₀ ) in the range between 10 and 60 μm, particularly preferably between 20 and 60 μm.

The intensive mixing of the functional components results in a mixture which, even under mechanical stress, is characterized by an outstanding stability of the mixture and a pronounced

Homogeneity of the distribution of the active ingredient on the substrate is characterized.

The special particle morphology of the carrier combined with a high BET surface area and high pore volume lead to a firm physical attachment of the fine granular active substance particles on the carrier surface. It comes to the formation of so-called orderly

Mixtures. In this way, a poorly miscible active ingredient can be converted into a homogneous preparation which hardly tends to separate the individual components even under mechanical stress. This improves the dosage accuracy of the active ingredient (content uniformity) in single doses, which are taken from such mixtures.

The active ingredient-containing powder according to the invention, which consists essentially of magnesium hydroxide carbonate as a carrier material and the selected active ingredient, has very good porosity

Tablettiereigenschaften and has particle diameter (laser, D ₅ o) in the range between 10 and 60 pm, preferably between 20 and 60 pm.

The advantage of the preparations provided by the present invention is that finely particulate or low-dose active ingredients are present homogeneously distributed bound to a carrier, whereby the production of low-dose preparations is possible, which would tend under normal conditions for segregation.

Advantageously, the mixture according to the invention is a product which, even under mechanical stress, is replaced by a pronounced homogeneity and stability of the mixture. In addition to the functional component and the magnesium hydroxide carbonate used as the carrier, it may contain active substances and adjuvants selected from the group of flow improvers, binders, lubricants, sweeteners and polymers.

Under the given conditions, it is particularly advantageous that the active ingredient, which is optionally present as a pure substance in the form of an oil, by binding to the porous, powdery

Magnesium hydroxide carbonate can be provided as a low-dose powder. Due to the porous properties, if desired, this powder can be directly tabletted, thereby obtaining tablets wherein the active ingredient is homogeneously distributed. As in the active ingredient-containing powder is in the tablet produced the

pharmaceutical active ingredient low doses, both in the tablet and in the active ingredient-containing powder, the active substance-containing mixture in solid form. In turn, the active substance-containing powder can advantageously be used for the production of active ingredient-containing tablets, capsules, powders, ointments, creams, suspensions, dispersions, in particular for the production of pharmaceutical formulations for oral or dermal application or of pharmaceutical, cosmetic, agricultural and technical formulations,

Food preparations and formulations for the

Food supplement.

The present description enables one skilled in the art to fully embrace the invention. Without further explanation, it is therefore assumed that a person skilled in the art can make the most of the above description.

If there are any ambiguities, it goes without saying that the cited publications and patent literature should be used. Accordingly, these documents are considered part of the disclosure of the present specification. This applies in particular to the disclosure of the application WO 2011/095269, which describes the preparation of the magnesium hydroxide carbonate used and is hereby part of the disclosure of the present invention. For a better understanding and clarification of the invention, various examples are given below, which are within the scope of the present invention. These examples also serve to illustrate possible variants. Due to the general validity of the described principle of the invention, however, the examples are not suitable for reducing the scope of protection of the present application only to these.

Furthermore, it is self-evident to the person skilled in the art that both in the given examples and in the remainder of the description, the amounts of components contained in the compositions add up to only 100% by weight or mol%, based on the total composition, and can not go beyond that, even if higher values could result from the indicated percentage ranges. Unless otherwise indicated,% values are in terms of% by weight or molar, with the exception of proportions given by volume.

The temperatures given in the examples and the description as well as in the claims are always in ° C.

Examples

The following materials, equipment and measurement methods were used to carry out the following examples:

methods:

1. Bulk density: according to DIN EN ISO 60: 1999 (German version)

 - indication in "g / ml"

2. Tamping density: according to DIN EN ISO 787-11: 1995 (German version)

- indication in "g / ml"

3. Surface determined according to BET: evaluation and execution

according to literature "BET Surface Area by Nitrogen Absorption" of S. Brunauer et a. (Journal of American Chemical Society, 60, 9, 1983) Apparatus: ASAP 2420 from Micromeritics Instrument Corporation (USA); Nitrogen; Weighing: approx. 3.0000g +/- 5%; Heating: 50 ° C (5 h);

