DE102004028977A1 - Pellet, useful to prepare pharmaceutical preparations and administer therapeutically and/or prophylactically active substances e.g. antirheumatic-, antidiabetic- or antiallergic- drug, comprises a water-soluble carrier e.g. mannitol - Google Patents

Abstract

Pellet (A) (with length-width-ratio of less than 1.4) comprises a water-soluble carrier, where (A) disintegrates under visually detectable loss of pellet structure into smaller fragments in a test carried out by: adding a pellet with demineralized water into a petri dish; subsequently fixing the petri dish directly on the measuring cylinder of a stampf volumeter; and subsequently the pellets are directly photographed. Pellet (A) (with length-width-ratio of less than 1.4) comprises a water-soluble carrier, where (A) disintegrates under visually detectable loss of pellet structure into smaller fragments in a test carried out by: (a) adding a pellet (200-800 mg) with demineralized water (0.5 ml) to a petri dish; (b) subsequently fixing the petri dish directly on the measuring cylinder of a stampf volumeter; (c) after 10 seconds, 30 stampf pitching is carried out; and (d) subsequently the pellets are directly photographed. Independent claims are also included for: (1) a pellet product (B), where at least 90% of it is similar to (A); (2) a pellet product comprising a majority of pellets, which comprise a core containing a water-soluble carrier and where at least 90% of the pellets show a length-width-ratio of less than about 1.4, where the decay time of the pellet product measured in a decay tester with sieve base amounts to less than 1:30 minutes; (3) a pellet product comprising majority of pellets, where the pellet core contains the water-soluble carrier and where 90% of the pellets show a length-width-ratio of less than about 1.4, where the pellet product in a sensory test is classified into 0 (that is equal to no foreign body feeling), 1 (that is equal to pulpy and soft), 2 (that is equal to sandy), 3 (that is equal to granular), where the second classification forms the majority after estimation at 5 seconds in at least 10 test persons; (4) the preparations of (A) and (B); (5) a pharmaceutical pellet (C) comprising (A) as a core and one or more layers of core, which contains at least an active agent; and a pharmaceutical pellet product comprising (C).

Description

The This invention relates to neutral pellets, pharmaceutical pellets, methods for their preparation and pharmaceutical preparations based on such Pellets.

It It is known to produce pharmaceutical pellets by conventional Starter cores provided with coatings which contain active substances. It is also known in such Pellets provide further coatings. As starter cores, for example, sugar crystals or pellets from sucrose / starch used. Starter cores made of other materials, such as silicon dioxide, have also been proposed. The properties of the previously known Starter cores, however, are not always satisfactory. Especially Prior art starter cores have the disadvantage that they are in contact with watery At best, media decay slowly and therefore for some dosage forms completely are unsuitable. So can Dosage forms where it is essential that the pellets completely complete disintegrate, with conventional starter cores not be provided. Also the other properties of Starter cores often admit wish you left. So show conventional Pellets often strong deviations from an ideal spherical shape. This complicates the application of drug coatings and other coatings.

It There is thus a need for the development of new starter pellets (Neutral pellets or short pellets) with improved properties. In particular, starter pellets are to be provided which are spherical and for themselves further processing to oral dosage forms, in particular those with rapid release of the drug, are suitable.

This is also against the background to see that the oral intake is firmer Dosage forms, such as tablets or capsules, especially at Children and older People are connected with problems, as such drugs are not let it swallow easily.

It There is thus a need for the development of drug forms, the can also be easily taken by patients, the usual tablets or capsules can not swallow easily, and in particular be taken without liquid can.

Furthermore is at conventional preparations drug release is often delayed. While in some cases quite he wishes is, can be a delay The release also be a disadvantage, especially in preparations, where the drug is already released in the mouth, such as in preparations for sublingual use. There is thus a need for preparations, from which the active substance is rapidly released, in particular also when ingested without liquid.

With pellets (starting pellets) be prepared, for example, for the production of pharmaceutical preparations can be used.

With The present invention is also an oral pharmaceutical preparation be provided, which can be easily taken, in which but the disadvantages of conventional preparations be avoided.

A Another object of the invention is an oral pharmaceutical preparation provide the drug immediately after ingestion releases.

Furthermore The invention also relates to a production process for a pharmaceutical preparation to be provided.

In order to achieve the above-mentioned objects, according to the present invention, there is provided a pellet having a length-to-width ratio of less than about 1.4 containing a water-soluble carrier, the pellet decomposing into smaller fragments with visually detectable loss of the pellet structure when the following test is performed (a) 200 to 800 mg of pellets are placed in a Petri dish containing 0.5 ml of demineralized water. (b) The Petri dish is then immediately fixed on the measuring cylinder holder of a tamping volumeter. (c) After 10 seconds, 30 pitching movements are performed. (d) Immediately thereafter, the pellets are photographed. In addition, pellet products are also provided a plurality of pellets of the invention.

• (a) Bereitstellung eines Ausgangsmaterialpulvers;
• (b) Pelletieren des Ausgangsmaterialpulvers unter Verwendung eines pharmazeutisch annehmbaren flüssigen Verdünnungsmittels;
• (c) Trocknen der erhaltenen Pellets.

According to the invention there is further provided a process for the preparation of a pharmaceutical pellet of the type indicated above, comprising the following steps:

• (a) providing a source powder;
• (b) pelletizing the raw material powder using a pharmaceutically acceptable liquid diluent;
• (c) drying the resulting pellets.

According to one Another aspect of the invention provides a pharmaceutical pellet. a pellet as discussed above and below still in detail is described as a core and one or more on the core applied layers, at least one of which contains an active ingredient comprises.

The The invention will be explained in more detail below with reference to the drawing. In this the decomposition behavior of different pellet products is illustrated. For this purpose, in each case a certain amount of pellets in a Petri dish added with 0.5 ml of demineralized water. Immediately afterwards became the Petri dish on the measuring cylinder holder of a tamping volumeter fixed. After 10 seconds, 10 tamping movements were performed. immediate subsequently the pellets were photographed. The results are in the figures shown.

1 shows the disintegration behavior of pellets of mannitol according to the invention with a particle size of the pellets of 250 to 500 microns, were used for the experiment 400 mg pellets.

2 shows the disintegration behavior of pellets of mannitol according to the invention with a particle size of the pellets of 250 to 500 microns, wherein 800 mg of pellets were used for the experiment.

