EP1965771A1 - Pellets comprising a core with a water-soluble carrier - Google Patents

Abstract

A pellet with a length/width ratio of less than about 1.4 is provided which comprises a core which comprises a water-soluble carrier and an active ingredient distributed homogeneously therein. The pellet disintegrates, with visually ascertainable loss of the pellet structure, into smaller fragments when the following test is carried out: (a) 200 to 800 mg of pellets are placed into a Petri dish with 0.5 ml of demineralized water. (b) The Petri dish is immediately afterwards fixed to the measuring cylinder holder of a stamping volumeter. (c) After 10 seconds, 30 stamping movements are carried out. (d) Immediately afterwards, the pellets are photographed.

Description

PELLETS CONTAINS A CORE WITH A WATER-SOLUBLE CARRIER

The invention relates to an oral pharmaceutical preparation and a method for its production. In particular, the invention relates to a preparation based on spherical pellets containing a water-soluble carrier and an active ingredient. The invention also relates to neutral pellets which can be used for the preparation of pharmaceutical preparations.

It is known to prepare pharmaceutical pellets by coating conventional starter cores with active agent-containing coatings. It is also known to provide further coatings for such pellets. Starch cores used are, for example, sugar crystals or sucrose / starch pellets. Starter cores made from other materials, such as silicon dioxide, have also been proposed. However, the properties of the prior art starter cores are not always satisfactory. In particular, prior art starter cores have the disadvantage that they decompose at most slowly on contact with aqueous media and therefore are completely unsuitable for some dosage forms. Thus, dosage forms in which it is essential that the pellets decompose rapidly completely, can not be provided with conventional starter cores. The other properties of starter cores leave much to be desired. Thus, conventional pellets often show strong deviations from an ideal spherical shape. This complicates the application of drug coatings and other coatings.

There is thus a need for the development of new starter pellets (neutral pellets or pellets in short) with improved properties. In particular, starter pellets are to be provided which are spherical and which are suitable for further processing into oral administration forms, in particular those with rapid release of the active ingredient.

This is also to be seen against the background that oral intake of solid dosage forms, such as tablets or capsules, especially in children and is associated with problems for the elderly, since such preparations are not easy to swallow. This often leads to insufficient patient compliance. This is especially true for patients who have trouble swallowing due to the nature of the condition. In addition, tablets and capsules must be taken with a sufficient amount of liquid to ensure that the solid dosage form gets into the stomach. This is not always respected by patients. However, ingestion of a conventional preparation, such as a capsule or tablet, without a sufficient amount of fluid may result in damage to the esophagus. Finally, patients who want to take medicines for acute medical conditions, such as travel sickness, headaches or allergic problems, are not always given water or a suitable drink.

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

In addition, in conventional preparations, the drug release is often delayed. While this may be desirable in some cases, a delay in release may also be detrimental, especially in preparations where the active ingredient is already to be released in the mouth, as in sublingual administration preparations. Thus, there is also a need for preparations from which the active ingredient is rapidly released, especially when ingested without liquid.

The prior art contains various proposals for such dosage forms, which, however, each associated with disadvantages. Thus, for example, WO 98/06385 A1 describes a well swallowable oral dosage form which comprises one or more coated particles, with more defined requirements being imposed on the nature of the coating layers. Thereby are Composition and preparation of dosage forms according to this document necessarily relatively complicated.

In addition, effervescent preparations for medicaments have been proposed in the prior art. For example, WO 99/59553 A1 describes effervescent preparations containing a effervescent composition of CO2 donor and CO2-releasing acid

Component, an active ingredient and other excipients. This composition requires complicated manufacturing steps. In addition, shower preparations often have disadvantages in terms of storage stability.

The present invention is now an oral pharmaceutical preparation is provided, which can be taken easily and in particular without liquid, but in which the disadvantages described above are avoided.

Another object of the invention is to provide an oral pharmaceutical preparation which releases the active ingredient immediately after ingestion.

In addition, the intention of the invention is also to provide a production process for a pharmaceutical preparation.

According to the invention, neutral pellets are also to be provided which can be used for the production of pharmaceutical preparations, in particular by applying one or more layers, of which at least one contains an active substance.

In order to achieve the above-mentioned objects, according to the present invention, there is provided a pharmaceutical pellet having a length-to-width ratio of less than about 1.4 which comprises a core containing a water-soluble carrier and a drug dispersed homogeneously therein. Further provided by the present invention is 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 tamping movements are performed, (d) Immediately thereafter the pellets photographed

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 another aspect of the invention, there is provided a pharmaceutical pellet comprising a pellet as discussed above and described in detail below as the core and one or more layers applied to the core, at least one of which contains an active agent.

The invention will be explained in more detail with reference to the drawing. It illustrates the decomposition behavior of various pellet products. For this purpose, a certain amount of pellets was placed in a Petri dish with 0.5 ml of demineralized water. Immediately afterwards ßend the Petri dish was fixed on the measuring cylinder holder of a tamping volumeter. After 10 seconds, 30 stamping movements were performed. Immediately thereafter, the pellets were photographed. The results are shown in the figures.

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

FIG. 2 shows the decomposition behavior of pellets of mannitol according to the invention with a particle size of the pellets of 250 to 500 μm, 800 mg of pellets being used for the test.

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

4 shows the decomposition behavior of pellets according to the invention from mannitol with a particle size of the pellets of 500 to 800 μm, 800 mg of pellets being used for the test.

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

6 shows the decomposition behavior of pellets according to the invention from mannitol with a particle size of the pellets of 800 to 1000 μm, 800 mg of pellets being used for the experiment.

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 was 250 to 500 microns and 800 mg of pellets were used for the experiment.

8 shows the decomposition behavior of pellets according to the invention of mannitol and PVP (1.5% by weight of PVP, based on the dry weight of all components), the particle size of the pellets being 500 to 800 μm and 800 mg of pellets being used for the experiment ,

9 shows the decomposition behavior of pellets according to the invention of mannitol and PVP (1.5% by weight of PVP, based on the dry weight of all components), the particle size of the pellets being 800 to 1000 μm and 800 mg of pellets being used for the experiment ,

10 shows the decomposition behavior of pellets according to the invention of mannitol, caffeine (7.5 wt .-%, based on the dry weight of all components) and PVP (1, 0 wt .-%, based on the dry weight of all components), wherein the Particle size of the pellets was 250 to 500 microns and 800 mg of pellets were used for the experiment.

