DE102004028975A1 - Pharmaceutical pellet, useful for preparing tablets, comprises a spherical shaped active substance core with smooth surface and a coat (which induces the release of the active substance, independent of the pH) on the core - Google Patents

Abstract

Pharmaceutical pellet (A) comprises a spherical shaped active substance core (I) with a smooth surface and a coat (II) on the core, which induces the release (independent of the pH) of the active substance. Independent claims are also included for (1) collection of pellets comprising (I) and (II); (2) collection of cores; (3) the preparation of (A); (4) a method for the preparation of a tablet comprising mixing (A) with one or more components (fillers, binders, decomposers, flow regulators and lubricants) to form a mixture; and pressing the mixture; and (5) a tablet prepared by the method.

Description

Territory of invention

The The present invention relates to novel pharmaceutical pellets, multiparticulate dosage forms the basis of such pellets, process for the preparation of pellets and methods of making dosage forms using the pellets. The pellets and the multiparticulate dosage forms on the Base of the pellets are characterized in particular by a controlled Release drug from.

background the invention

at oral administration of drugs, the drug is released in the gastrointestinal tract, and a portion of the drug is absorbed. By controlling the Release of the drug can the extent of Absorption and duration of action can be influenced. Corresponding are different suggestions been made to release the drug by appropriate galenic Control formulation of the drug.

One Approach is to provide dosage forms with coatings, the Drug release dependent from solubility or permeability the coatings influenced can be. Such coatings can, for example be applied to tablets or capsules. In this case exists however, a disadvantage in that a faulty or damaged coating to do so to lead may not release the entire drug dose in the desired Way is controlled.

When Alternative offers multiparticulate forms of administration, in the total amount of the active substance to a larger number of smaller units, like pellets, is distributed. If the individual pellets are provided with coatings, so in the case of a faulty coating is subject to a pellet only a correspondingly small proportion of the total drug dose not the desired Release.

One Another advantage of such dosage forms on the basis of Pellets is that sufficiently small pellets after ingestion relatively quickly from the stomach to the intestine. Tablets, however can, if they do not decay, stay in the stomach for a longer time, The time is also quite variable.

regardless the known advantages of pellets or multiparticulate dosage forms However, it is difficult, a desired Set release behavior. This is related to having it after the prior art is difficult to provide evenly coated pellets. Even the pellet cores, the coated should be of insufficient quality. Especially pellets, which are made by extrusion are often uneven in theirs Shape and also have a rough and uneven surface, which the subsequent one Making filming difficult and resulting in poor quality films can be.

The Various films or coatings used to control release can be used Have compositions. So proposals have been made, the release dependent of pH, time, or bacterial enzymes involved in the Intestine are available to control.

at However, a problem with pH controlled systems is that the Release of active ingredient through food intake, which is the pH in the gastrointestinal tract influenced, changed becomes. In addition, there are significant differences between different people in terms of pH in the gastrointestinal tract. Also with enzymatically controlled Dosage forms with controlled release is about one Variability reported Service.

Known Dosage forms with controlled release are thus not completely satisfactory. In addition, there is the problem that desired (given) Do not set release profiles. Furthermore, the production is of controlled release dosage forms is often difficult. There is thus a need for new dosage forms with controlled Release as well as new methods for the preparation of dosage forms with controlled release.

Tasks and Brief description of the invention

A Object of the present invention is to provide a pharmaceutical Provide pellet in which the drug release regardless of pH and independent of the action of enzymes can be controlled.

A another object is to provide a pharmaceutical pellet, in which the drug release a profile with a lag phase follows. Furthermore, an object is to provide a pellet, in which the drug release after a lag phase with a fixed rate. In addition, according to the invention Pellet products or collectives of pellets are provided, comprising a plurality of individual pellets, each containing the meet specified requirements. Finally, should according to the invention for the production of pellets, pellet products and other dosage forms to be provided.

According to the invention was now found that preparations can be provided in which the drug release pH-independent and independent of Enzyme occurs when pellets are used that contain a spherical drug Core with smooth surface and a coating on the core.

Short description the figures

The The invention will be explained in more detail below with reference to the figures.

1 shows the influence of the thickness of the release-controlling coating on the release of active ingredient in pellets containing the active ingredient ADD 006, the coating consists of polyvinyl acetate and, based on the weight of the polyvinyl acetate, 10 wt% triethyl citrate and 10 wt .-% talc. Plotted is the cumulative release (%) versus time (minutes). As a measure of the thickness of the coating is given for the individual batches, the percentage amount of coating material (polyvinyl acetate, triethyl citrate and talcum in the above-mentioned composition), based on the weight of the active ingredient-containing pellet cores.

2 shows the influence of the thickness of the release-controlling coating on the release of active ingredient in pellets containing the active ingredient ADD 006, wherein the coating of polyvinyl acetate and, based on the weight of the polyvinyl acetate, 7.5 wt .-% triethyl citrate and 10 wt .-% talc consists. Plotted is the cumulative release (%) versus time (minutes). As a measure of the thickness of the coating is given for the individual batches, the percentage amount of coating material (polyvinyl acetate, triethyl citrate and talcum in the above-mentioned composition), based on the weight of the active ingredient-containing pellet cores.

3 Figure 12 shows the effect of press force on drug release from 12 mm diameter tablets weighing 884.2 mg containing 200 mg ADD 006. The tablets were each made using pellets having a pellet core with drug ADD 006. Applied to the pellet core were 40% by weight of a coating, based on the weight of the pellet cores, of polyvinyl acetate, triethyl citrate (10% by weight based on the weight of the polyvinyl acetate) and talc (10% by weight based on the weight of the polyvinyl acetate) Weight of the polyvinyl acetate) and a protective coating of hydroxypropylmethylcellulose and colloidal silica (2% by weight of protective coating, based on the weight of the pellets with the polyvinyl acetate coating). Shown is the cumulative release (%) plotted against time. The curves show the release from the pellets themselves as well as tablets made under different conditions.