3 shows the decomposition behavior of pellets of mannitol according to the invention with a particle size of the pellets of 500 to 800 microns, were used for the experiment 200 mg pellets.

4 shows the disintegration behavior of pellets of mannitol according to the invention with a particle size of the pellets of 500 to 800 microns, wherein 800 mg of pellets were used for the experiment.

5 shows the decomposition behavior of pellets of mannitol according to the invention with a particle size of the pellets of 800 to 1000 microns, were used for the experiment 400 mg pellets.

6 shows the decomposition behavior of pellets of mannitol according to the invention with a particle size of the pellets of 800 to 1000 microns, were used for the trial 800 mg pellets.

7 shows the decomposition behavior of pellets according to the invention of mannitol and polyvinylpyrrolidone (PVP) (1.5 wt .-% PVP, based on the dry weight of all components), wherein the particle size of the pellets 250 to 500 microns and 800 mg of pellets were used for the experiment ,

8th shows the decomposition behavior of pellets according to the invention of mannitol and PVP (1.5 wt .-% PVP, based on the dry weight of all components), wherein the particle size of the pellets was 500 to 800 microns and 800 mg of pellets were used for the experiment.

9 shows the decomposition behavior of pellets according to the invention of mannitol and PVP (1.5 wt .-% PVP, based on the dry weight of all components), wherein the particle size of the pellets was 800 to 1000 microns and 800 mg of pellets were used for the experiment.

10 shows the disintegration behavior of pellets of mannitol, caffeine (7.5% by weight, based on the dry weight of all components) and PVP (1.0% by weight, based on the dry weight of all components), the particle size of the pellets being 250 to 500 microns and 800 mg pellets were used for the experiment.

11 shows the disintegration behavior of pellets of mannitol, caffeine (7.5% by weight, based on the dry weight of all components) and PVP (1.0% by weight, based on the dry weight of all components), the particle size of the pellets being 500 to 800 microns and 800 mg of pellets were used for the experiment.

12 shows the disintegration behavior of pellets of mannitol, caffeine (7.5% by weight, based on the dry weight of all components) and PVP (1.0% by weight, based on the dry weight of all components), the particle size of the pellets being 800 to 1000 microns and 800 mg of pellets were used for the experiment.

13 shows for comparison purposes, the behavior of commercially non-pareils with a particle size of 250 to 500 microns, were used for the experiment 400 mg non-Pareils.

14 shows for comparison purposes, the behavior of commercially non-pareils having a particle size of 250 to 500 microns, were used for the trial 800 mg non-Pareils.

15 shows for comparison purposes, the behavior of commercially non-pareils having a particle size of 500 to 800 microns, were used for the experiment 200 mg non-Pareils.

16 shows for comparison purposes, the behavior of commercially non-pareils having a particle size of 500 to 800 microns, with the trial 600 mg non-Pareils were used.

17 shows for comparison purposes, the behavior of commercially non-pareils with a particle size of 800 to 1000 microns, were used for the experiment 400 mg non-Pareils.

18 shows for comparison purposes, the behavior of commercially non-pareils having a particle size of 800 to 1000 microns, were used for the trial 800 mg non-Pareils.

The pellet according to the invention is a spherical one Particles having a length-to-width ratio (i.e. relationship the length (largest dimension) of the pellet, divided by the width (smallest dimension), the at an angle of 90 ° in Terms of length is detected) of less than about 1.4, preferably less than about 1.3, stronger preferably less than about 1.2, even more preferably less than about 1.1, and more preferably less than about 1.05.

The Pellet typically has a size in the range of 0.01 to 5 mm up. Preferably, the size is in the range of 0.1 to 1 mm, in particular in the range of 0.1 to 0.6 mm. A special preferred range is 0.2 to 0.6 mm. Even more preferred is an area from 0.3 to 0.5 mm.

The Pellet (neutral pellet / starting pellet) contains unlike the later still pronounced pharmaceutical pellet no active ingredient.

The Contains pellet a water-soluble Carrier. Particularly suitable are water-soluble carbohydrates. As examples for that can be called are dextran, dextrin, dextrose (glucose), fructose, lactose, maltodextrin, Mannitol, sucrose, sorbitol and xylitol. Preference is given to sugar alcohols. Preferably, a non-hygroscopic carrier material is used. Especially Mannitol and mixtures of mannitol and one or more are preferred several of the aforementioned support materials. Most notably preferred is mannitol.

The Amount of carrier material in the pellet of the invention is not particularly limited. Typically, this is they are 50 parts by weight or more, in particular 70 parts by weight or more, preferably 80 parts by weight or more, especially 90 parts by weight or more, based on the dry weight of all core constituents.

As already executed, include the pellets of the invention a water-soluble Carrier. According to one preferred embodiment if the pellet consists of the carrier, specific examples of which are given above were specified.

According to a further preferred embodiment, the core contains as a further constituent at least one water-soluble binder. The water-soluble binder is preferably selected from the group Calciumcarbo xymethylcellulose, polymers based on acrylic acid (Carbopol), gelatin, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol (Macrogol), methylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, polyoxypropylene-polyoxyethylene block polymers (poloxamer), polyvinyl alcohol, polyvinylpyrrolidone (Povidone) and strength. Preferred binders include gelatin, sodium carboxymethylcellulose and polyvinylpyrrolidone (povidone). Very particular preference is given to polyvinylpyrrolidone. Polyvinylpyrrolidone (povidone) is commercially available in a suitable form, in U.S. Pat for example as Kollidon 30.

If the pellet core contains binder, is the amount preferably not more than 20 parts by weight, especially not more than 10 parts by weight, stronger preferably not more than 5 parts by weight, in particular not more than 2 parts by weight and most preferably not more than 1 part by weight, based on the dry weight of all core constituents. preferred Areas for the amount of binder is 0.5 to 20 parts by weight, especially 0.5 up to 10 parts by weight, stronger preferably 0.5 to 5 parts by weight, in particular 0.5 to 2 parts by weight and most preferably 0.5 to 1 parts by weight. According to one preferred embodiment the pellet consists of a water-soluble carrier and a binder.

Of the Kern may contain other optional ingredients. It can both water-soluble as well as water-insoluble Auxiliary substances in addition be included. This includes Flavor enhancers, flavorings, colorants, Preservatives, physical stabilizers and chemical stabilizers, such as acidic, basic or buffering components. Among the optional Ingredients also belong Anti-caking agents, decay accelerators and decay inhibitors. The Amount of optional ingredients is typically no longer as 10 parts by weight, based on the dry weight of all core constituents.