11 shows the decomposition behavior of pellets according to the invention 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), where Particle size of the pellets was 500 to 800 microns and 800 mg of pellets were used for the experiment.

FIG. 12 shows the decomposition behavior of pellets according to the invention 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), where Particle size of the pellets was 800 to 1000 microns and 800 mg of pellets were used for the experiment. FIG. 13 shows, for comparison purposes, the behavior of commercially available non-particles having a particle size of 250 to 500 μm, with 400 mg of nonpareil being used for the test.

FIG. 14 shows, for comparison purposes, the behavior of commercially available non-pareils with a particle size of 250 to 500 μm, 800 ppm of non-pareils being used for the test.

FIG. 15 shows for comparison purposes the behavior of commercially available non-pareils having a particle size of 500 to 800 μm, 200 mg of non-pareil being used for the test.

FIG. 16 shows, for comparison purposes, the behavior of commercially available non-pareils with a particle size of 500 to 800 μm, with 600 mg of non-pareil being used for the test.

FIG. 17 shows for comparison purposes the behavior of commercially available non-pareils with a particle size of 800 to 1000 μm, wherein 400 mg of non-pareil were used for the test.

FIG. 18 shows for comparison purposes the behavior of commercially available non-pareils having a particle size of 800 to 1000 μm, 800 ppm of non-pareils being used for the test.

Figure 19 shows the particle size distribution of pellets of the invention containing mannitol, crospovidone and citric acid.

According to the invention, pharmaceutical pellets containing an active ingredient and neutral pellets (starting pellets) containing no active ingredient are provided. The pellet of the present invention is a spherical particle having a length-to-width ratio (ie, a ratio of the length (largest dimension) of the pellet divided by the width (smallest dimension) detected at an angle of 90 ° with respect to the length ), of less than about 1.4, preferably less than about 1.3, more preferably less than about 1.2, even more preferably less than about 1.1, and most preferably less than about 1.05.

The pellet typically has a size in the range of 0.01 to 5 mm. The size is preferably in the range from 0.1 to 1 mm, in particular in the range from 0.1 to 0.6 mm. A particularly preferred range is 0.2 to 0.6 mm. Even more preferred is a range of 0.3 to 0.5 mm.

The core of the pellet contains a water-soluble carrier. Particularly suitable are water-soluble carbohydrates. As examples there may be mentioned 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. Particular preference is given to mannitol and mixtures of mannitol and one or more of the abovementioned support materials. Very particularly preferred is mannitol.

The amount of carrier material in the pellet of the present invention is not particularly limited. Typically, it is 50 parts by weight or more, more preferably 70 parts by weight or more, based on the dry weight of all the core ingredients.

Basically, compositions according to the invention are suitable for administering any biologically active substances, such as therapeutically and / or prophylactically active substances (active substances) which can be administered orally. Examples of drug classes are analgesics, COX2 inhibitors,

Antacids, antiasthmatics, broncholytics, antibiotics, psychotropic drugs, anti- tirheumatics, antidiabetics, antiallergic drugs, antihistamines, antihypotonics, antitussives, antihypertensives, laxatives, mucolytics, expectorants, H2 blockers, topical anesthetics, antiemetics, prokinetic agents, lipid lowering agents, 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 COX2 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 of psychotropic drugs are benzodiazepines, haloperidol, amitriptyline and carbamazepine. Examples of anti-inflammatory drugs are phenylbutazone, indomethacin, diclofenac and piroxicam. Examples of antidiabetics are metformin, glibenclamide, acarbose and glisoxepid. Examples of antiallergic drugs and antihistamines are astemizole, terfenadine, loratadine, clemastine, bamipine and ceterizine. Examples of antihypotonics are ethyl-fryne, norfenefrine and dihydroergotamine mesilate. Examples of antitussives are codeine, dextromethorphan, clobutinol and dropropizine. Examples of antihypertensive agents are beta-blockers such as propranolol, atenolol, metoprolol and prazosin as well as 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 of 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 of lipid lowering agents are fenofibrate, bezafibrate, pravastatin and fluvastatin. Examples of anti-migraine agents are caffeine, dihydroergotamine, ergotamine, sumatriptan and pizotifen. Examples of 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.

Pharmaceutically acceptable salts or esters of active ingredients can also be used according to the invention.

According to a preferred embodiment, a readily water-soluble derivative (salt or ester) of an active ingredient is used.

The pellets according to the invention offer particular advantages in the case of low-dose active ingredients, sublingually bioavailable active ingredients, active agents with rapidly desired onset of action and active ingredients in which the improvement of patient compliance is essential.

According to the invention, the active substance may also be a combination of two or more substances, which are preferably selected from the abovementioned agents.

The amount of the active ingredient in the pharmaceutical pellet of the present invention is not particularly limited. Typically, the pellet contains 50 parts by weight or less and preferably 30 parts by weight or less of active ingredient, based on the dry weight of all core ingredients, as 100 parts by weight. It is particularly preferred if the active ingredient content is between 1 and 20 parts by weight, for example between 3 and 10 parts by weight, based on the abovementioned basis. As already stated, the pellets according to the invention comprise a core which contains a water-soluble carrier and an active ingredient homogeneously distributed therein. According to a preferred embodiment, the core consists of the two named constituents, specific examples of which have been given above.

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 calcium carboxymethylcellulose, acrylic acid-based polymers (Carbopol), gelatin, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol (macrogol), methylcellulose, sodium carboxymethylcellulose, sodium carboxymethylstarch, polyoxypropylene-polyoxyethylene block polymers (poloxamer ), Polyvinyl alcohol, polyvinylpyrrolidone (povidone) and starch. 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, for example as Kollidon 30.