The Measurement series A relates to tablets which have a compression pressure of 141 MPa were prepared and a hardness of 80 N and a disintegration time less than 1 minute. Measurement series B concerns tablets, which were manufactured with a pressure of 168 MPa and a Hardness of 125 N and a disintegration time of 1 to 2 minutes. The Measurement series C relates to tablets which have a compression pressure of 221 MPa were prepared and a hardness of 170 N and a disintegration time from 3 to 4 minutes.

4 Figure 12 shows the effect of press force on drug release from 12 mm diameter tablets weighing 884.2 mg containing 200 mg ADD 006. The tablets were each prepared using pellets having a pellet core with the active ingredient ADD 006. Applied to the pellet core was 40% by weight of a coating, based on the weight of the pellet cores, of polyvinyl acetate, triethyl citrate (7.5% by weight based on the weight of the polyvinyl acetate) and talc (10% by weight) on the weight of the polyvinyl acetate) and a protective coating of hydroxypropylmethylcellulose and colloidal silica (2% by weight of protective coating, based on the weight of the pellets with the polyvinyl acetate coating). Shown is the cumulative release (%) plotted against time. The curves show the release from the pellets themselves as well as tablets made under different conditions.

The Measurement series A relates to tablets which have a compression pressure of 180 MPa were prepared and a hardness of 80 N and a disintegration time less than 1 minute. Measurement series B concerns tablets, which were manufactured with a pressure of 240 MPa and a Hardness of 120 N and a disintegration time less than 1 minute have. The measurement series C relates to tablets made with a compacting pressure of 256 MPa were and a hardness of 160 N and have a disintegration time less than 1 minute.

5 shows a scanning electron micrograph (50X magnification) of an extrusion pellet with non-uniform shape and rough surface.

6 shows an electron micrograph (25X magnification) of pellets of the batch designation SFD E 0724, which do not meet the criteria for a pellet core with a smooth surface according to the invention.

7 illustrates data obtained by scanning with a laser profilometer which characterize the surface of a pellet of the batch designation SFD E 0724. It is 7A a graphical representation of the measurement results as surface graphics. In 7B the measurement results are shown as a contour line diagram. 7C shows a surface graphic based on a reduced data set. 7D shows the corresponding contour line diagram. 7E shows the distances of the measurement points of the reduced data set from the ideal surface determined by the least squares method.

8th illustrates data obtained by scanning with a laser profilometer which characterize the surface of another pellet of the batch designation SFD E 0724. It is 8A a graphical representation of the measurement results as surface graphics. In 8B the measurement results are shown as a contour line diagram. 8C shows a surface graphic based on a reduced data set. 8D shows the corresponding contour line diagram. 8E shows the distances of the measurement points of the reduced data set from the ideal surface determined by the least squares method.

9 shows an electron micrograph (25X magnification) of pellets of batch designation SFD E 0718, which do not meet the criteria for a pellet core with a smooth surface according to the invention.

10 illustrates data obtained by scanning with a laser profilometer, which characterize the surface of a pellet of the batch designation SFD E 0718. It is 10A a graphical representation of the measurement results as surface graphics. In 10B the measurement results are shown as a contour line diagram. 10C shows a surface graphic based on a reduced data set. 10D shows the corresponding contour line diagram. 10E shows the distances of the measurement points of the reduced data set from the ideal surface determined by the least squares method.

11 illustrates data obtained by scanning with a laser profilometer which characterize the surface of another pellet of the batch designation SFD E 0718. It is 11A a graphical representation of the measurement results as surface graphics. In 11B the measurement results are shown as a contour line diagram. 11C shows a surface graphic based on a reduced data set. 11D shows the corresponding contour line diagram. 11E shows the distances of the measurement points of the reduced data set from the ideal surface determined by the least squares method.

12 shows an electron micrograph (25X magnification) of pellets of batch designation SFD E 0572, which do not meet the criteria for a pellet core with a smooth surface according to the invention.

13 Figure 3 illustrates data obtained by scanning with a laser profilometer which characterize the surface of a pellet of batch designation SFD E 0572. It is 13A a graphic representation of the measurement results as surface graphics. In 13B the measurement results are shown as a contour line diagram. 13C shows a surface graphic based on a reduced data set. 13D shows the corresponding contour line diagram. 13E shows the distances of the measurement points of the reduced data set from the ideal surface determined by the least squares method.

14 shows an electron micrograph (25X magnification) of pellets of batch designation SFD E 0614 that do not meet the criteria for a pellet core with a smooth surface according to the invention.

15 illustrates data obtained by scanning with a laser profilometer which characterize the surface of a pellet of batch designation SFD E 0614. It is 15A a graphical representation of the measurement results as surface graphics. In 15B the measurement results are shown as a contour line diagram. 15C shows a surface graphic based on a reduced data set. 15D shows the corresponding contour line diagram. 15E shows the distances of the measurement points of the reduced data set from the ideal surface determined by the least squares method.

16 illustrates data obtained by scanning with a laser profilometer which characterize the surface of another pellet of batch designation SFD E 0614. It is 16A a graphical representation of the measurement results as surface graphics. In 16B the measurement results are shown as a contour line diagram. 16C shows a surface graphic based on a reduced data set. 16D shows the corresponding contour line diagram. 16E shows the distances of the measurement points of the reduced data set from the ideal surface determined by the least squares method.

Full Presentation of the invention

definitions

below some technical terms are explained in the description and the claims be used.

Of the Expression "core" of a pharmaceutical Pellets should be understood here so that the entire inner Part of the pellet underneath a coating containing the pH-independent drug release controls, is detected. The core can be homogeneous or an inner one Structure have. Examples include cores in which the active ingredient homogeneous in a carrier material is distributed; Cores in which the active ingredient together with a or more excipients is distributed in a carrier material; With an active substance layer coated seed cores, wherein the drug layer in addition to the active ingredient or one or more May contain adjuvants; and cores of the aforementioned Kind of, in addition one or more coatings under the release controlling coating have, for example, protective coatings or Separating layers of water-soluble Excipients, such as water-soluble Film formers.