According to one another embodiment has the pellet of the invention a core of the type described above and, applied to the core, one or more coatings on. Water-soluble coatings are prefers. A coating can serve as a protective layer.

Also according to the invention provided a method for producing pharmaceutical pellets. The The method comprises, in a first stage, the provision of a Raw material powder. The starting material powder includes one water-soluble Carrier. The starting material powder is preferably a treatment, for example in a shear mixer, subjected to destroy aggregates. at the starting material powder may also be a mixture of a water-soluble carrier and one or more other ingredients of the manufactured Pellets, such as binders act. In this case includes the provision of the starting material powder typically Mixing the components.

Preferably In this case, a homogeneous mixture of the ingredients is achieved. Also this can be done in a shear mixer.

Preferably a feedstock powder whose grain size is limited is used is. In particular, the starting material powder comprises a carrier whose Grain size limited is. Furthermore, a narrow particle size distribution for the starting material powder and in particular for the carrier prefers.

For example it has in the production of pellets with a size of 300 up to 500 μm proven, a Starting material powder, in particular a carrier, especially mannitol, too use in which the sieve residue at a Siebmaschenweite of 160 microns less than 10 wt .-% and especially less than 5 wt .-% is. Further preferred Starting material powder, in particular powder of a carrier, such as specifically Mannitol in which the sieve residue at a mesh size of 40 μm in the range from 50 to 80% by weight lies. Particularly preferably, the sieve residue is at a mesh size of 160 μm in the range of 1 to 5 wt .-% and at a mesh size of 40 microns in the range from 50 to 70% by weight.

The Feedstock powder may be moistened prior to the step of pelleting become. This is done with a pharmaceutically acceptable diluent added. This may be the same diluent as that used in the subsequent pelleting stage is used, or a different compound diluent act. For the diluent it can be an organic liquid. Preferably it is water or an aqueous solution or dispersion. In the liquid can as components a binder and / or other core ingredients available. The amount of the pharmaceutically acceptable diluent is preferably such that a wetted starting material powder is achieved, wherein the added amount of liquid below the Quantity is required for the formation of granular structures is. Preferably is for a uniform moistening of the Feedstock powder taken care of. This can be done using a suitable mixer, such as a shear mixer done.

Become several powdered Components can be used Mixing and pre-moistening in one step, for example in one Fast mixer, done.

In the Pelletierstufe be from the optionally pre-moistened starting material with the addition of a pharmaceutically acceptable liquid diluent pellets. For the nature of the diluent, the same criteria apply as for the diluent used for pre-moistening.

It is possible, too, powdery Ingredients during to feed the pelletization.

• (a) Bereitstellung eines Ausgangsmaterialpulvers, das einen wasserlöslichen Träger umfasst;
• (b) Einführen des Ausgangsmaterialpulvers, das wahlweise mit einem pharmazeutisch geeigneten flüssigen Verdünnungsmittel benetzt ist, in eine Vorrichtung, die aufweist: eine Rotorkammer mit einer sich axial erstreckenden zylindrischen Wand, eine Einrichtung, um Luft durch die Rotorkammer vom Boden aus zu leiten, eine Sprüheinrichtung für die Zufuhr von Flüssigkeit in die Kammer, eine oder mehrere Einlassöffnungen zur Einführung des Pulvergemisches, einen Rotor, der sich um eine vertikale Rotorachse dreht, wobei der Rotor in der Rotorkammer angeordnet ist, eine zentrale horizontale Oberfläche und in mindestens dem äußeren Drittel des Rotors die Form einer konischen Mantelfläche mit einer nach außen und oben gerichteten Neigung zwischen 10° und 80° aufweist, wobei die konische Mantelfläche eine kreisförmige obere Kante aufweist, die in einer Ebene liegt, die senkrecht zu der Rotorachse ist, eine Mehrzahl von Leitschaufeln jeweils mit einem äußeren Ende, das statisch an der zylindrischen Wand der Rotorkammer oberhalb der Ebene befestigt ist, die von der oberen Kante der konischen Mantelfläche des Rotors gebildet wird, und einem inneren Ende, das sich in die Rotorkammer erstreckt und tangential zu der zylindrischen Wand der Rotorkammer angeordnet ist und im Querschnitt zur Rotorachse im Wesentlichen die Form eines Kreisbogens oder einer Spirale aufweist,
• (c) Rotation des Rotors, so dass das pulverförmige Produkt durch kinetische Energie in dem Rotor unter dem Einfluss der kinetischen Energie im Kreis geführt wird, sich von dem Rotor zu der inneren Oberfläche der Leitschaufeln bewegt, bevor es zurück auf den Rotor fällt, während Luft zugeführt und eine pharmazeutisch annehmbare Flüssigkeit in die Rotorkammer für einen ausreichenden Zeitraum gesprüht wird, um feste Pellets mit einem gewünschten Durchmesser zu bilden.

According to a preferred embodiment, the method comprises the following stages:

• (a) providing a raw material powder comprising a water-soluble carrier;
• (b) introducing the starting material powder, optionally wetted with a pharmaceutically acceptable liquid diluent, into an apparatus comprising: a rotor chamber having an axially extending cylindrical wall, means for directing air through the rotor chamber from the bottom; Spraying means for supplying liquid into the chamber, one or more inlet openings for introducing the powder mixture, a rotor rotating about a vertical rotor axis, the rotor being disposed in the rotor chamber, a central horizontal surface and in at least the outer third of the rotor Rotor has the shape of a conical lateral surface with an outwardly and upwardly directed inclination between 10 ° and 80 °, wherein the conical lateral surface has a circular upper edge, which lies in a plane which is perpendicular to the rotor axis, a plurality of vanes respectively with an outer end that is static the cylindrical wall of the rotor chamber is fixed above the plane formed by the upper edge of the conical surface of the rotor, and an inner end extending into the rotor chamber and arranged tangentially to the cylindrical wall of the rotor chamber and in cross section to the rotor axis has substantially the shape of a circular arc or a spiral,
• (c) rotating the rotor so that the powdery product is cycled by kinetic energy in the rotor under the influence of kinetic energy, moving from the rotor to the inner surface of the vanes before falling back onto the rotor, during Air is supplied and a pharmaceutically acceptable liquid is sprayed into the rotor chamber for a sufficient period of time to form solid pellets of a desired diameter.