Heating rate 3K / min; Indication of the arithmetic mean of three determinations Particle size determination by laser diffraction with

Dry dispersion: Mastersizer 2000 with dispersing unit Scirocco 2000 (Malvern Instruments Ltd. UK), determinations at 1, 2 and 3 bar counter-pressure; Evaluation Fraunhofer; Dispersant Rl: 1,000,

 Obscuration Limits: 0.0-10.0%, Tra Type: General Purpose,

Background Time: 7500 msec, Measurement Time: 7500 msec,

Execution in accordance with ISO 13320-1 and the specifications of the technical manual and the specifications of the equipment manufacturer; Data in% by volume Particle size determination by laser diffraction with wet dispersion: Mastersizer 2000 with wet dispersion unit Hydro 2000S (from Malvern Instruments Ltd. UK); Dispersion medium demineralized water;

Dispersant R1: 1,330; Pump Speed: 2000 rpm; Stirrer Speed: 2000 rpm;

Ultrasonic Duration: 1 sec; Ultrasonic Level: 100%; Tray Type: General Purpose; Background Time: 7500 msec; Measurement Time: 7500 msec; Obscuration Limits: 10.0-20.0% l; Execution in accordance with ISO 13320-1 and the specifications of the technical manual and the specifications of the equipment manufacturer; Data in% by volume Particle size determination by dry sieving over a sieving tower: Retsch AS 200 control, Fa.Retsch (Germany); Substance quantity: approx. 110.00 g; Sieving time: 30 minutes; Amplitude intensity: 1mm; Interval: 5 seconds; Test sieves with metal wire mesh according to DIN ISO 3310;

Screen widths (in pm): 710, 600, 500, 400, 355, 300, 250, 200, 150, 100, 75, 50, 32; Indication of the quantity distribution per sieve fraction in the

 Tables as "weight% of the weight" iodometric determination of ascorbic acid in the

Mixtures: the implementation consists of the steps Titer determination of the iodine solution with sodium thiosulfate, control by titration against a standard ascorbic acid known

 Salary, titration of the carriers without ascorbic acid loading

 (Blank value) and a 6-fold determination of the

 Ascorbic acid content in the mixtures produced both before and after the mixing process, with subsequent calculations of the means and standard deviations

The basic procedure is also described in the specialist literature, such as e.g. in G. Jander, K. F. year, H. Knoll "dimensional analysis - theory and practice of the classical and the electrochemical titration", publishing house Walter de Gruyter, 1973 ISBN 3 11 005934 7

The sample (amount of sample depends on the ascorbic acid content in the mixture) is placed in a 100 ml beaker and slurried with about 10 ml of demineralized water. Over a

 The piston stroke pipette is gently shaken with 25%

 Sulfuric acid dissolved the material, then 1 ml

 Zidjididstärkelösung added and immediately titrated with iodine solution until the color change from colorless to blue.

chemicals:

- iodine solution 0.05 mol / l Merck KGaA (Germany) Art. 1.09099

- Zinc iodide starch solution Merck KGaA (Germany) Art. 1.05445

- Sulfuric acid 25% Merck KGaA (Germany) Art. 1.00716

 - Micronized ascorbic acid obtained from ascorbic acid in one

 Purity according to Ph Eur, BP, JP, USP and E 300 (as described under Materials)

 Ascorbic acid, prod. 83568,290, VWR (Germany); Ph Eur, NF, USP as a standard ascorbic acid substance

Equipment:

- Titroprocessor 682, Metrohm (Switzerland)

- Dosimat 665, Metrohm (Switzerland) - burette brown glass 20ml, Metrohm (Switzerland)

 - Stirrer Ti Stand 703, Metrohm (Switzerland)

 - Kolbenhubpipette Research 5000, Eppendorf (Germany) 8. Spectrophotometric determination of the content of riboflavin in the

 Mixtures: the implementation consists of the steps of creating a calibration curve, control by photometric measurement of a standard riboflavin substance known content, photometric

 Measurement of the carriers without riboflavin loading (blank value) and a 6-fold determination of the riboflavin content in the produced

Mixtures both before and after the mixing process with subsequent calculations of the means and the

 Standard deviations The sample (amount of sample is determined by the amount of riboflavin in the mixture) is placed in a 500 ml amber glass volumetric flask, slurried with 5 ml of demineralised water and then with 5 ml