When Active ingredients come inventively arbitrary biologically active substances, such as therapeutic and / or prophylactic effective substances, which can be administered orally.

Of the The core of a pharmaceutical pellet typically has a diameter in the range of 0.2 to 2 mm, in particular from 0.4 to 1.6 mm and especially from 0.4 to 1.4 mm.

One Pellet or a core is said to be spherical when the length-to-width ratio (i.e. The relationship the length (largest dimension) of the pellet or core divided by the width (smallest dimension), at an angle of 90 ° in Terms of length determined) is less than about 1.4.

Preferably is the length-to-width ratio of a spherical Particle 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.

According to the invention, the spherical active ingredient-containing core of the pharmaceutical pellet and typically also the pellet itself have a smooth surface. This means that the roughness of the surface does not exceed a certain limit. The roughness in turn describes the deviation of a real one Surface of an ideally smooth surface.

It has according to the invention proved to be useful, a suitable section of the surface of the pellet core or the Scanning pellets, especially with optical methods. From the results of such a scan can then be a numerical Value for the roughness is gained. More specifically, the surface profile becomes for one Section of the surface of the pellet core or of the pellet. The clipping should preferably so chosen be that he is representative for the surface of the particle is. Then a section of the surface will be measured 5 to 50%, especially 5 to 25%, especially 5 to 15% of the total surface of the pellet. For be this cutout from the surface Set measurement points that correspond to a raster. Points of the Rasters are typically between 2.5 and 50 μm, in particular between 12.5 and 50 μm separated from each other. The number of measuring points is typically in the range of 50 to 5000.

ermittelt. In der vorliegenden Anmeldung wird σ_d als "mittlere Rauheit" bezeichnet. Die mittlere Rauheit beträgt für einen glatten Pelletkern bzw. ein glattes Pellet typischerweise weniger als 10 μm und vorzugsweise weniger als 7,5 μm. Die relative mittlere Rauheit, d.h. die Rauheit dividiert durch den Kugelradius R, beträgt vorzugsweise weniger als 2 %, insbesondere weniger als 1,5 % und ganz besonders bevorzugt weniger als 1,2 %.The data obtained is then compared to an ideal surface. For this purpose, it is assumed that the measured surface area can be represented by a section of a spherical surface. This idealized spherical surface can be mathematically determined by calculating the section of a spherical surface which is optimally adapted to the experimentally determined topography. The function that is minimized is the mean square distance of the measured profile points from the sphere surface. The free parameters are the coordinates of the center point of the sphere (x _0s , y _0s , z _0s ) and the sphere radius R. The roughness can then finally be determined by the distances d _{i of} the measured profile points in the ideal sphere surface. This will be a mean square value

determined. In the present application, σ _{d is} referred to as "average roughness". The average roughness is typically less than 10 μm and preferably less than 7.5 μm for a smooth pellet core or a smooth pellet. The relative average roughness, ie the roughness divided by the sphere radius R, is preferably less than 2%, in particular less than 1.5% and most preferably less than 1.2%.

On the basis of the measurements described above, the smooth Texture of the surface a drug-containing core also described by other parameters become. One parameter is the maximum deviation, i. the maximum absolute distance of a profile point from the ideal smooth surface. This Value is preferably not more than 40 μm, in particular not more than 30 μm, even stronger preferably not more than 25 microns and most preferably not more than 20 microns.

For a spherical pellet let yourself also specify a maximum relative deviation. Below that is the maximum absolute deviation, divided by that in the context of Optimization determined spherical radius, to understand. Preferably is the maximum relative deviation is not more than 5%, in particular not more than 3%.

One preferred method for determining the roughness of a pellet is later Job described.

A pH-independent Drug release means that the drug release is not significantly varies when pellets of the invention exposed to pH media as they are found in various sections of the gastrointestinal tract become. These pH values are in the range of 1.0 to 8.0.

methods for the determination of drug release are in the USP (American Pharmacopoeia) and in PH. EUR. Are defined. On these methods will referred to here. In particular, a paddle apparatus is used. The stirring speed is 50 revolutions per minute. The temperature of the test medium is 37 ° C. As a test medium a phosphate buffer with a pH of 6.8 is used.

According to one Aspect of the invention, the drug release takes place with a particular profile. The profile has a lag phase, during which Lag phase a share of 5% by weight or less of the active ingredient is released. The lag phase takes 60 to 840 minutes, preferably 60 minutes to 540 minutes.

According to one aspect of the invention, after a lag phase, at least 80% by weight of the remaining active ingredient is released within 60 minutes, preferably within 30 minutes. According to a further aspect of the invention, the release of the active ingredient after a lag phase is between 3 and 25 wt .-% per hour, preferably between 3 and 15 wt .-% per hour and in particular between 3 and 6.5 wt .-% per hour.

preferred Embodiments - pellets

Inventive pharmaceutical Pellets have a core containing one or more active ingredients contains. Preference is given to active substances with high water solubility. Further preferred are water-soluble Salts of heavy water soluble Agents. An example of this is ADD 006 with a water solubility of about 210 mg / ml at 25 ° C.

Of the Core contains furthermore typically one or more binders. Prefers are water-soluble Binder. This includes Calcium carboxymethyl cellulose, acrylic acid based polymers (Carbopol), gelatin, hydroxyethylcellulose, hydroxypropylcellulose, Hydroxypropylmethylcellulose, polyethylene glycol (macrogol), methylcellulose, Sodium carboxymethyl cellulose, 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 suitable form, for example as Kollidon 30.

Of the Core can also excipients or fillers contain. For example, carbohydrates are suitable. As examples can water-soluble Called carbohydrates, such as dextran, dextrin, dextrose (glucose), Fructose, lactose, maltodextrin, mannitol, sucrose, sorbitol and xylitol. Another example of a carrier or filler is microcrystalline cellulose.