If the pellet core contains binders, the amount is preferably not more than 20 parts by weight, especially not more than 10 parts by weight, more preferably not more than 5 parts by weight, especially not more than 2 parts by weight most preferably not more than 1 part by weight, based on the dry weight of all core constituents, as 100 parts by weight. Preferred ranges for the amount of binder are 0.5 to 20 parts by weight, especially 0.5 to 10 parts by weight, more preferably 0.5 to 5 parts by weight, especially 0.5 to 2 parts by weight. Parts and most preferably 0.5 to 1 parts by weight.

According to another preferred embodiment, the pellets contain a water-insoluble but swellable excipient. examples are crospovidone

alginic acid

calcium sulphate

Calcium carboxymethylcellulose, calcium

Sodium Carboxymethylcθllulose

Microcrystalline cellulose

Powdered cellulose

Croscarmellose sodium

Modified cellulose gum

guar gum

Hydroxypropylcellufose

methylcellulose

sodium alginate

sodium

Starch (corn, potato, rice, tapioca, wheat)

Pregelatinized starch, pregelatinized corn starch

amylose

amylopectin

pectin

agar

xanthan gum

Soy polysaccharides

xylan

Polymeric cyclodextrin

Polacrilin potassium

bentonite

sodium carboxymethyl

Preferred swellable adjuvants exhibit a maximum swelling of greater than 5%, more preferably greater than 30%, especially greater than 40%, more particularly greater than 60%, even more preferably greater than 80%, and most preferably greater than 100%. The determination of the maximum Swelling is described by D. Gissinger and A. Stamm, A Comparative Evaluation of the Properties of Some Tablet Disintegrants, Drug Development and Industrial Pharmacy, 6 (5), 511-536 (1980). It is expressly referred to.

Preferred substances are starch, pregelatinized starch, sodium starch glycolate, guar gum, carboxymethylcellulose sodium, croscarmellose sodium and crospovidone. Especially preferred is crospovidone.

According to the invention, it is preferred if the swellable substance is in finely divided form. It can be used advantageously a micronized material.

The amount of the swellable excipient is in the range of 0.5 to 30 wt .-%, based on the total amount of the ingredients of the pellet. The optimum amount is determined by experiments. For example, an amount of from 5 to 15% by weight is suitable. An amount in the range from 5 to 25% by weight, in particular more than 10 to 25% by weight, such as more than 10 to 15% by weight, is advantageous.

According to the invention, it has been found that the swellable excipient improves the process control. The setting of a given narrow particle size distribution is facilitated. The properties of the pellets are not affected.

The core may contain, in addition to the constituents mentioned, further optional constituents. Both water-soluble and water-insoluble auxiliaries may be additionally present. These include flavor enhancers, flavorings, colorants, preservatives, physical stabilizers and chemical stabilizers such as acidic, basic or buffering components. Optional ingredients also include detackifiers, decay accelerators and decay inhibitors. The amount of other optional ingredients is typically not more than 30 parts by weight, based on the dry weight of all core ingredients as 100 parts by weight θ. Preferably, the amount of other optional ingredients is not more than 10 parts by weight.

According to a further preferred embodiment, pellets are provided which comprise in the core 100 parts by weight of water-soluble carrier, such as a water-soluble carbohydrate, in particular mannitol, 1 to 10 parts by weight and in particular 3 to 10 parts by weight of active compound, 0.5 to 20 parts by weight, especially 0.5 to 10 parts by weight, more preferably 0.5 to 5 parts by weight, especially 0.5 to 2 parts by weight and most preferably 0.5 to 1 weight. Parts contain water-soluble binder and 0 to 10 parts by weight of other excipients and preferably consist thereof.

According to a further preferred embodiment, pellets are provided, which in the core 100 parts by weight of water-soluble carrier, such as a water-soluble carbohydrate, in particular mannitol, 0.5 to 20 parts by weight, especially 0.5 to 10 parts by weight, stronger preferably 0.5 to 5 parts by weight, in particular 0.5 to 2 parts by weight and very particularly preferably 0.5 to 1 parts by weight of water-soluble binder, and 0 to 10 parts by weight of other auxiliaries and preferably consist of it.

According to a further preferred embodiment, pellets are provided which contain in the core 100 parts by weight of water-soluble carrier, such as a water-soluble carbohydrate, in particular mannitol, 1 to 10 parts by weight and in particular 3 to 10 parts by weight of active compound, 5 to 35 wt Parts, preferably 5 to 25 parts by weight and in particular more than 10 to 25 parts by weight of a swelling excipient, in particular with the swelling behavior defined above, especially crospovidone, and 0 to 10 parts by weight of other excipients and preferably consist of it.

According to a further preferred embodiment, pellets are provided which comprise, in the core, 100 parts by weight of water-soluble carrier, such as a water-soluble carbohydrate, in particular mannitol, 5 to 35 parts by weight, preferably 5 to 25 parts by weight and in particular more than 10 to 25 parts by weight of a swellable excipient, in particular with the above-defined swelling behavior, especially crospovidone, and 0 to 10 parts by weight of other excipients and preferably consist thereof.

According to a preferred embodiment, the pellet according to the invention consists of the core defined above.

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

The invention also provides a process for producing pharmaceutical pellets. The method comprises, in a first step, providing a source material powder. The raw material powder comprises a water-soluble carrier. The starting material powder is preferably subjected to a treatment, for example in a shear mixer, to destroy aggregates. The starting material powder may also be a mixture of a water-soluble carrier and one or more further ingredients of the pellets to be produced, for example binders. In this case, the provision of the feedstock powder typically involves mixing the components. For example, therefore, a water-soluble carrier and an active ingredient are mixed.

Preferably, a homogeneous mixture of the constituents is achieved. This too can be done in a shear mixer.

Preferably, a raw material powder is used whose grain size is limited. In particular, the starting material powder comprises a carrier whose grain size is limited. Furthermore, a narrow particle size distribution is preferred for the starting material powder and in particular for the carrier. For example, it has proven in the production of pellets with a size of 300 to 500 microns to use a starting material powder, in particular a carrier, especially mannitol, in which the sieve residue at a mesh size of 160 microns less than 10 wt .-% and especially less than 5 wt .-% is. Preference is furthermore given to starting material powders, in particular powders of a carrier, such as, in particular, mannitol, in which the sieve residue is in a range of from 50 to 80% by weight for a sieve mesh size of 40 .mu.m. Particularly preferably, the sieve residue is in the range of 1 to 5 wt .-% at a mesh size of 160 microns and in a mesh size of 40 microns in the range of 50 to 70 wt .-%.