A suitable device is in DE 197 50 042 A1 described. Further details of the structure of the device and its operation are described in the examples presented below and reference examples.

During the Pelleting becomes a pharmaceutically acceptable diluent supplied as described above. The amount will be special dependent on from the components of the starting material, the desired Pellet size as well the other operating parameters, such as the amount of air supplied, selected. A suitable amount, the expert from the presented here Determine examples and reference examples by routine experimentation.

The obtained pellets can used as a pellet product comprising a plurality of pellets. A pellet product comprises a collective of pellets, typically 50 or more, preferably 100 or more pellets. A pellet product according to the invention includes predominantly Pellets that meet the criteria of the invention fulfill. Preferably, at least 90%, in particular at least 95 % and most preferably at least 98% of the pellets have a length-to-width ratio of less than about 1.4, preferably less than about 1.3, more preferably less than about 1.2, even stronger preferably less than about 1.1, and more preferably less than about 1.05 on. The pellets have the preferred length-to-width ratios preferably also have the other requirements pellets according to the invention on, especially the requirements laid down in the claims or are listed as preferred in the present specification.

The Amount of pellets in a pellet product according to the invention can also on the Weight be set. For example, a pellet product 50 to 2000 mg, preferably 100 to 1000 mg and especially 200 contain up to 800 mg of pellets.

The Size of the pellets in a pellet product according to the invention may for example be in the range of 250 to 1000 microns.

According to the invention, a pellet product having a narrow particle size distribution of the pellets contained is preferred. Preferably, at least 90 wt .-%, in particular at least 95 wt .-% of the pellets of the pellet product has a diameter which is within a range of ± 30%, preferably ± 20% and in particular ± 10% of the mean diameter of all pellets.

The after all obtained pellets are dried. If you want, you can still use one or several coatings become.

Especially can Pellets of the type described above for the preparation of a pharmaceutical preparation be used. Can do this Pellets (or a pellet product) provided in a conventional manner with coatings become. Accordingly, according to the invention is also a pharmaceutical Pellet provided a pellet of the invention as a core and a or more layers applied to the core, at least one contains an active substance, includes.

Active substance Layers can be applied in any way. For example, a solution of a Active substance, which may also contain excipients such as binders, contains sprayed become. Instead of a solution also a suspension can be used. Also the application of powdered active ingredient is possible. For this purpose, pellets are suitably in contact with active ingredient powder in addition, besides a solvent and a binder supplied become.

Compositions according to the invention which can be prepared using the pellets are in principle suitable for administering any biologically active substances, such as therapeutically and / or prophylactically active substances (active ingredients) which can be administered orally. Examples of drug classes are analgesics, COX ₂ inhibitors, antacids, antiasthmatics, broncholytics, antibiotics, psychotropic drugs, antirheumatics, hypoglycaemic agents, antiallergic drugs, antihistamines, antihypotonics, antitussives, antihypertensives, laxatives, mucolytics, expectorants, H2 blockers, local anesthetics, antiemetics, prokinetics , Lipid-lowering drugs, anti-migraine agents, sympathomimetics, psychotropic drugs, vitamins and minerals. Preferred classes of drugs are analgesics, migraine, allergy, psychotropic and vitamins and minerals.

Examples of analgesics are ibuprofen, ketoprofen, paracetamol and acetylsalicylic acid. Examples of COX ₂ inhibitors are nimesulide, meloxicam, naproxen, propyphenazone and metamizole. Examples of antacids are hydrotalcite, magaldrate and calcium carbonate. Examples of antiasthmatics and broncholytics are salbutamol, tulobuterol, terbutaline, cromoglycic acid, ketotifen and theophylline. Examples of antibiotics are quinolones, tetracyclines, cephalosporins, penicillins, macrolides, sulfonamides and polypeptides.

Examples for psychotropic drugs are benzodiazepines, haloperidol, amitriptyline and carbamazepine. examples for Anti-inflammatory drugs include phenylbutazone, indomethacin, diclofenac and piroxicam. examples for Antidiabetics are metformin, glibenclamide, acarbose and glisoxepid. examples for Antiallergic and antihistamines are astemizole, terfenadine, loratadine, Clemastine, Bamipin and Ceterizine. Examples of antihypotonics are ethilefrin, Norfenefrin and dihydroergotamine mesilate. Examples of antitussives are codeine, dextromethorphan, clobutinol and dropropizine. Examples for antihypertensives are beta blockers such as propranolol, atenolol, metoprolol and prazosin and calcium antagonists, such as nifedipine, nitrendipine, diltiazem, Verapamil, felodipine and nimodipine. Examples of Laxantia are sodium picosulfate, Lactulose and lactitol. Examples of mucolytics and expectorantia are ambroxol, bromhexine, guaifenesin, acetylcysteine and carbocistein. examples for H2 blockers are ranitidine, famotidine and pirenzepine. Examples of local anesthetics are benzocaine, lidocaine and procaine. Examples of antiemetics and prokinetics are metoclopramide, domperidone, meclocine and dimenhydrinate. examples for Lipid lowering agents are fenofibrate, bezafibrate, pravastatin and fluvastatin. examples for Means against migraine are caffeine, dihydroergotamine, ergotamine, sumatriptan and pizotifen. examples for Sympathomimetics are pseudoephedrine and pholedrine.

A preferred group of drugs includes zolmitriptan, acetylsalicylic acid, rizatriptan, Risperidone, selegiline, olonzapine, cetirizine, ondansetron, loperamide, Buprenorphine, mirtazapine, apomorphine and piroxicam.

Also according to the invention pharmaceutically acceptable Salts or esters of active substances are used.

According to one preferred embodiment becomes a good water soluble Derivative (salt or ester) of an active ingredient used.

The pellets according to the invention offer particular advantages in the case of low-dose active substances, Sublingual bioavailable drugs, drugs with rapid onset of action, and drugs where improving patient compliance is essential.

According to the invention it can the active ingredient is also a combination of two or more Substances are preferably those of the above Funds selected are.

The Amount of active ingredient in the coated pharmaceutical pellet is not particularly limited. typically, contains the pellet is 50 parts by weight or less and preferably 30 parts by weight or less active ingredient, based on the dry weight of all Ingredients. It is particularly preferred if the active ingredient content between 1 and 20 parts by weight, for example between 3 and 10 Parts by weight, on the basis given above.