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 Preservatives, physical stabilizers and chemical Stabilizers, such as acidic, basic or buffering components. Furthermore, wetting agents and solver be included. The cores can also entail osmotically active substances. This is special for active ingredients which are only slightly soluble in water. Here can one osmotically active substance to serve as an entraining agent. Among the optional Components include also anti-adhesive.

Of the Pellet core may be coated with a protective layer. Preferred materials are water-soluble Polymers, in particular hydroxypropylmethylcellulose.

According to the invention, the pellet cores which are provided with the coating which controls the release of active substance should be as round as possible and as smooth as possible. In order to be able to check the quality of pellet cores or pellets, therefore, an upper limit for the roughness is set. In order to determine the roughness of a pellet, the surface profile of a suitably selected cutout is recorded, preferably non-contact with optical methods, for example using an auto-focusing laser profilometer, such as a UBM laser profilometer. Its operation can be described as follows:
A laser beam is imaged onto the surface of the structure to be measured (section of the surface of a pellet core or pellet) via an optical system. The sensor head consists of a lens system and two photodetectors arranged symmetrically with respect to its optical axis. At the height of the focal point of the lens system, a diaphragm is attached, which cuts the image of the laser beam on one side. If the sample is in the focus of the sensor, the laser beam reflected at the sample is focused in the area of the diaphragm and not trimmed. In this case, both detectors measure the same intensity. If the sample is outside the focus range, no sharp image of the laser beam is generated. Rather, there is a broader intensity distribution in the region of the diaphragm, which is trimmed by the latter. As a result, the detectors measure different intensities. To measure the height difference Δh, the sensor head is moved vertically until the sample is in focus again and both detectors measure the same intensity. The vertical displacement of the sensor, which is done via magnetic control elements, then returns the height difference. While the sensor head continuously measures the height of the sample, it is moved over motorized xy tables under the sensor head. The lateral resolution of the profilometer is 0.5 .mu.m, which is essentially determined by the beam diameter. The vertical accuracy is specified by the manufacturer as 100 nm.

The section to be measured from the surface is determined so that typical profile structures are detected. For example, in the case of a spherical pellet having a radius between 400 and 600 μm, a surface area of 600 μm × 600 μm can be scanned. The scanning is done in thirteen paral Lelen line scans at intervals of 50 microns. For each line scan, sampling occurs at intervals of 2.5 μm, resulting in a total of 241 points per line scan.

The Mathematical evaluation of the data is typically done with a Data reduction connected. While the beginning of the line scan, the optical instrument must first a Focusing on the surface to reach. The first measurements are therefore uncertain afflicted. Therefore, the first fifteen measurement points become each line scan excluded from the analysis. Occasionally on the first line scans no convergence of the focusing procedure is achieved, which is his Cause may be that start point or end point of the line scan outside the perimeter of the spherical one Particles, such line scans will be taken from the analysis locked out. Similar Focusing problems occasionally occur in the last line scans which are also excluded from the analysis.

The Data of the line scan are thinned by a factor of 5, which to a reduction of 241-15 Measuring points per line to typically 45 measuring points per line leads. Experimentally, it has been shown that this is not significant Loss of a surface profile structure leads, since typical profile structures extend over 50 to 100 microns.

As previously stated, a section from an ideal spherical surface is then fitted to the reduced set of data points by the least squares method. Deviations from the ideal surface are used as a measure of the roughness. For this purpose, an average roughness σ _d can be defined.

This texture parameter corresponds to the usual definition of the mean square roughness R _RMS used widely for planar textured surfaces. In addition, a relative mean square roughness is defined, which can be calculated from the average roughness σ _d defined above and the spherical radius R according to σ _d / R. The relative mean square roughness is also given in percent in the present application (σ _d / R × 100%).

pellet cores with a smooth surface, as described above are provided according to the invention with a coating, the pH independent controls the drug release.

The coatings for pH-independent drug release preferably contain a polymer which is under ammonium methacrylate copolymer, Cellulose acetate butyrate, cellulose acetate, cellulose acetate propionate, ethylcellulose, Poly (ethyl acrylate-methyl acrylate) and polyvinyl acetate is selected. Particularly preferred is polyvinyl acetate. When using such Film former can release the drug from the pellets the layer thickness of the applied film and by selecting appropriate additional Auxiliary substances (in particular pore formers) are modified.

Corresponding can the coating to control the pH independent Release of active substances Pore images, in particular water-soluble polymers or other water-soluble Links.

The coating for Control of the pH independent Drug release may also contain plasticizers. These include acetyltributyl citrate, Triacetin, acetylated monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl triethyl citrate, glycerol sorbitol, Diethyl oxalate, diethyl malate, diethyl fumarate, dibutylsucchinate, diethyl malonate, dioctyl stalate, Dibutyl sebacate, diethyl citrate, tributyl citrate, glycerol, tributyrate, Polyethylene glycol, propylene glycol and mixtures thereof.

In the coating may also contain a release agent. An example of this is talc.

The pellets according to the invention can also have an outer protective cover. Preferred materials for it are water-soluble Polymers, in particular hydroxypropylmethylcellulose.

Under Use of the pellets according to the invention can multiparticulate Dosage forms are provided. For example, the Pellets filled in capsules become. From the pellets can but also tablets are produced.

preferred Embodiments - Manufacturing Method

Production processes are also provided according to the invention. These include procedures for Production of pellet cores and methods for coating pellet cores, but the invention is not limited to a particular method of preparation.