The raw material powder may be moistened prior to the step of pelleting. For this purpose it is mixed with a pharmaceutically acceptable diluent. This may be the same diluent as that used in the subsequent pelleting step or a different diluent. The diluent may be an organic liquid. Preferably, it is water or an aqueous solution or dispersion. In the liquid may be present as constituents a binder and / or an active ingredient and / or other core ingredients. The amount of the pharmaceutically acceptable diluent is preferably adjusted to provide a wetted source powder, the amount of liquid added being less than that required to form granule structures. Preferably, a uniform moistening of the starting material powder is provided. This can be done using a suitable mixer, such as a shear mixer.

If several pulverulent components are used, mixing and prewetting can be carried out in one step, for example in a high-speed mixer. In the pelleting stage pellets are formed from the optionally pre-moistened starting material with the addition of a pharmaceutically acceptable liquid diluent. For the nature of the diluent, the same criteria apply as for the diluent used for pre-moistening.

The diluent may contain an active ingredient.

It is also possible to supply pulverulent constituents, for example pulverulent active ingredient, during the pelleting, if homogeneous mixing is provided by the process control. Since the pellets according to the invention contain an active ingredient, it must either be present in the starting material powder or be added during pelleting as a constituent of the diluent or in powder form. Combinations of these measures are also possible.

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 a device comprising:

a rotor chamber having an axially extending cylindrical wall,

means for directing air through the rotor chamber from the ground,

a spraying device for the supply of liquid into the chamber, one or more inlet openings for introducing the powder mixture,

a rotor which rotates about a vertical rotor axis, wherein the rotor is arranged in the rotor chamber, a central horizontal surface and in at least the outer third of the rotor, 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 each having an outer end statically fixed to the cylindrical wall of the rotor chamber 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 tangent is arranged 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 product, which is recirculated by kinetic energy for a sufficient period of time, moves from the rotor to the inner surface of the vanes before falling back onto the rotor, while optionally supplying air and or a pharmaceutically acceptable liquid is sprayed into the rotor chamber to form solid pellets of a desired diameter.

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

During pellet formation, a pharmaceutically acceptable diluent is added as described above. The amount depends in particular on the components of the starting material, the desired pellet size and other operating parameters, such as the amount of air supplied, selected. A suitable amount can be determined by the person skilled in the art on the basis of the examples presented here and reference examples by routine experimentation.

The finally obtained pellets are dried. If desired, they can then be provided with one or more coatings.

In particular, neutral pellets according to the invention of the type described above can be used for the preparation of a pharmaceutical preparation. For this purpose, the neutral pellets can be provided in a conventional manner with coatings. Accordingly, the invention also provides a pharmaceutical pellet comprising a neutral pellet according to the invention as a core and one or more layers applied to the core, at least one of which contains an active substance.

Active substance-containing layers can be applied in any desired manner. For example, a solution of an active substance, which may also contain excipients such as binders, are sprayed on. Instead of a solution, a suspension can also be used. The application of powdered active ingredient is possible. For this purpose, neutral pellets are brought into contact with active ingredient powder in a suitable manner, wherein in addition a solvent and / or a binder are supplied.

Compositions according to the invention which can be prepared using the neutral 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. Reference is made to the above-mentioned groups of active ingredients and to the specific examples of active ingredients already mentioned. The pellets obtained according to the invention can be 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 comprises predominantly pellets which fulfill the criteria according to the invention. Preferably, at least 90%, more preferably 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 more preferably less than about 1.1, and more preferably less than about 1.05. The pellets which have the preferred length-to-width ratios preferably also have the further requirements for pellets according to the invention, especially also the requirements which are laid down in the claims or which are listed as preferred in the present description.

The amount of pellets in a pellet product according to the invention can also be determined by weight. A pellet product may contain, for example, 50 to 2000 mg, preferably 100 to 1000 mg and especially 200 to 800 mg 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% by weight, especially at least 95% by weight, of the pellets of the pellet product have a diameter which is within a range of ± 30%, preferably ± 20% and most preferably ± 10% of the mean diameter of all pellets.

For example, to provide a pellet product, a suitable amount of pellets may be packaged in a bag. The pellet product may contain, in addition to the pellets according to the invention, further components. The preparation can be made available to patients in this packaged form. Patients can remove the pellet product from the pouch and take it without liquid. Alternatively, the patient may take the product with a drink or in a drink and take the resulting solution / suspension.

Another alternative is to make a pellet from the pellets by compaction. For example, to pellets, optionally together with one or more excipients, such as lubricants, are pressed. For the production of a tablet, it is also possible to use a pellet product according to the invention. The tablet can be used for oral and especially for sublingual administration of an active ingredient.

If pellets according to the invention, in particular pellets with mannitol as support material, are taken without liquid, they disintegrate on the tongue into smaller, very soft particles and then dissolve within a few seconds. The feeling during melting until completely dissolved can be described as pleasant. The soft consistency of the pellets in the mouth and the rapid release leaves no foreign body sensation in the mouth.

The rapid disintegration of pellets according to the invention can be determined visually. (A) 200 to 800 mg of pellets are placed in a Petri dish containing 0.5 ml of demineralised water, (b) The Petri dish is immediately fixed on the measuring cylinder holder of a tamping volumeter, (c) After 10 seconds, 30 Immediately afterwards, the pellets are photographed.

In the case of pellets according to the invention, loss of the pellet structure and disintegration into small fragments can be visually determined. Further, for a pellet product containing a plurality of pellets as defined above, the disintegration time can be measured. This is done in a disintegration tester with sieve bottom. In it, the disintegration time of the pellets in demineralized water at 37 ⁰ C is tested. The amount of water is chosen so that the pellets are just completely covered. The amount of the pellets is preferably 500 mg. The time to disintegration or dissolution of the pellets is measured.