The pharmaceutical pellets can except one or more active substance-containing layers have further coatings. For example, you can still protective covers or functional coatings provided be.

The Pharmaceutical pellets (active substance-containing pellets) can be used as a pharmaceutical pellet product containing a plurality of pharmaceutical Includes pellets, find use. A pharmaceutical pellet product includes a collective of pharmaceutical pellets, typically 50 or more, preferably 100 or more pellets. A pharmaceutical according to the invention Pellet product includes predominantly pharmaceutical pellets that meet the criteria of the invention. Preferably have at least 90%, especially at least 95% and especially preferably at least 98%, a pellet core having the above described properties, in particular with regard to the length-width ratio, Fulfills.

to For example, providing a pharmaceutical pellet product a suitable amount of pharmaceutical pellets in a bag be packaged. The pharmaceutical pellet product can be used in addition to pellets according to the invention still contain other components. The preparation can be packaged in this Form patients available be put. The patients can remove the pharmaceutical pellet product from the bag and without liquid taking. Alternatively you can Patients take the product with a drink or in one drink give and the resulting solution / suspension taking.

A Another alternative is from the pharmaceutical pellets make a tablet by compacting. For example, you can do that pharmaceutical pellets, optionally together with one or several excipients, such as lubricants, are pressed. For the production A tablet can also be a pharmaceutical pellet product according to the invention be used. The tablet can be for oral and especially too used for sublingual administration of an active substance.

Become pellets according to the invention, in particular pellets with mannitol as carrier material, without liquid taken, they decay on the tongue into smaller, very soft Particles and dissolve afterwards within a few seconds. The feeling during the melting until the complete Can solve be described as pleasant. Due to the soft consistency of the Pellets in the mouth and quick release leaves no foreign body sensation in the mouth.

Of the rapid disintegration of pellets according to the invention can be visually detected. The following test is carried out for this purpose: (a) 200 to 800 mg of pellets are demineralized in a Petri dish containing 0.5 ml Given water. (b) The Petri dish is opened immediately afterwards fixed to the measuring cylinder holder of a tamping volumeter. (c) After 10 paces are carried out 30 pounding movements. (d) Immediately thereafter the pellets photographed.

at pellets according to the invention is a loss of pellet structure and disintegration into small fragments visually ascertainable.

For a pellet product, the plurality of pellets according to the above definition contains, can Furthermore, the decay time can be measured. This is done in a decay tester with sieve bottom. Therein, the disintegration time of the pellets in demineralized Water at 37 ° C checked. The amount of water is chosen so that the pellets just completely are covered. The amount of the pellets is preferably 500 mg. It the time to disintegration or dissolution of the pellets is measured.

at a pellet product according to the invention is a disintegration time of less than 1:30 min, preferably less than 1:00 min, measured.

0

= kein Fremdkörpergefühl

1

= breiartig, weich

2

= sandig

3

= körnig

Pellet products can also be evaluated by sensors. The evaluation is done by test persons. Preferably, at least 10 test persons are consulted. The following options for the classification of the product by a test person are specified:

0

= no foreign body sensation

1

= mushy, soft

2

= sandy

3

= grainy

The Rating assigned to a pellet product corresponds to that which is indicated by the majority of the test persons.

Preferably the subjects receive the opportunity for comparison purposes to test a pellet product which has a long disintegration time, in particular more than 1:30 min. commercial Non-pareils are one such product. The pellets of the reference product typically have a size in the same Area like the pellets of the product to be evaluated.

For the sensory Test typically 200 mg pellets are used. After the evaluation In each sample, the subjects are given the opportunity to take the Rinse mouth with water.

The Evaluation is carried out according to the classifications indicated above in fixed intervals after ingestion of the pellet product. Particularly suitable time intervals are 5, 10 and / or 20 seconds.

at the specified test is a pellet product according to the invention by the majority of at least 10 subjects at rating after 5 seconds maximum classified as 2 = sandy. A pellet product according to the invention is from the test subjects preferably not classified as grainy. Farther becomes a pellet product according to the invention preferably by the majority of at least 10 subjects Rating after 10 seconds maximum as 1 = mushy, soft classified. Furthermore, it is preferred that a pellet product according to the invention in the majority of at least 10 subjects after evaluation No foreign body sensation for 20 seconds in the mouth (classification = 0).

example 1

The present example describes the preparation of pellets Mannitol.

1250 g Mannitol 60 are placed in a shear mixer (type Glatt VG-10). The device is for 2 minutes to destroy aggregates. The settings are with: chopper (2000 rpm); Impeller (500 rpm). Then be 200 g of demineralized water added within 5 minutes, wherein the shear mixer at the above settings is operated to a uniformly moistened To get material. The added amount of liquid is below the amount required to form granule structures is (drying loss about 13%; the loss of drying can be determine experimentally with the aid of an infrared balance).

thereupon are made from the moistened mannitol powder pellets. For this purpose, the moistened mannitol powder is transferred to a device, such as as described above. More specifically, that is moistened Material is placed in a device in which a rotor with conical lateral surface the pre-wetted material into a horizontal product stream to the edge of the rotor vessel directs. It pushes the centrifugal force the product against the wall (main product stream). In the area of the air gap between rotor and wall (stator) increases the rolling product upwards (secondary product flow). fixed Press vanes against the wall the rolling bed in the middle of the rotor back down. The product stream can as a spiral be described rotating current.

The Rotational speed of the rotor (which influences the friction), the inclination of the conical surface of the rotor, the number the guide vanes and the shape of the vanes influence the Product flow and thus also the shape and density of the pellets formed.

For example, pellets using a rotor with a slope of the lateral surface of 30 ° or 45 ° using two or four flat or two steep vanes. An exemplary diameter of the rotor is 29 cm. Such a rotor was used for the examples below. A suitable rotor speed is in the range of 600 to 1200 rpm.

at explained Manufacturing process will also a pharmaceutically acceptable liquid, especially water or an aqueous one solution of a binder, to be sprayed directly onto the rolling bed. This happens, for example, with the help of a centrifugal atomizer. A suitable amount of liquid is in the range of 50 to 600 g, a suitable spray rate in the Range of 10 to 30 g / min.

The Amount of liquid, the at the pre-moistening and during fed to the pelleting will affect processes and product properties. The humidity depends, however also of the supplied air volume, the inlet temperature of the air and its moisture. On The basis of the parameters exemplified here can be the Expert in individual cases by routine tests suitable parameters for the production to find pellets.