One Process for the production of pellet cores is fluidized bed agglomeration. The granulation can be carried out without seed cores. It can thereby Pellet cores with a comparatively high proportion of active ingredient getting produced. For example, pellet cores can be made which are 80 parts by weight or more, preferably 90 parts by weight or more, of active ingredient and also a binder. With the help of a classifier, with the continuous pellet cores taken from the process leaves a very narrow particle size distribution achieve. For example, a pellet core product can be obtained in which 95 wt.% Or more, preferably 99 wt.% Or more, of the pellet cores a size between 100 and 300 μm or between 200 and 300 μm exhibit.

to execution the process becomes a liquid, preferably aqueous solution or dispersion with an active ingredient and optionally one or more Excipients, such as a binder, at the beginning of the process of sprayed below in an empty fluidized bed plant. Through the spray granulation Start cores form for the pelleting. Reach by addition of additional material the cores finally such a size, that she over exit a sifter from the system.

Suitable devices for performing fluidized-bed agglomeration are disclosed in U.S. Pat EP 163 836 B1 . EP 332 031 B1 as in EP 332 929 B1 described.

One Another method for producing pellet cores comprises the Provision of seed cores and the subsequent application of an active substance layer (Layering). An active substance, possibly together with other ingredients, is applied to cores. This can be done in a fluidized bed pad take place, wherein a powdered Material and a liquid, which allows binding of the powder constituents to the cores. The powder may be an active ingredient or a mixture from an active ingredient and one or more excipients. At the liquid it may be water or an organic solvent; the liquid can also be a solution or dispersion.

Prefers is also a process for the preparation of active ingredient-containing pellet cores, in the starter cores, for example in a fluidized bed apparatus, with a solution or dispersion containing an active ingredient and optionally one or more Contains excipients coated become.

The above-described preparation of pellet cores by application An active ingredient layer on seed cores is preferably carried out in one Fluidized bed apparatus with Wurster insert (according to the Wurster method).

One Another method for the production of pellet cores comprises in one first stage, the provision of a starting material powder. The Feedstock powder comprises a carrier. The starting material powder is preferably a treatment, for example in a shear mixer, subjected to destroy aggregates. For the starting material powder it can also be a mixture of a carrier and one or more other ingredients of the pellet cores to be produced, for example Binders, act. In this case, the deployment includes of the starting material powder typically mixing the components.

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 been in the production of pellet cores with a size of 300 proven to 500 microns, a Starting material powder, in particular a carrier to use, in which the sieve residue at a Siebmaschenweite of 160 microns less than 10 wt .-% and in particular less than 5 wt .-% is. Farther Preference is given to starting material powders, in particular powders of one support where 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 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 pelletizing step, or a different one altogether act diluents act. 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 achieve a wetted source powder, with 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.

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

In the pelleting stage are from the optionally pre-moistened Starting material with the addition of a pharmaceutically acceptable liquid diluent Shaped pellets. For the nature of the diluent The same criteria apply as those used for pre-moistening Diluent.

The thinner may contain an active substance.

It is possible, too, powdery Ingredients, such as powdered drug, during pelleting supply, if a homogeneous mixing is given by the process control is. Since the pellets of the invention contain an active ingredient, this must either contain powder in the starting material be or during pelleting as a component of the diluent or in powder form supplied become. Combinations of these measures are also possible.

• (a) Bereitstellung eines Ausgangsmaterialpulvers, das einen 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 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 apparatus for carrying out the first method for the production of pellet cores is in DE 197 50 042 A1 described.

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.

The after all obtained pellet cores are dried.

Preferably, it is checked whether the produced pellet cores meet the requirements of the invention In particular, it is checked whether a pellet core product according to the invention is present. That is, preferably, the pellets of the obtained pellet core product composed of a collective or a plurality of pellet cores are predominantly spherical and have smooth surfaces. Preferably, at least 90% of the pellet cores of a pellet core product meet the requirements of the invention in terms of spherical shape and smooth surface.

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, in the claims and are laid down in the description.

The Pellet cores obtained by one of the above methods may possibly provided according to known methods with one or more coatings become. These include coatings of water-soluble Film formers.

The Pellet cores - with or without a coating, like a coating from a water-soluble Film former, are coated with a polymer for pH-independent drug release.

According to the invention may also tablets be prepared by adding pharmaceutical pellets, if necessary together with excipients, to be pressed. It is possible according to the invention, tablets to obtain, comparing the release curve of the drug in comparison is shifted parallel to the release curve from the pellets. With In other words, the lag phase that occurs when released from the Tablets occurs, opposite the lag phase that occurs when released from the pellets, shortened, while the steepness of the release curve remains essentially unchanged. The release behavior can be measured, as described above has been described.

The following Preparations, Examples and Test Examples explain The invention. The active ingredient is ADD 006, whose Water at 25 ° C about 210 mg / ml.

Production Example 1

The Example relates to the preparation of ADD 006 containing pellets.

The following starting materials are used to prepare pellet cores with the active ingredient ADD 006: Sugar spheres 300 g Syloid 244 FP (Precipitated Silica) 45 g ADD 006 1200 g Demineralized water 2757 g

One Proportion of demineralized water (2457 g) is heated to approximately 60 ° C. The ADD 006 is heated in the Water dissolved. The silica (Syloid 244 FP) is in a further proportion of demineralised water (300 g) with a ten homogenizer Minutes suspended. Subsequently the silica dispersion is poured into the drug solution. The resulting mixture (coating dispersion) becomes with stirring at a temperature of about Kept at 50 ° C.

To coat the starter cores are placed in a fluidized bed coater (Smooth GPCG I). Subsequently, the coating dispersion with a spray rate sprayed from the beginning 6 g / min. The spray rate will follow increased to 8 to 10 g / min. The intake air temperature is while of coating about 55 ° C.

After the coating dispersion is sprayed on, the cores obtained are used in the apparatus for dried at an inlet air temperature of about 60 ° C for ten minutes. Subsequently, the cores are removed and dried overnight at 45 ° C.

On the manner described above can ADD 006 cores with a Active ingredient content of 77.67 wt .-% can be obtained.