 Caustic soda 2M added. The suspension is shaken for 0 minutes and then successively added 100 ml of deionized water and 2.5 ml of glacial acetic acid, briefly shaken again and with deionized

Water filled up to 500ml mark. About 70ml of this yellow

 Suspension are centrifuged for 3 min at 3800 rpm. 20.0 ml of the supernatant are pipetted into a 200 ml amber glass volumetric flask, mixed with 3.5 ml sodium acetate solution 14 g / l (Item No. 1.06268) and made up to 200 ml with demineralized water. This solution is in the

Measure the photometer at 444 nm and a layer thickness of 1 cm against the solvent.

chemicals:

Sodium hydroxide 2M Merck KGaA (Germany) Art. 1.09136

 - Glacial acetic acid Merck KGaA (Germany) Art. 1.00063

 - Sodium acetate MerckKGaA (Germany) Art. No. 1.06268

- micronised riboflavin obtained from riboflavin in a purity according to Ph Eur, BP.USP and E 504 (as described under Materials) - Riboflavin Merck KGaA (Germany) ItemNo. 500257, Ph Eur, BP, USP, E 101 as riboflavin standard substance

Equipment:

- 2-beam photometer Lambda 35 Perkin Elmer (USA)

 - Disposable cuvettes Piastibrand macro 2.5 ml, Brand (Germany)

 Item No. 759005

 - Centrifuge Heraeus Sepatech Minifuge T (Germany) with

 Centrifuge tubes 80 ml

 - Piston Lifting Pipette Research 5000, Eppendorf (Germany)

 - Glass pipette 20,0 ml Hirschmahn EM (Germany)

 - Brown glass volumetric flask Blaubrand, according to ISO 1042, Fa. Brand

 (Germany)

Used directly compressible DC-magnesium hydroxide carbonates and their properties:

Sample A: Parteck Mg DC magnesium hydroxide carbonate heavy Ph Eur, BP, USP, E 504, Merck KGaA, Darmstadt (Germany), Art. No. 1.02440, Batch: K0076840

Sample B: NutriMag MC DC magnesium carbonate heavy, pharm., Gran. i. d. Reinh. BP, USP, Ph Eur; CALMAGS GmbH, Lüneburg (Germany);

 Batch: 308075060

Additional characterization of samples A and B in terms of bulk density, tamped density, BET surface area, BET pore volume, particle distribution by laser diffraction with wet dispersion (in water) and tower sieving: TABLE 1 Bulk density, tamped density, BET surface area, BET pore volume:

(For details on the measuring methods see Methods)

Table 2: Particle distribution determined by laser diffraction with

Wet dispersion in water:

 Data in μιη (for details on the measuring method see Methods)

Sample D (5) D (10) D (20) D (25) D (30) D (50) D (75)

Sample A 2.26 5.62 1, 87 14.10 16.11 23.76 36.09

Sample B 1, 24 2.02 4.37 6.01 7.84 15.96 31, 37

Continuation:

Sample D (90) D (95) D (99) D (100)

 Sample A 50.07 59.41 75.81 93.54

 Sample B 67.61 197.37 455.59 684.57

Table 3: Particle distribution determined by tower sieving:

 Data in% by weight (for details on the measuring method see Methods)

 Continuation:

Used micronized model agents and their properties:

Modellwirkstoff Ascorbic acid micronised: Milling of a

commercially available powdered ascorbic acid having a purity according to Ph Eur, BP, JP, USP, E 300 on an Aeroplex spiral jet mill Type 200 AS from Hosokawa Alpine, Augsburg (Germany) under nitrogen as inert gas; the target grain size D (50) measured by laser diffraction with dry dispersion is in the range of 4pm to 6pm

- The more accurate particle distribution of the material used is shown in the following table.