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

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 = kömig

The rating assigned to a pellet product is the same as that given by the majority of subjects.

Preferably, the subjects are given the opportunity to test for comparison purposes a pellet product having a long disintegration time, in particular greater than 1: 30 min. Commercially available non-pareils are such a product. The pellets of the comparative product are typically sized in the same range as the pellets of the product being evaluated. For the sensory test typically 200 mg pellets are used. After evaluating a sample, each subject has the opportunity to rinse his mouth with water.

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

In the specified test, a pellet product according to the invention is classified by the majority of at least 10 test persons when evaluated after 5 seconds at most as 2 = sandy. A pellet product according to the invention is preferably not classified by the test persons as granular. Furthermore, a pellet product according to the invention is preferably classified by the majority of at least 10 test persons when evaluated after 10 seconds at most as 1 = pulpy, soft. Furthermore, it is preferred that a pellet product according to the invention in the majority of at least 10 test persons, when evaluated after 20 seconds, causes no foreign body sensation in the mouth (classification = 0).

example 1

The present example describes the preparation of mannitol pellets containing no active ingredient. However, it will be readily apparent to those skilled in the art that, with appropriate application of the described process, for example, to a composition containing an active ingredient besides mannitol, active ingredient-containing pellets can be prepared.

1250 g of mannitol 60 are placed in a shear mixer (type Glatt VG-10). The device is operated for 2 minutes to destroy aggregates. The settings are: Chopper (2000 rpm); Impeller (500 rpm). 200 g of demineralized water are then added within 5 minutes, the shear mixer at the above settings is operated to obtain a uniformly moistened material. The amount of liquid added is less than the amount required to form granules (loss of drying about 13%, and the loss of drying can be determined experimentally using an infrared balance).

Then pellets are made from the moistened mannitol powder. For this, the moistened mannitol powder is transferred to a device as described above. More specifically, the moistened material is placed in a device in which a conically-flared rotor directs the pre-wetted material into a horizontal product flow toward the edge of the rotor vessel. The centrifugal force presses the product against the wall (main product stream). In the area of the air gap between the rotor and the wall (stator), the rolling product rises (secondary product flow). Fixed vanes on the wall push the rolling bed back down in the middle of the rotor. The product stream can be described as a spiraling rotating stream.

The rotational speed of the rotor (which influences the friction), the inclination of the conical surface of the rotor, the number of 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 can be made using a rotor with a 30 ° or 45 ° lateral surface slope 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.

In the illustrated production process, a pharmaceutically acceptable liquid, in particular water or an aqueous solution of a Nes binder, 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 that is supplied during pre-wetting and during pelleting influences processes and product properties. However, the humidity also depends on the air volume supplied, the inlet temperature of the air and their moisture. On the basis of the parameters given here by way of example, the skilled person can find suitable parameters for the production of pellets in individual cases by routine tests.

Particularly good results are achieved with the following parameters: The inclination of the conical surface of the rotor is 45 °. The device is equipped with two flat vanes. The rotor is operated at a speed of 1000 rpm. For pelleting, liquid is sprayed at a spray rate of 20 g / min. The amount of liquid supplied is from 50 to 600 g, depending on the target pellet size and the composition of the liquid (eg water, solution, dispersion). After completion of the spraying process, the rotor is operated for a further 2 minutes at a reduced rotor speed of 600 rpm. The mannitol pellets thus obtained are dried at 60 ^° C. until the loss on drying is less than 0.5%.

Example 2

The present example describes the preparation of mannitol pellets containing gelatin as the water-soluble binder. It will be readily apparent to those skilled in the art that, with appropriate application of the described process, for example, to a composition which additionally contains an active ingredient, pellets containing active ingredient can be prepared. 1250 g of mannitol 60 are moistened in a shear mixer with 200 g of demineralized water as in Reference Example 1.

This is followed by pelleting. A rotor is used in which the inclination of the conical lateral surface is 45 °. The device is equipped with two flat vanes. The rotor is operated at a speed of 1000 rpm. 130 g of a 5% aqueous solution of gelatin (soluble in cold water, Solugel LB type A) are sprayed at a spray rate of 20 g / min. The pellets thus obtained are finally dried at 37 ° C until the loss on drying 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 containing gelatin as a binder wherein the gelatin is added as a solid in the prewetting step. It will be readily apparent to one skilled in the art that, with appropriate application of the described method, for example, to a composition which additionally contains an active ingredient, pellets containing active ingredient can be prepared.

Add 1247.5 g of Mannitol 60 and 2.5 g of cold water soluble gelatine (Solugel LB Type A) to a Scherm mixer (Glatt VG-10 type). Operate for 2 minutes to destroy aggregates. The settings are: Chopper (2000 rpm); Impeller (500 rpm). Subsequently, 200 g of de-mineralized water are added within 5 minutes to wet the powder. The amount of liquid added should be below the amount required to form granule structures (approximately 13% drying loss). During the liquid addition, the shear mixer is operated at the above settings to obtain a uniformly wetted material. Subsequently, the mixture is introduced into a device as described above. It is used a rotor with a conical surface whose inclination is 45 °. The device is equipped with two flat vanes. The rotor is operated at a speed of 1000 rpm and 86 g of water are sprayed at a spray rate of 20 g / min. After completion of the spraying, the rotor is operated at a reduced speed of 600 rpm for 2 minutes. Subsequently, the pellets are dried at 37 ° C until the loss on drying is less than 0.2%.

Example 4

This example describes the preparation of mannitol pellets with gelatin as a binder, wherein the gelatin is supplied in dissolved form in the pre-wetting stage. It will be readily apparent to those skilled in the art that, with appropriate application of the described process, for example, to a composition which additionally contains an active ingredient, pellets containing active ingredient can be prepared.

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

The wetted mixture is then introduced into a device as described above.