The obtained active ingredient-containing cores can be provided with a coating which controls pH-independent drug release. A suitable coating material is polyvinyl acetate. The example approach is based on the following starting materials: ADD 006 cores (as described above) 300.00 g Kollicoat SR 30 D (polyvinyl acetate dispersion) 277.78 g (solids content: 83.33 g) Avicel PH 105 (microcrystalline cellulose) 5.00 g triethylcitrate 8.33 g talc 8.33 g Demineralized water 280.00 g

to Preparation of the coating dispersion will be first the microcrystalline cellulose in the demineralized water dispersed using a homogenizer and for five minutes touched. Then, triethyl citrate and talc are added to the dispersion and the dispersion is again for Homogenized for ten minutes. The polyvinyl acetate dispersion is sieved and stirred slowly mixed with the excipient dispersion obtained above. The resulting coating dispersion is for stirred for an hour, before starting to reinforce the cores.

The Applying the coating takes place in a fluidized bed coater (Glatt GPCG I). The active ingredient-containing cores are heated to about 30 ° C. Subsequently, will the coating dispersion with a spray rate of about 7 to 8 g / min sprayed. The intake air temperature is at about 35 ° C.

Under the same conditions as above, a first outer pellet phase is subsequently applied first. The following auxiliaries are used in the following amounts: Syloid 244 FP (precipitated silica) 7.03 g Pharmacoat 603 (hydroxypropyl methylcellulose) 1.07 g Demineralized water 50.81 g

Hydroxypropylmethylcellulose is dissolved in the water and then the silica is added portionwise with stirring. After applying this dispersion to the coated pellets, the pellets are removed from the fluidized bed apparatus. They are then added with the following components as the second outer pellet phase: Syloid 244 FP (precipitated silica) 4.13 g talc 4.13 g

The Pellets added with these excipients will be left for five minutes mixed in a diffusion mixer (Turbula T2C). The obtained Product is over Night in a ventilated Oven at 60 ° C dried.

Production Example 2

The Example relates to the preparation of ADD 006 containing pellets as well as the further processing of the pellets into tablets.

The production of pellet cores with the active ingredient ADD 006 is carried out in the same manner as in Preparation Example 1. For a preparation with a dose strength of 200 mg ADD 006 starting materials are used in the following proportions: Sugar spheres NF (starter cores) 50,000 mg ADD 006 200,000 mg Colloidal silica 7,500 mg Subtotal 257.500 mg

The active substance-containing pellet cores are provided with a coating for controlled release. Thus, two different formulations are examined. The proportions in the first formulation, based on 257,500 mg of active ingredient-containing cores, are as follows: Polyvinyl acetate dispersion, solids 75.100 mg Talcum (10%) 7,500 mg Triethyl citrate (10%) 7,500 mg Subtotal 90.100 mg

In the second formulation for the controlled release coating, a minor amount of plasticizer (triethyl citrate) is used. The proportions of the formulation, based on 257,500 mg pellets containing the active ingredient, are as follows: Polyvinyl acetate dispersion, solids 76.700 mg Talcum (10%) 7,700 mg Triethyl citrate (7.5%) 5,800 mg Subtotal 90.100 mg

On the basis of the formulations, coated pellets are prepared as described in Preparation Example 1. A protective coating (2%) is then applied to the pellets. The proportions of the components of this protective coating are as follows: hydroxypropyl methylcellulose 3,500 mg Colloidal silica 3,500 mg Subtotal 7,000 mg

The resulting pellets are then used to prepare tablets. The tabletting phase contains the following proportions of excipients: Microcrystalline cellulose 105.9 mg lactose 337.3 mg corn starch 53.0 mg crospovidone 26.5 mg Colloidal silica 1.6 mg magnesium stearate 5.3 mg Subtotal 529.6 mg

The with the drug release controlling coating and the protective coating Pellets are mixed with said excipients and made into tablets pressed. There will be tablets with a weight of 884,200 mg obtained containing 200,000 mg ADD 006.

On appropriate way can also tablets of other dose strengths to be obtained.

example 1

The Example relates to the investigation of the release behavior of products according to the invention. In particular, it is clarified that the release profile lets set, by pellet cores according to the invention provided with coatings which control the release, whereby the composition of the coatings varies becomes.

The Release was in each case carried out with a paddle apparatus (USP / PH. EUR.) at a stirring speed of 50 revolutions per minute in phosphate buffer pH 6.8 as a test medium at a temperature of 37 ° C certainly.

First, pellets were prepared with the active ingredient ADD 006, as described in Preparation Examples 1 and 2. These pellets were then coated to control release. For this purpose, a polyvinyl acetate dispersion containing talc (10 wt .-%) and triethyl citrate (10 wt .-%) was used. The thickness of the coating was varied by using different amounts of coating dispersion with polyvinyl acetate and 10% by weight of talc and 10% by weight of triethyl citrate, based in each case on the amount of polyvinyl acetate solid. These amounts were in the individual experiments, based on the active substance-containing pellet cores, 30 wt .-%, 32.5 wt .-%, 35 wt .-%, 37.5 wt .-% and 40 wt .-%. pellets with a coating of 40% by weight of the above polyvinyl acetate composition was further provided with 2% by weight of a hydroxypropylmethylcellulose-colloidal silica coating, the latter being by weight of the weight of solid constituents of the protective coating, based on the weight of the Pellets with the polyvinyl acetate coating, calculated.

Samples of the individual batches were then subjected to release tests in each case. The results are in 1 shown.

Example 2

The Example relates to the investigation of the release behavior of products according to the invention. In particular, it is clarified that the release profile lets set, by pellet cores according to the invention provided with coatings which control the release, whereby the composition of the coatings varies becomes.