Table 4: Particle distribution of micronized ascorbic acid determined by laser diffraction with dry dispersion (various pressure conditions):

Information in pm (for details on the measuring method see Methods)

Model active substance riboflavin micronised: Milling of a commercially available powdered riboflavin with a purity according to Ph Eur, BP, USP, E 504 on an Aeroplex spiral jet mill Type 200 AS from Hosokawa Alpine, Augsburg (Germany) under nitrogen as protective gas; the

Target particle size D (50) measured by laser diffraction with

Dry dispersion is in the range of 1, 5pm to 2.5pm - The more accurate particle distribution of the material used is shown in the following table:

Table 5: Particle distribution of the micronized riboflavin determined by laser diffraction with dry dispersion (various

Pressure conditions):

 Information in m (for details on the measuring method see Methods)

Pressure 1 bar

 Sample D (10) D (25) D (50) D (75) D (90)

Micronized 0.54 0.96 2.08 3.89 5.88 riboflavin

 continuation

Pressure 2 bar

 Sample D (10) D (25) D (50) D (75) D (90)

Micronized 0.43 0.73 1, 72 3.28 4.74 riboflavin

 continuation

Pressure 3 bar

 Sample D (10) D (25) D (50) D (75) D (90)

Micronized 0.43 0.73 1, 72 3.18 4.40 riboflavin

Example 1 Determination of the loading capacity and the homogeneity of various amounts of micronized ascorbic acid on samples A and B after mixing in a tumble mixer

Mixtures of 2%, 5%, 7%, 10%, 20% and 30% micronized ascorbic acid with the two DC-magnesium hydroxide carbonate samples A and B were respectively prepared

· In order to determine the homogeneity of the mixtures, 6

 determined in different places of these mixtures of ascorbic acid content

 • The deviations of the relative standard deviations are indicators of the homogeneity of the mixes and it can thereby

 Differences in loading capacity are closed

Execution:

In a 250ml wide-necked glass bottle (VWR Germany), the DC magnesium hydroxide carbonate samples A and B respectively with the in the

Quantities of micronized ascorbic acid added and in a laboratory tumble mixer (Turbula T2A, Fa. Willy A. Bachofen,

Switzerland). After a mixing time of 15 minutes, the material is deposited on a 1 mm sieve without mechanical stress and any loose agglomerates present with a paper sheet are carefully passed through the

 Sieve mesh pressed. Then mix again for 15 minutes in a tumble mixer.

Table 6:

After mixing, the material is spread on an area of 21x30 cm with the same thickness as possible and sampled at 6 different locations, their ascorbic acid content determined and the standard deviations calculated.

Result:

The theoretical amounts of ascorbic acid by weight (in% by weight), the quantities of sample used for the analytical determination of ascorbic acid (in g), the actually found amounts of ascorbic acid as arithmetic mean of 6 determinations ( in% by weight) and the relative

Standard deviations S (rel) from these determinations (in%)

Table 7:

Pattern A shows a lower relative for all blends

Standard deviation than the samples made on the basis of Sample B, i. the mixtures based on sample A have a much better homogeneity.

Example 2: Comparative Examination of the Adsorption Between Micronized Ascorbic Acid and Samples A and B

Principle:

• Mixtures of the two samples A and B were each prepared with 1% micronized ascorbic acid and their homogeneity was tested by determining the ascorbic acid content at 6 different sites of these mixtures.

 • Subsequently, these mixtures were mechanically loaded (in a tamping volumeter at 2500 and 20000 impacts and in a

 Turmsiebmaschine) and the homogeneity of the mixtures tested again after this load

 • The deviations of the relative standard deviations in the

 Ascorbic acid content before and after mechanical stress is an indicator of the stability of the mixtures and thus also of the

 Binding forces between the ascorbic acid and the carrier particles.

Execution:

148.5 g of sample A or sample B are micronized with 1.5 g each

Weighed ascorbic acid into a 500 ml wide-mouth glass bottle (VWR Germany) and mixed it in a laboratory tumble mixer (Turbula T2A, Willy A. Bachofen, Switzerland). After a mixing time of 15 minutes, the material is deposited on a 1 mm sieve without mechanical stress and any loosely packed agglomerates are carefully pressed through the sieve meshes with a paper sheet. The mixture is then mixed again for 5 minutes in a tumble mixer. After mixing, the material is spread over an area of 21x30 cm with the same thickness as possible and samples are taken at 6 different places

Ascorbic acid contents tested and calculated the standard deviations

Each of these mixtures is subjected to a mechanical load: a) A pounding load in a tamping volumeter, as in Ph Eur 7th Edition (7.02, Grundwerk 2011, Volume 1, 2.9.34