It is used a rotor with a conical surface whose inclination is 45 °. The device is equipped with two flat vanes. Of the The rotor is operated at a speed of 1000 rpm and 161 g of water are sprayed at a spray rate of 20 g / min. After completion of the spraying, the rotor is operated at a reduced speed of 600 rpm for 2 minutes. Subsequently, the pellets are dried at 37 ° C until the loss on drying 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 pre-wetting stage. It will be readily apparent to those skilled in the art that, with appropriate application of the described process, for example, to a composition which additionally contains an active ingredient, pellets containing active ingredient can be prepared.

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 g of Kollidon 30.

The povidone is dissolved in demineralised water. The mannitol is placed in a shear mixer (type Glatt VG-10). The device is operated for 2 minutes. The settings are: Chopper (2000 rpm); 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 3O ⁰ C. The intake air volume is 100 m ³ / h. The centrifugal atomizer is operated at 50%. In the first approach, a rotor is used with a slope of the conical surface of 45 °. Two flat vanes are provided and the rotor speed is 1000 rpm. There are sprayed 132 g of liquid with a spray rate of 20 g / min.

In a second approach, a rotor is also used with a slope of the conical lateral surface of 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.

After spraying is complete, the process is continued for 2 minutes at a rotor speed of 600 rpm.

The pellets of Formulation A are dried in an oven at 6O ⁰ C to a loss on drying of less than 0.5%. Of the pellets from batch B, a portion in an oven (60 ⁰ C) dried, the other in a fluidized bed (Glatt 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. Citric acid serves as a model substance for an active substance.

1187.5 g of mannitol 60 and 62.5 g of citric acid (anhydrous) are placed in a shear mixer (type Glatt VG-10). The device is initially operated for 2 minutes. Prewetting is then carried out by adding demineralised water (90.0 g) within 5 minutes. A drying loss of about 5% is achieved. In the pre-wetting stage, the 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 ⁰ 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 resulting pellets are finally dried in an oven at 60 ^° C. to a drying loss of less than 0.5%.

Example 7

This example relates to the preparation of mannitol pellets containing povidone as a binder and citric acid. Citric acid serves as a model substance for an active substance.

1175.0 g of mannitol and 62.5 g of citric acid (anhydrous) are added to a shear mixer (type Glatt VG-10). The device is operated for 2 minutes. 12.5 g of Kollidon 30 are added to 110.0 g of demineralized water. The colloidone solution is then added to the mixture of mannitol and citric acid within 5 minutes in the shear mixer. The total operating time of the shear mixer is 7 minutes. A drying loss of about 6% is achieved.

The shear mixer (type Glatt VG-10) is operated with the following settings: Chopper (2000 rpm); Impeller (500 rpm). Subsequently, the mixture is introduced into a device as described above. It is used a rotor with a conical surface whose inclination is 45 °. The device is equipped with two flat vanes. The rotor is operated at a speed of 1000 rpm and 170 g of demineralized water are sprayed at a spray rate of 20 g / min. After completion of the spraying, the rotor is operated at a reduced speed of 600 rpm for 2 minutes.

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

Example 8

This example relates to the preparation of mannitol pellets containing povidone as a binder and citric acid.

1206.25 g of mannitol 60 and 37.5 g of citric acid (anhydrous) are added to a shear mixer (type Glatt VG-10). The device is operated for 2 minutes. 6.25 g of povidone (Kollidon 30) are dissolved in 120.0 g of demineralized water. The solution is added to the shear mixer with the mixture of mannitol and citric acid within 5 minutes. 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, the mixture is introduced into a device as described above. It is used a rotor with a conical surface whose inclination is 45 °. The device is equipped with two flat equipped with shovels. The rotor is operated at a speed of 1000 rpm and 220 g of water are sprayed at a spray rate of 20 g / min. After completion of the spraying, the rotor is operated at a reduced speed of 600 rpm for 2 minutes.

In the subsequent drying step, the pellets are dried in a fluidized bed (Strea-1) at an inlet air temperature of 6O ⁰ C and an air flow level of 5 to a drying loss of less than 0.6%. Orange flavor (0.01 g) is dissolved in demineralised water (10 ml); 5 ml are added during the drying step.

Example 9

This example relates to the preparation of mannitol pellets containing povidone as a binder and caffeine.

1143.75 g of mannitol 60 are mixed with 93.75 g of caffeine in a shear mixer (type Glatt VG-10) for 2 minutes. 12.50 g of povidone (Kollidon 30) are dissolved in 200 g of demineralised water. The solution is added to the mixture in the shear mixer within 5 minutes. The total operating time of the shear mixer is 7 minutes. A drying loss of about 11% is achieved. The shear mixer is operated with the following settings: Chopper (2000 rpm); Impeller (500 rpm).

Subsequently, the mixture is introduced into a device as described above. It is used a rotor with a conical surface whose inclination is 45 °. The device is equipped with two flat vanes. The rotor is operated at a speed of 1000 rpm and 160 g of water are sprayed at a spray rate of 20 g / min. After completion of the spraying, the rotor is operated at a reduced speed of 600 rpm for 2 minutes. In the drying step, the pellets are dried in a fluidized bed (GPCG) at an inlet air temperature of 7O ⁰ C and an inlet air volume of 50 m ³ / h to a drying loss of less than 0.6%.

Example 10

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

To compress the pellets, a mixture with 1, 2% magnesium stearate is prepared. To this end, 98.8 g of mannitol pellets (500-800 μm) are mixed with 1.2 g of magnesium stearate in a Turbula mixer for 5 minutes and then compressed on a Korsch EKO tablet press into tablets of different sizes.

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

Diameter weight

(mm) (mg)

9,230

12 240

Example 11

The present example describes the preparation of pellets from mannitol and crospovidone, a swellable excipient. The pellets contain no active ingredient. However, it will be readily apparent to one skilled in the art that, with appropriate application of the described process, for example, to a composition containing an active ingredient besides mannitol, pellets containing active ingredient may be prepared. The mannitol is ground with an Alpine C 100 UPZ device and passed through a sieve with a mesh size of 0.8 mm. The crospovidone is passed through a sieve with a mesh size of 0.5 mm.