Especially good results are achieved with the following parameters: the inclination the conical lateral surface of the rotor is 45 °. The Device is equipped with two flat vanes. Of the Rotor is operated at a speed of 1000 rpm. to Pelleting becomes liquid with a spray rate of 20 g / min sprayed. The amount of supplied liquid is 50 to 600 g, depending from the target pellet size and the Composition of the liquid (eg water, solution, Dispersion). Upon completion of the spraying process, the rotor will continue for more 2 minutes with a reduced rotor speed of 600 rpm operated. The mannitol pellets thus obtained are dried at 60 ° C., until the drying loss is less than 0.5%.

Example 2

The present example describes the preparation of mannitol pellets, as water-soluble Binder gelatin included.

1250 g Mannitol 60 are in a shear mixer as in Reference Example 1 moistened with 200 g of demineralised water.

Then done a pelletization. It is used a rotor in which the inclination the conical lateral surface 45 °. The Device is equipped with two flat vanes. Of the Rotor is operated at a speed of 1000 rpm. It 130 g of a 5% aqueous solution of gelatine (cold water soluble, Solugel LB type A) with a spray rate sprayed in at 20 g / min. The pellets thus obtained are finally dried at 37 ° C., until the drying loss is less than 0.2%. The pellets contain based on the dry weight of the components, 99.5% mannitol and 0.5% gelatin.

Example 3

This Example relates to the preparation of mannitol pellets, the gelatin as a binder, wherein the gelatin as a solid in the Pre-wetting level added becomes.

1,247.5 g mannitol 60 and 2.5 g cold water soluble gelatin (Solugel LB Type A) are placed in a shear mixer (type Glatt VG-10) Das Device becomes for 2 minutes operated to destroy aggregates. The settings are: Chopper (2000 rpm); Impeller (500 U / min). Subsequently 200 g of demineralised water are added within 5 minutes, to wet the powder. The added amount of liquid should be below the amount required for the formation of granular structures is (drying loss about 13%). While the addition of liquid becomes the shear mixer at the above settings operated to a uniformly moistened To get material.

Subsequently, will the mixture is introduced into a device as described above has been. It is used a rotor with a conical surface, whose inclination is 45 °. The Device is equipped with two flat vanes. Of the Rotor is operated at a speed of 1000 rpm, and 86 g of water are sprayed with a spray rate of 20 g / min. To Stop spraying the rotor is at a reduced speed of 600 rpm still for 2 minutes. Subsequently the pellets are at 37 ° C dried until the drying loss is less than 0.2%.

Example 4

This Example describes the preparation of mannitol pellets with gelatin as a binder, wherein the gelatin in dissolved form in the prewetting step supplied becomes. For the skilled person is readily apparent that with appropriate Application of the described method, for example to a Composition, in addition still contains an active substance, active ingredient-containing pellets can be produced.

6.25 g cold water soluble Gelatine (Solugel LB type A) is dissolved in 200 g of demineralised water solved. 1250 g of Mannitol 60 are placed in a shear mixer (type Glatt VG-10) introduced. The mixer is for 2 minutes to destroy aggregates. Subsequently, will the gelatin solution added within 5 minutes while the mixer is operated, to produce a wetted powder mixture.

The wetted mixture is subsequently inserted in a device, as described above.

It a rotor with a conical surface is used whose inclination 45 °. The Device is equipped with two flat vanes. Of the Rotor is operated at a speed of 1000 rpm, and 161 g of water are sprayed with a spray rate of 20 g / min. To Stop spraying the rotor is at a reduced speed of 600 rpm still for 2 minutes. Subsequently the pellets are at 37 ° C dried until the drying loss is less than 0.2%.

Example 5

This Example describes the preparation of mannitol pellets with povidone as a binder, wherein povidone is supplied in the prewetting step.

Two Formulations are examined. The first formulation (formulation A) comprises 1250 g of mannitol 60 and 6.25 g of Kollidon 30. The second Formulation (formulation B) comprises 1250 g of mannitol 60 and 18.75 Kollidon 30.

The Povidone is dissolved in demineralised water. The Mannitol is placed in a shear mixer (type Glatt VG-10). The Device becomes 2 minutes. The settings are: Chopper (2000 U / min); Impeller (500 rpm).

The Amount of water is 200 g each.

The liquid is added within 5 minutes, achieving a drying loss of about 13%. Subsequently, pellets are produced from the individual mixtures. For this purpose, the humidified mixtures are each transferred to a device as described above. The intake air temperature is 30 ° C. The intake air volume is 100 m ³ / h. The centrifugal atomizer is operated at 50%.

in the The first approach is a rotor with a slope of the conical surface of 45 ° used. There are two flat vanes, and the rotor speed is 1000 rpm. It will be 132 g of liquid with a spray rate sprayed in at 20 g / min.

In a second approach is also a rotor with a slope the conical lateral surface used by 45 °, and again two flat vanes are provided. The rotor speed is 1000 Rpm, the amount of sprayed liquid 108 g and the spray rate 20 g / min.

To Termination of spraying will the procedure for Continued for 2 minutes at a rotor speed of 600 rpm.

The pellets from batch A are dried in an oven at 60 ° C to a drying loss of less than 0.5%. Of the pellets from batch B, one portion is dried in an oven (60 ° C), the other in a fluidized bed (smooth GPCG-1). The intake air temperature is 60 ° C, the intake air volume 50 to 100 m ³ / h. A drying loss of less than 0.5% is achieved.

Example 6

This Example relates to the preparation of citric acid-containing mannitol pellets.

It Add 1187.5 g of mannitol 60 and 62.5 g of citric acid (anhydrous) to a shear mixer (Type Glatt VG-10). The device is initially operated for 2 minutes. Then done pre-wetting by addition of demineralised water (90.0 g) within 5 minutes. A drying loss of about 5% is achieved. In the pre-wetting stage, the shear mixer is operated with the following settings: Chopper (2000 rpm); Impeller (500 rpm).

Subsequently, pellets are produced from the mixture. For this purpose, the humidified mixture of mannitol and citric acid is transferred to a device as described above. The device comprises a rotor in which the inclination of the conical lateral surface is 45 °. There are two flat vanes are provided. The rotor speed is 1000 rpm. 390 g of liquid (demineralized water) are sprayed with a spray rate of 20 g / min. The intake air temperature is 30 ° C, the intake air volume 100 m ³ / h. The centrifugal atomizer is operated at a speed of 50%. After spraying, the process is continued for a further 2 minutes at a rotor speed of 600 rpm.