At first were Pellets prepared with the active ingredient ADD 006, as described in Preparation Examples 1 and 2 has been described. These pellets were then used for control covered by the release. This was a polyvinyl acetate dispersion containing talc (10% by weight) and triethyl citrate (7.5% by weight) used. The thickness of the coating was varied by varying amounts of coating dispersion with polyvinyl acetate and 10 wt .-% talc and 7.5 wt .-% triethyl citrate, each based on the amount of polyvinyl acetate solid, were used. These Quantities were in the individual experiments, based on the drug-containing Pellet cores, 30 wt .-%, 32.5 wt .-%, 35 wt .-%, 37.5 wt .-% and 40% by weight. Pellets with a coating of 40% by weight of the above polyvinyl acetate composition also with 2% by weight of a coating of hydroxypropylmethylcellulose and colloidal silica provided, wherein the latter percentage by weight from the weight the solid constituents of the protective coating, based on the weight the pellets with the polyvinyl acetate coating, calculated.

Samples of the individual batches were then subjected to release tests in each case. The release tests were carried out as described in Example 1. The results are in 2 shown.

Example 3

The Example relates to the investigation of the release behavior of products according to the invention. In particular, the example illustrates the influence of tabletting on the release behavior.

First, pellets were prepared with the active ingredient ADD 006, as described in Preparation Examples 1 and 2. These pellets were then coated to control release. For this purpose, a polyvinyl acetate dispersion containing talc (10 wt .-%) and triethyl citrate (10 wt .-%) was used. The pellets were coated with an amount of 40% by weight of coating dispersion, the percentage by weight being based on the solids content of the coating (polyvinyl acetate, talc and triethyl citrate), based on the weight of the pellet cores. The pellets were then provided with 2% by weight of a hydroxypropylmethylcellulose-colloidal silica coating, the latter percentage by weight being calculated from the weight of the solid components of the protective coating, based on the weight of the polyvinyl acetate-coating pellets. The release behavior of these pellets is in 3 shown.

Pellets were also made from the pellets. The release behavior of the tablets was also investigated, as described in Example 1, and is in 3 shown.

Example 4

The Example relates to the investigation of the release behavior of products according to the invention. In particular, the example illustrates the influence of tabletting on the release behavior.

First, pellets were prepared with the active ingredient ADD 006, as described in Preparation Examples 1 and 2. These pellets were then coated to control release. For this purpose, a polyvinyl acetate dispersion with a content of talc (10 wt .-%) and triethyl citrate (7.5 wt .-%) was used. The pellets were coated with an amount of 40% by weight of coating dispersion, the percentage by weight being based on the solids content of the coating (polyvinyl acetate, talc and triethyl citrate), based on the weight of the pellet cores. The pellets were then provided with 2% by weight of a hydroxypropylmethyl cellulose and colloidal silica coating, the latter weight percent Tangabe from the weight of the solid components of the protective coating, based on the weight of the pellets with the polyvinyl acetate coating, calculated. The release behavior of these pellets is in 4 shown.

Pellets were also made from the pellets. The release behavior of the tablets was also investigated, as described in Example 1, and is in 4 shown.

test Examples

The The following examples concern the investigation of pellet cores for determining the surface roughness.

Test Example 1

Pellets of the batch designation SFD E 0724 were investigated. An electron micrograph of pellets of this type is in 6 shown. A section of the surface of a pellet of this batch was scanned with a laser profilometer as described above. A graphical representation of the measurement results is in 7A as surface graphics and in 7B shown as a contour line diagram. To calculate the roughness, a reduced data set was used as described above. A surface graphic based on the reduced data set is in 7C shown the corresponding contour line in 7D ,

Using the method of least squares, a sphere was determined which optimally reproduces the measurement points of the reduced set. The center coordinates of this sphere became 385 μm; Determined 324 microns and -293 microns. The optimum radius R was 516 μm. The distribution of the data after the adaptation is in 7E shown. In this figure, the horizontal axis indicates the measured data points. The vertical axis denotes the distance of the measured profile points from the surface of the ideal sphere with the center coordinates and the radius as indicated above. The data points are evenly distributed above and below the horizontal axis.

The statistical analysis of the data shows that the average roughness σ _d is 13.6 μm and that the relative mean roughness σ _d / R is 2.64%. The absolute roughness has a value of more than 50 μm. The investigated pellet core thus does not fulfill the criteria according to the invention for a pellet core with a smooth surface.

Test Example 2

Another pellet from the same lot already mentioned in Test Example 1 was tested in the same manner as described above. A graphical representation of the measurement results is in 8A as surface graphics and in 8B shown as a contour line diagram. The reduced data set used to calculate the roughness is the basis of the surface graph that is used in 8C is shown, as well as the contour line diagram which is shown in FIG 8D is shown.

Using the method of least squares, a sphere was determined which optimally reproduces the measurement points of the reduced set. The center coordinates of this sphere became 434 μm; 336 μm and -841 μm. The optimum radius R was 983 μm. The distribution of the data after the adaptation is in 8E shown. The statistical analysis of the data shows that the mean roughness σ _d is 15.9 μm and that the relative mean roughness σ _d / R is 1.62%. The absolute roughness has a value of more than 50 μm. The investigated pellet core thus does not fulfill the criteria according to the invention for a pellet core with a smooth surface.

Test Example 3

Pellets of the batch designation SFD E 0718 were investigated. An electron micrograph of pellets of this type is in 9 shown. A section of the surface of a pellet of this batch was scanned with a laser profilometer as described above. A graphical representation of the measurement results is in 10A as surface graphics and in 10B shown as a contour line diagram. To calculate the roughness, a reduced data set was used as described above. A surface graphic based on the reduced data set is in 10C shown, and the corresponding contour line is in 10D shown.

Using the method of least squares, a sphere was determined which optimally reproduces the measurement points of the reduced set. The center coordinates of this sphere became 391 μm; 337 μm and -680 μm. The optimum radius R was 713 μm. The distribution of the data after the adaptation is in 10E shown. The statistical analysis of the data shows that the average roughness σ _{d has} the value 10.7 μm and that the relative mean roughness σ _d / R has the value 1.5%. The absolute roughness has a value of about 50 μm. The investigated pellet core thus does not fulfill the criteria according to the invention for a pellet core with a smooth surface.