A mixture of 937.50 g (75% by weight) of mannitol and 312.50 g (25% by weight) of crospovidone is placed in a shear mixer (type Glatt VG-10). The device is operated for 2 minutes to destroy aggregates. The settings are: Chopper (2000 rpm); Impeller (100 rpm). Subsequently, 550 g of a saturated aqueous mannitol solution are fed. The feed takes place via a binary nozzle with a nozzle diameter of 1, 2 mm at a spray rate of 25 g / min and a atomization air pressure of 1 bar. Meanwhile, the shear mixer is operated at the above settings to obtain a uniformly wetted material. The process step lasts 24 min. The resulting moistened mass is passed through a sieve with a mesh size of 3.15 mm. The drying loss is 24.51%.

Then pellets are made from the moistened mass. For this purpose, the mass is introduced into a device as described above. It is used a rotor with a conical surface whose inclination is 30 °. The device is equipped with two flat vanes. During operation (75 m ³ / hr) was passed a stream of air with an inlet air temperature of 30 ⁰ C and a dew point of 4.4 ° C through the bed of forming pellets. The rotor is operated at a speed of 800 rpm. 445 g of purified water are sprayed at a spray rate of 22 g / min. After completion of the spraying, the rotor is operated at a reduced speed of 350 rpm for 2 minutes. The process step lasts 23 min. The drying loss is 31, 19%. The pellets thus obtained are dried in a fluid bed dryer (Glatt GPCG) at 60 ⁰ C air inlet temperature exceeding 4O ⁰ C until the product temperature. The drying loss is 1.81%.

The pellets obtained have an average particle size of 0.35 mm (minimum: 0.17 mm, maximum: 0.43 mm).

Example 12

The present example describes the preparation of pellets from mannitol and crospovidone, a swellable excipient. The pellets contain no active ingredient. However, it will be readily apparent to one skilled in the art that, with appropriate application of the described process, for example, to a composition containing an active ingredient besides mannitol, pellets containing active ingredient may be prepared.

The mannitol is ground with an Alpine C 100 UPZ device and passed through a sieve with a mesh size of 0.8 mm. The crospovidone is passed through a sieve with a mesh size of 0.5 mm.

A mixture of 1125.00 g (90% by weight) of mannitol and 125.00 g (10% by weight) of crospovidone is placed in a shear mixer (type Glatt VG-10). The device is operated for 2 minutes to destroy aggregates. The settings are: Chopper (2000 rpm); Impeller (100 rpm). Subsequently, 200 g of a saturated aqueous mannitol solution are fed. The feed takes place via a binary nozzle with a nozzle diameter of 1, 2 mm at a spray rate of 47 g / min and a atomization air pressure of 1 bar. Meanwhile, the shear mixer is operated at the above settings to obtain a uniformly wetted material. The process step lasts 6 min. The resulting moistened mass is passed through a sieve with a mesh size of 3.15 mm. The drying loss is 11, 21%. Then pellets are made from the moistened mass. For this purpose, the mass is introduced into a device as described above. It is used a rotor with a conical surface whose inclination is 30 °. The device is equipped with two flat vanes. During operation, a stream of air (75 m ³ / h) with an inlet air temperature of 3O ⁰ C and a dew point of 6.2-6.7 ° C through the bed of forming pellets passed. The rotor is operated at a speed of 800 rpm. There are sprayed 508 g of purified water with a spray rate of 18 g / min. After completion of the spraying, the rotor is operated at a reduced speed of 350 rpm for 2 minutes. The process step lasts 31 min. The drying loss is 20.79%.

The pellets thus obtained exceeds a fluid bed dryer (Glatt GPCG) at 60 ⁰ C air inlet temperature dried until the product temperature is 42.5 ° C. The drying loss is 0.71%.

The resulting pellets have an average particle size of 0.18 mm (minimum: 0.14 mm, maximum: 0.26 mm).

Example 13

The present example describes the preparation of pellets from mannitol, crospovidone, a swellable excipient, and citric acid.

The mannitol is ground with an Alpine C 100 UPZ device and passed through a sieve with a mesh size of 0.8 mm. The crospovidone is passed through a sieve with a mesh size of 0.5 mm.

A mixture of 1112.50 g (89% by weight) of mannitol, 125.00 g (10% by weight) of crospovidone and 12.50 g (1% by weight) of citric acid is poured into a shear mixer (type Glatt VG- 10). The device is operated for 2 minutes to Destroying aggregates. The settings are: Chopper (2000 rpm); Impeller (100 rpm). Subsequently, 200 g of a saturated aqueous mannitol solution are fed. The feed takes place via a binary nozzle with a nozzle diameter of 1, 2 mm at a spray rate of 45.5 g / min and a atomization air pressure of 1 bar. Meanwhile, the shear mixer is operated at the above settings to obtain a uniformly wetted material. The process step lasts 6 min. The resulting moistened mass is passed through a sieve with a mesh size of 3.15 mm. The drying loss is 10.70%.

Then pellets are made from the moistened mass. For this purpose, the mass is introduced into a device as described above. It is used a rotor with a conical surface whose inclination is 30 °. The device is equipped with two flat vanes. During operation, a stream of air (75 m ³ / h) with an inlet air temperature of 3O ⁰ C and a dew point of from 4.8 to 7, 4 ° C passed through the bed of the forming pellets. The rotor is operated at a speed of 800 rpm. 460 g of purified water are sprayed at a spray rate of 21 g / min. After completion of the spraying, the rotor is further operated at a speed of 800 rpm for 2 minutes. The process takes 25 min. The drying loss is 21.09%.

The pellets thus obtained are dried in a fluid bed dryer (Glatt GPCG) at 60 ⁰ C air inlet temperature exceeding 40.9 ⁰ C until the product temperature. The drying loss is 0.89%.

The pellets obtained have a mean particle size of 0.43 mm (minimum: 0.26 mm, maximum: 0.52 mm). The particle size distribution was determined by sieve analysis with an ATM Sonic Sifter L3P (sieve time: 3 min, amplitude of sift and pulse in setting 5). It is shown in FIG. 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 designated SDF E 0901, SDF E 0911 and SDF E 0919 were prepared in a similar manner as described in the above Examples and Reference Examples.