The The obtained pellets are finally heated in an oven at 60 ° C a drying loss less than 0.5% dried.

Example 7

This Example relates to the preparation of mannitol pellets, the povidone as a binder and citric acid contain.

1,175.0 g mannitol and 62.5 g citric acid (anhydrous) are placed in a shear mixer (type Glatt VG-10). The device is for 2 minutes. 12.5 g of Kollidon 30 are demineralized in 110.0 g Given water. The Kollidon solution is then added to the mixture within 5 minutes in the shear mixer from mannitol and citric acid given. The total operating time of the shear mixer is 7 minutes. A drying loss of about 6% is achieved.

Of the Shear mixer (type Smooth VG-10) comes with the following settings operated: Chopper (2000 rpm); Impeller (500 rpm).

Subsequently, will the mixture is introduced into a device as described above has been. It is used a rotor with a conical surface, whose inclination is 45 °. The Device is equipped with two flat vanes. Of the Rotor is operated at a speed of 1000 rpm, and There are 170 g of demineralized water with a spray rate of 20 g / min sprayed. After completing the spraying the rotor is at a reduced speed of 600 rpm still for 2 minutes.

In the subsequent Drying step, the pellets are placed in a fluidized bed (Strea-1) at an intake air temperature of 60 ° C and an air flow level from 5 to a drying loss less than 0.5% dried. orange flavor (0.01 g) is dissolved in demineralised water (10 ml); 5 ml be during the Supplied drying stage.

Example 8

This Example relates to the preparation of mannitol pellets, the povidone as a binder and citric acid contain.

1,206.25 g of mannitol 60 and 37.5 g of citric acid (anhydrous) are added in a shear mixer (type Glatt VG-10) given. The device will last for 2 minutes operated. 6.25 g of povidone (Kollidon 30) are demineralized in 120.0 g Water dissolved. The solution is within 5 minutes in the shear mixer with the mixture from mannitol and citric acid given. The total operating time of the shear mixer is 7 minutes. A drying loss of about 7% is achieved. The shear mixer is operated with the following settings: Chopper (2000 rpm); Impeller (500 rpm).

Subsequently, will the mixture is introduced into a device as described above has been. It is used a rotor with a conical surface, whose inclination is 45 °. The Device is equipped with two flat vanes. Of the Rotor is operated at a speed of 1000 rpm, and 220 g of water are sprayed with a spray rate of 20 g / min. To Stop spraying the rotor is at a reduced speed of 600 rpm still for 2 minutes.

In the subsequent Drying step, the pellets are placed in a fluidized bed (Strea-1) at an intake air temperature of 60 ° C and an air flow level from 5 to a drying loss of less than 0.6%. orange flavor (0.01 g) is dissolved in demineralised water (10 ml); 5 ml be during the Drying added.

Reference Example 1

This Example relates to the preparation of mannitol pellets, the povidone as a binder and caffeine.

1,143.75 g of mannitol 60 are mixed with 93.75 g of caffeine in a shear mixer (type Smooth VG-10) for Mixed for 2 minutes. 12.50 g of povidone (Kollidon 30) will be in 200 dissolved demineralized water. The solution will be added to the mixture in the shear mixer within 5 minutes. The total operating time of the shear mixer is 7 minutes. There will be a loss of drying of about 11% achieved. The shear mixer will come with the following settings operated: Chopper (2000 rpm); Impeller (500 rpm).

Subsequently, will the mixture is introduced into a device as described above has been. It is used a rotor with a conical surface, whose inclination is 45 °. The Device is equipped with two flat vanes. Of the Rotor is operated at a speed of 1000 rpm, and 160 g of water are sprayed with a spray rate of 20 g / min. To Stop spraying the rotor is at a reduced speed of 600 rpm still for 2 minutes.

In the drying step, the pellets are dried in a fluidized bed (GPCG) at an inlet air temperature of 70 ° C and an inlet air volume of 50 m ³ / h to a drying loss of less than 0.6%.

Reference Example 2

This Example describes the preparation of a tablet by compression of rapidly disintegrating mannitol pellets.

to Compression of the pellets is a mixture with 1.2% magnesium stearate produced. For this purpose, 98.8 g of mannitol pellets (500-800 microns) with 1.2 g Magnesium stearate mixed for 5 minutes in a Turbula mixer and then on a Korsch EKO tablet press to tablets different size pressed.

It is possible to prepare tablets from a mixture of the mannitol pellets with magnesium stearate. The produced tablets have the following dimensions:

For the expert It can be seen that in a corresponding manner also from pharmaceutical Pellets can be produced in which one or more of a starter core according to the invention Layers are applied, of which at least one is an active ingredient contains.

test Examples

Analytical methods are to be developed with which the characteristic of the decomposition and melting behavior of pellets according to the invention can be determined and determined. The decay characteristic is tested against neutral pellets (Sugar Spheres). The following pellets are used in the test examples:
SDF E 0901, mannitol pellets
SDF E 0911, mannitol pellets with 1.5% PVP
SDF E 0919, mannitol pellets with 7.5% caffeine and 1.0% PVP
Non-Pareils (Lot. 90183540X), Neutral Pellets
Non-Pareils (Lot. 71762025X), Neutral Pellets

used Particle sizes: 250-500 μm, 500-800 μm and 800-1000 μm.

The Pellets of the designations SDF E 0901, SDF E 0911 and SDF E 0919 were prepared in a similar manner as described in the preceding Examples and Reference Examples is described.

Test Example 1

The dissolution behavior The pellets are demineralized in a small volume of liquid (0.5 ml Water) and tested under mechanical stress to the physiological To represent conditions. The liquid volume corresponds to the saliva volume at rest (no chewing or swallowing), the mechanical stress corresponds to tongue movements.

Place in a Petri dish different amounts of pellets (200-800 mg) with different particle size distributions in 0.5 ml of demineralised water. The Petri dish is fixed on the measuring cylinder holder of a tamping volumeter. After 10 seconds, 30 stamping movements are performed. For subsequent evaluation, the shape or appearance of the pellets is compared with the neutral pellets. The 1 to 12 show the decay behavior of rapidly disintegrating pellets 13 to 18 show conventional non-pareils. By comparing the figures, it can be clearly seen that rapidly disintegrating pellets according to the present invention disintegrate into smaller fragments during the course of the described test with visually detectable loss of the pellet structure. Traditional non-pareils, on the other hand, retain their shape. These pellets do not meet the criterion of disintegration.