Puncture density described; for use comes on page 430 under Fig. 2.9.34-3 shown tamping volumeter for powder samples with a fixed drop height of 3 +/- 0.2 mm. Notwithstanding the number of ramming movements specified there, the sample is subjected to 2500 strokes. Then the material is carefully placed on a surface of 21x30 cm with the same thickness as possible laid out and at 6 different places samples on their

 Ascorbic acid contents tested and the standard deviation calculated, b) as described under a); however with 20000 push movements as

 burden

c) A mechanical load in a sieve tower of Retsch

 (Germany) Type AS 200 control, g ': the sample is spread on the sieve bottom (200 mm) and moved for 60 minutes at an amplitude of 1.5 mm (without interval). Subsequently, 6 samples are taken directly at different points of the sieve bottom, the ascorbic acid content is determined and the standard deviation is calculated.

Result:

The tables show the quantities (initial weight) of sample used for the analytical determination of ascorbic acid (in g), the amounts of ascorbic acid actually found

arithmetic mean of 6 determinations (in% by weight) and the relative standard deviations S (rel) from these determinations (in%). All details are given both before and after the mechanical

Load listed.

Table 8: Content and S (rel) of ascorbic acid before and after a mechanical load in the tamping volumeter after 2500 impacts

Table 9: Content and S (rel) of ascorbic acid before and after a mechanical load in the tamping volumeter after 20,000 impacts

Table 10: Content and S (rel) of ascorbic acid before and after mechanical stress in a Retsch sieving tower

Pattern A shows a lower relative for all blends

Standard deviation than the samples prepared on the basis of Sample B, i. the mixtures based on sample A have a significantly lower tendency to segregation and the like. also due to stronger ones

Adsorption between the ascorbic acid particles and the

Carrier particles.

Example 3 Determination of the loading capacity and the homogeneity of various amounts of micronized riboflavin on samples A and B after mixing in a tumble mixer

Principle:

Mixtures of 5%, 10% and 20% micronized riboflavins with the two DC-magnesium hydroxide carbonate samples A and B were prepared

 • In order to determine the homogeneity of the mixtures, 6

 determined in different places of these mixtures of riboflavin content

• The deviations of the relative standard deviations are indicators of the homogeneity of the mixtures and it can thereby

 Differences in loading capacity are closed

Execution:

In a 1000 ml plastic bottle (VWR Germany), the DC magnesium hydroxide carbonate samples A and B are each added to the amounts of micronized riboflavin indicated in the table and in a laboratory tumble mixer (Turbula T2A, Fa. Willy A. Bachofen, Switzerland) mixed. After a mixing time of 1 minute, the material is deposited over a 1 mm sieve without mechanical stress and any loose agglomerates which may be present are carefully passed through with a paper sheet

Sieve mesh pressed. Then mix again for 1 minute in a tumble mixer.

Table 10:

After mixing, the material is spread on an area of 21 × 30 cm with the same thickness as possible and at 6 different locations samples are determined for their ascorbic acid content and the standard deviations are calculated.

Result:

Table 11 compares:

a) the theoretical amounts of riboflavin, by weight in% by weight, b) the amounts of samples in mg used for the analytical determination of riboflavin,

c) the actually found amounts of riboflavin as arithmetic mean of 6 determinations in wt .-%

 such as

d) the relative standard deviations S (rel) from these determinations in%. Table 11:

Pattern A shows a lower relative for all blends

Standard deviation than those samples prepared on the basis of Sample B, i. the mixtures based on sample A have a much better homogeneity.

Example 4: Comparative Study of Adsorption Between Micronized Riboflavin and Samples A and B

Principle:

• Mixtures of the two samples A and B were each prepared with 5% and 10% micronized riboflavin and their homogeneity was tested by determining the riboflavin content at 6 different points of these mixtures.

 • Subsequently, these mixtures were subjected to mechanical stress in a tower screening machine and the homogeneity of the mixtures was tested again after this loading. The deviations of the relative

 Standard deviations in riboflavin content before and after

 mechanical stress are indicators of the stability of the

 Mixtures and thus also for the binding forces between the riboflavin and the carrier particles.