Test Example 1

The dissolution behavior of the pellets is tested in a small volume of liquid (0.5 ml of demineralized water) and under mechanical stress to represent the physiological conditions. The fluid 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 placed on the measuring cylinder holder of a tamping meters fixed. After 10 seconds, 30 tamping movements are performed. For subsequent evaluation, the shape or appearance of the pellets is compared with the neutral pellets. The Figg. Figures 1 to 12 show the decomposition behavior of rapidly disintegrating pellets shown in Figs. Figures 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 disintegration tester with sieve bottom, the disintegration time of the pellets in demineralised water (37 ⁰ C) is checked. The amount of water is chosen so that the pellets only so far immersed in water to completely wet their entire surface. The time to disintegration or dissolution of the pellets is measured.

Decay with a decay tester - results

Pellets Particle size Quantity (mg) Decay time

(μm) (min: sec)

SDF E 0901 500-800 500 00: 40-00: 50

SDF E 0911 500-800 500 00: 40-01: 00

SDF E 0919 500-800 500 00: 30-00: 50

Non-Pareils 600-710 500 01: 30-02: 00

The tested mannitol pellets disintegrate with loss of their pellet structure within 10-20 seconds and then dissolve completely within one minute. The decay behavior of non-pareiis is not comparable to the mannitol pellets investigated. They disintegrate / erode from their surface and lose their size. The neutral pellets remain until complete Decay received in their structure. Only after about 2 minutes, the neutral pellets are decayed.

Test Example 3

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

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 determined at intervals of 5, 10 and 20 seconds using a scale. 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 break up into smaller, soft fragments, with loss of the pellet structure. Both the particle size and the amount of all mannitol pellets tested do not play a significant role in the decay behavior. The pellets disintegrate independently of the amount used (200-800 mg) and particle size (250-1000 microns), without significant external differences are observed.

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

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

Sensory testing of the melting behavior by 10 test persons

Criteria:

0 = no foreign body sensation

1 = mushy, soft

2 = sandy

3 = grainy

1st rating after 5 seconds

2nd rating after 10 seconds

4 ^

Evaluation of the melting behavior

Results (majority rating by 10 test persons):

Particle Rating Rating Rating large (μm) (5 sec) (10 sec) (20 sec)

SDF E 0901 250-500 1 0 0

SDF E 0901 500-800 1 1 0

SDF E 0901 800-1000 2 1 0

SDF E 0911 250-500 1 1 0

SDF E 0911 500-800 1 1 0

SDF E 0911 800-1000 2 1 0

Non-Pareils 250-500 3 2 2

Non-Pareils 500-800 3 3 2

Non-Pareils 800-1000 3 3 3

The tested mannitol pellets have the property, after contact with a very small volume of liquid, to disintegrate within a short time while losing their pellet structure into smaller particles. Neutral pellets of the prior art remain unchanged under the same experimental conditions. These different properties allow conclusions about the actual decay behavior in the mouth.

In the disintegration tester, the mannitol pellets disintegrate within 20 seconds and dissolve within one minute. The neutral pellets disintegrate after about 2 minutes. The decay tester can be used to indicate a time to complete decay. However, it is difficult to draw conclusions about the actual melting behavior and the resulting feeling on the tongue, because in this experiment, the amount of liquid is significantly larger and therefore does not reflect the physiological conditions in the mouth. With the help of sensory testing, it is possible to characterize the different behavior of mannitol pellets to non-pareils. The mannitol pellets disintegrate after a few seconds to a soft mass that is not perceived as unpleasant or even disturbing. In comparison, non-pareils are perceived as granular particles, which are still perceived as unpleasant even if the tested mannitol pellets have already completely disintegrated and are no longer perceptible.

Claims

claims

A pellet having a length-to-width ratio of less than about 1.4, comprising a core containing a water-soluble carrier and optionally a drug homogeneously distributed therein.

2. A pellet according to claim 1, wherein the carrier is selected from water-soluble carbohydrates.

A pellet according to any one of the preceding claims, wherein the carrier comprises mannitol.

4. Pellet according to one of the preceding claims, which additionally contains a binder.

5. Pellet according to one of the preceding claims, which additionally contains a water-swellable excipient.

A pellet according to any one of the preceding claims, further comprising one or more ingredients selected from the group consisting of flavor enhancers, flavoring agents, colorants, preservatives, physical stabilizers, chemical stabilizers, anti-sticking agents, disintegrants and anti-decay agents.

A pellet according to any one of the preceding claims, which decomposes into smaller fragments with visually detectable loss of the pellet structure when the following test is performed: (a) 200 to 800 mg pellets are placed in a Petri dish with 0.5 ml demineralized water, (b ) The Petri dish is then immediately fixed on the measuring cylinder holder of a tamping volumeter, (c) After 10 seconds, 30 tamping movements are carried out, (d) Immediately thereafter, the pellets are photographed.

A pellet product comprising a plurality of pellets of which at least 90% conform to the definition of any one of claims 1 to 6.

A pellet product according to claim 7, wherein the disintegration time measured in a sieve-plate disintegration tester is less than 1: 30 minutes.

10. Pellet product according to claim 7 or 8, which in a sensory test with the classifications

0 = no foreign body sensation 1 = mushy, soft 2 = sandy 3 = grainy

rated by the majority of at least 10 subjects rated 5 seconds later than 2 = sandy.

11. Pellet product according to claim 9, which is rated by the majority of at least 10 subjects rated at 10 seconds at most as 1 = mushy, soft.

12. A pellet product according to claim 9 or 10, wherein the majority of at least 10 subjects, when evaluated after 20 seconds, no longer perceive foreign body sensation (rating = 0).

The pellet product according to any one of claims 7 to 11, further comprising one or more ingredients selected from the group consisting of flavor improvers and flavorings.

14. Pellet product according to any one of claims 7 to 12 for sublingual administration.

15. Use of pellets according to any one of claims 1 to 6 or a pellet product according to any one of claims 7 to 13 for the preparation of a pharmaceutical preparation.

16. A tablet obtainable by compacting pellets according to any one of claims 1 to 6.

17. A process for producing a pellet according to any one of claims 1 to 6 or a pellet product according to any one of claims 7 to 13, 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.