Test Example 2

In the decay tester with sieve bottom, the disintegration time of the pellets in demineralised water (37 ° C) is tested. The amount of water is chosen so that the pellets only so far immersed in water to fully wet their entire surface. The time to disintegration or dissolution of the pellets is measured. Decay with a decay tester results

The tested mannitol pellets disintegrate with loss of their pellet structure within 10-20 Seconds and solve then fully within a minute. The decay behavior of non-pareils is not comparable to the studied mannitol pellets. They disintegrate / erode from their surface and lose weight Size. The Neutral pellets remain in their structure until completely disintegrated receive. Only after about 2 minutes, the neutral pellets are decayed.

Test Example 3

The The melting behavior of the pellets to be examined in the mouth becomes sensory determined by test persons using a rating scale.

0

= kein Fremdkörpergefühl

1

= breiartig, weich

2

= sandig

3

= körnig

To evaluate the disintegration of the pellets in the mouth, the feel of a sample of 200 mg pellets of different particle sizes in the mouth is measured at intervals of 5, 10 and 20 seconds using a scale certainly. Between the samples, the mouth is rinsed with water.

0

= no foreign body sensation

1

= mushy, soft

2

= sandy

3

= grainy

The investigated mannitol pellets disintegrate into smaller, soft fragments, with loss of pellet structure. Both the particle size and the amount of all mannitol pellets tested play for the decay behavior not essential. The pellets disintegrate independently of the amount used (200-800 mg) and particle size (250-1000 μm), without that while essential external Differences are detectable.

The tested neutral pellets do not disintegrate in the sensory test, independently their size or quantity. The pellets are dimensionally stable even after the end of the experiment.

Bewertung des Schmelzverhaltens Ergebnisse (Mehrheitliche Beurteilung durch 10 Testpersonen):

The results confirm the melting behavior of mannitol pellets and the sensation on the tongue. While the mannitol pellets disintegrate quickly and feel soft on the tongue, non-pareils show no comparable melting behavior. These feel hard and grainy on the tongue.

Evaluation of the melting behavior Results (majority judgment by 10 test persons):

The tested mannitol pellets have the property after contact with a very small volume of liquid, within a short time of losing their pellet structure into smaller ones Particles decay. Neutral pellets of the prior art remain unchanged under the same experimental conditions. These different ones Properties allow conclusions to be drawn the actual Decay behavior in the mouth too.

in the Decay testers disintegrate the mannitol pellets within 20 seconds and solve get up within a minute. The neutral pellets disintegrate about 2 minutes. With the decay tester can be a time until complete disintegration be specified. However, it is difficult to draw conclusions about the actual Melting behavior and the resulting feeling on the To make tongue, because in this experiment, the amount of liquid is significantly larger and therefore does not reflect the physiological conditions in the mouth.

With Help the sensory examination Is it possible, the different behavior of mannitol pellets to non-pareils to characterize. The mannitol pellets disintegrate after a few seconds to a soft mass that does not feel uncomfortable or even disturbing becomes. In comparison, non-pareils are perceived as granular particles that even then be perceived as unpleasant when the tested mannitol pellets already completely disintegrated and are no longer noticeable.

Claims (18)

Pellet with a length-to-width ratio of less than about 1.4, which contains a water-soluble carrier, wherein the pellet is under visually detectable loss of pellet structure into smaller fragments crumbles when following test performed will: (a) 200 to 800 mg of pellets are in a Petri dish with Added 0.5 ml of demineralized water. (b) The Petri dish becomes immediately afterwards fixed on the measuring cylinder holder of a tamping volumeter. (c) After 10 paces are carried out 30 pounding movements. (d) Immediately thereafter the pellets photographed. Pellet according to claim 1, wherein the carrier is below water-soluble Carbohydrates selected is. Pellet according to one of the preceding claims, wherein the carrier Mannitol covers. Pellet according to one of the preceding claims, which additionally contains a binder. Pellet product comprising a plurality of pellets, of which at least 90% of the definition according to one of claims 1 to 4 correspond. A pellet product comprising a plurality of pellets, the pellets comprising a core comprising a and wherein at least 90% of the pellets have a length to width ratio of less than about 1.4 with the disintegration time of the pellet product measured in a sieve bottom disintegration tester being less than 1:30 min. Pellet product comprising a plurality of pellets, wherein the pellets comprise a core which is a water-soluble carrier contains and wherein at least 90% of the pellets have a length-to-width ratio of less than about 1.4, wherein the pellet product in a sensory test with the classifications 0 = no foreign body sensation 1 = mushy, soft 2 = sandy 3 = grainy by the majority of at least 10 subjects at rating after 5 seconds maximum is classified as 2 = sandy. A pellet product according to claim 7, which is of the majority of at least 10 subjects at rating after 10 seconds maximum as 1 = mushy, soft is classified. A pellet product according to claim 7 or 8, wherein the Majority of at least 10 subjects rated at 20 seconds no foreign body feeling anymore perceives (classification = 0). Pellet product according to one of claims 6 to 9, wherein the water-soluble carrier under water-soluble Carbohydrates selected and especially includes mannitol. A pellet product according to claim 10, wherein the pellets additionally contain a binder. Use of pellets according to one of claims 1 to 4 for the preparation of a pharmaceutical preparation. Use of a pellet product according to any one of claims 5 to 11 for the preparation of a pharmaceutical preparation. Process for the preparation of a pellet after a the claims 1 to 4, comprising the following stages: (a) Provision of a Raw material powder; (b) pelletizing the raw material powder using a pharmaceutically acceptable liquid diluent; (C) Dry the resulting pellets. Process for the preparation of a pellet product one of the claims 5 to 11, comprising the following stages: (a) Provision of a Raw material powder; (b) pelletizing the raw material powder using a pharmaceutically acceptable liquid diluent; (C) Dry the resulting pellet product. Pharmaceutical pellet containing a pellet after a the claims 1 to 4 as a core and one or more applied to the core Layers, at least one of which contains an active ingredient comprises. A pharmaceutical pellet product comprising a plurality of pharmaceutical pellets according to claim 16. Use of pellets according to claim 16 or one Pellet product according to claim 17 for the preparation of a pharmaceutical Preparation.