Execution:

The 5% and 10% mixed riboflavin samples from Example 3 are subjected to mechanical stress for 60 minutes by means of a tower screening machine from Retsch (Germany) type AS 200 control, g '. For this, the samples are placed on the sieve bottom (200 mm) at an amplitude of 1, 5 mm moves without interval switching. Subsequently, 6 samples are taken directly at different points of the sieve, the

Determined ascorbic acid content and calculated the standard deviation. Result:

In the tables the quantities of sample (initial weight) used for the analytical determination of the riboflavin (in mg), the actually found amounts of riboflavin as arithmetic mean of 6 determinations in wt .-%, as well as the relative

 Standard deviations S (rel.) From these determinations in%. All information is listed both before and after the mechanical load. Table 12: Content and S (rel) of riboflavin before and after one

mechanical load on a Retsch tower screen machine; Target loading with 5% riboflavin

 Table 13: Content and S (rel) of riboflavin before and after mechanical stress in a sieving tower; Nominal load of 10%

 riboflavin

 Pattern A shows a lower relative for all blends

Standard deviation than the samples prepared on the basis of sample B, ie the samples A-based mixtures have a lower one Demixing tendency, including due to strong adsorption between the Riboflavinpartikein and the carrier particles.

Claims

P A T E N T A N S P R E C H E

Solid formulation, characterized in that they

a) at least one porous support consisting of

 Magensiumhydroxidcarbonat,

 and

b) one or more functional substances.

Formulation according to claim 1, characterized in that it comprises an ordered mixture consisting of 50 to 99.9% by weight.

Magnesium hydroxide carbonate and 50 to 0.1% by weight of at least one micronised functional component.

A formulation according to claim 1 or 2, characterized in that the magnesium hydroxide carbonate is a material having a BET surface area in the range from 25 to 70 m ² / g, preferably greater than 44 m ² / g, particularly preferably greater than 50 m ² / g, and a bulk density in the range of 0.40 to 0.60 g / ml and a tamped density in the range of 0.50 to 0.80 g / ml.

Formulation according to one or more of claims 1 to 3, characterized in that it is a directly compressible

Magnesium hydroxide carbonate having a particle diameter (laser, D ₅₀ ) in the range between 10 and 60 m.

Formulation according to one or more of claims 1 to 4, characterized in that it comprises at least one functional component in the form of a micronized substance with a

Grain size (laser, D ₅ o) from 1 to 20pm, preferably from 1 to 10pm contains.

A formulation according to claims 1-5, characterized in that the porous magnesium hydroxide carbonate contained as carrier together with one or more functional substances form a stable ordered mixture with particularly good homogeneity. Formulation according to claim 5, characterized in that it is a functional component in the field of

 pharmaceutical agents, diagnostics, nutritional supplements, cosmetics, herbicides, fungicides, reagents, dyes,

 Minerals, catalysts or enzymes or microorganisms.

Formulation according to one or more of claims 1 to 7, characterized in that it is a mixture which, even under mechanical stress, characterized by a pronounced homogeneity and stability of the mixture.

Formulation according to claim 8, characterized in that it comprises active ingredients and excipients selected from the group

 Flow improvers, binders, lubricants, sweeteners and, polymers.

10. A formulation according to one or more of claims 1 to 9, characterized in that it is a powder or a

 Tablet is. Formulation according to one or more of claims 1 to 9, characterized in that it is a powder or a

 Tablet, wherein the pharmaceutical agent is low-dose.

12. Use of a formulation according to one or more of claims 1 to 9 for the preparation of mixtures in solid form.

13. Use of a formulation according to one or more of

Claims 1 to 9 for the preparation of active ingredient-containing tablets, capsules, powders, ointments, creams, suspensions, dispersions.

14. Use of a formulation according to one or more of claims 1 to 9 for the preparation of pharmaceutical

 Formulations for oral or dermal application. 5. Use of a formulation according to one or more of claims 1 to 9 for the production of pharmaceutical,

 cosmetic, agricultural and technical formulations.

16. Use of a formulation according to one or more of claims 1 to 9 for the preparation of food preparations and

Formulations for food supplementation.

17. A process for the preparation of a formulation according to claims 1 to 7, characterized in that at least one porous support consisting of a porous magnesium hydroxide with a large

Surface, with at least one functional substance in the form of a micronized powder in a mixer selected from the group of tumble mixers, screw-cone mixers, compulsory mixers,

 Agitator mixer, high-speed mixer and fluidized bed mixer are mixed intensively with each other.