Test Example 4

Another pellet from the same lot already mentioned in Test Example 3 was tested in the same manner as described above. A graphical representation of the measurement results is in 11A as surface graphics and in 11B shown as a contour line diagram. The reduced data set used to calculate the roughness is the basis of the surface graph that is used in 11C is shown, as well as the contour line diagram which is shown in FIG 11D is shown.

Using the method of least squares, a sphere was determined which optimally reproduces the measurement points of the reduced set. The center coordinates of this sphere became 309 μm; 297 microns and -656 microns determined. The optimum radius R was 804 μm. The distribution of the data after the adaptation is in 11E shown. The statistical analysis of the data shows that the average roughness σ _d is 14.31 μm and that the relative mean roughness σ _d / R is 1.78%. The absolute roughness has a value of 45 μm. The investigated pellet core thus does not fulfill the inventive criteria of the pellet core with a smooth surface.

Test Example 5

Pellets of batch designation SFD E 0572 were investigated. An electron micrograph of pellets of this type is in 12 shown. A section of the surface of a pellet of this batch was scanned with a laser profilometer as described above. A graphical representation of the measurement results is in 13A as surface graphics and in 13B shown as a contour line diagram. To calculate the roughness, a reduced data set was used as described above. A surface graphic based on the reduced data set is in 13C shown, and the corresponding contour line is in 13D shown.

Using the method of least squares, a sphere was determined which optimally reproduces the measurement points of the reduced set. The center coordinates of this sphere became 349 μm; 315 microns and -369 microns determined. The optimum radius R was 595 μm. The distribution of the data after the adaptation is in 13E shown. The statistical analysis of the data shows that the average roughness σ _{d has} the value 5.5 μm and that the relative mean roughness σ _d / R has the value 0.92%. The absolute roughness has a value of 17 μm. The investigated pellet core thus fulfills the criteria according to the invention for a pellet core with a smooth surface.

Test Example 6

Pellets of the batch designation SFD E 0614 were investigated. An electron micrograph of pellets of this type is in 14 shown. A section of the surface of a pellet of this batch was scanned with a laser profilometer as described above. A graphical representation of the measurement results is in 15A as surface graphics and in 15B shown as a contour line diagram. To calculate the roughness, a reduced data set was used as described above. A surface graphic based on the reduced data set is in 15C shown, and the corresponding contour line is in 15D shown.

Using the method of least squares, a sphere was determined which optimally reproduces the measurement points of the reduced set. The center coordinates of this sphere became 293 μm; 919 microns and -358 microns determined. The optimum radius R was 677 μm. The distribution of the data after the adaptation is in 15E shown. The statistical analysis of the data shows that the average roughness σ _d is 7.1 μm and that the relative mean roughness σ _d / R is 1.06%. The absolute roughness has a value of 19 μm. The investigated pellet core thus fulfills the criteria according to the invention for a pellet core with a smooth surface.

Test Example 7

Another pellet from the same lot already mentioned in Test Example 6 was tested in the same manner as described above. A graphical representation of the measurement results is in 16A as surface graphics and in 16B shown as a contour line diagram. The reduced data set used to calculate the roughness is the basis of the surface graph that is used in 16C is shown, as well as the contour line diagram which is shown in FIG 16D is shown.

Using the method of least squares, a sphere was determined which optimally reproduces the measurement points of the reduced set. The center coordinates of this sphere became 272 μm; 200 microns and -491 microns determined. The optimum radius R was 652 μm. The distribution of the data after the adaptation is in 16E shown. The statistical analysis of the data shows that the average roughness σ _{d has} the value 8.2 μm and that the relative mean roughness σ _d / R has the value 1.26%. The absolute roughness has a value of 30 μm. The investigated pellet core thus fulfills the criteria according to the invention for a pellet core with a smooth surface.

Claims (23)

A pharmaceutical pellet comprising a spherical drug-containing Core with smooth surface and a coating on the nucleus, which is pH independent controls the drug release. A pellet according to claim 1, wherein the core has 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 1.05 having. A pellet according to claim 1 or 2, wherein the core has a Diameter in the range of 0.2 to 2 mm, in particular from 0.4 to 1.6 mm and especially from 0.4 to 1.4 mm. Pellet according to one of the preceding claims, wherein the core has an average roughness of less than 10 μm, and preferably less than 7.5 μm having. Pellet according to one of the preceding claims, wherein the core has a relative mean roughness of less than 2%. Pellet according to one of the preceding claims, wherein the coating contains a polymer, that under ammonium methacrylate copolymer, cellulose acetate butyrate, Cellulose acetate, cellulose acetate propionate, ethylcellulose, poly (ethylacrylate-methylacrylate) and polyvinyl acetate is. Pellet according to one of the preceding claims, wherein additionally an outer protective cover provided that is a water-soluble one Film former, preferably hydroxypropylmethyl cellulose contains. Pellet according to one of the preceding claims, wherein between the active ingredient-containing core and the coating, the drug release controls, an intermediate layer is provided which contains a water-soluble film former, preferably hydroxypropylmethylcellulose. Pellet according to one of the preceding claims, wherein the core is made up of an active agent-free starter core and a drug-containing layer thereon, wherein the starter core preferably contains one or more carbohydrates and in particular under sugar globules and globules is selected from microcrystalline cellulose. A pellet according to claim 9, wherein the active ingredient Layer 50% or more, preferably 70% or more, of active ingredient contains. A pellet according to any one of claims 1 to 8, wherein the core contains the active substance in a homogeneous distribution. A pellet according to claim 11 wherein the core is adjacent to Active ingredient a carrier and / or a binder. Pellet according to one of the preceding claims, wherein it is the active ingredient is a water-soluble drug or a water-soluble Salt of a sparingly soluble Active ingredient acts. Pellet according to one of the preceding claims, wherein the release of the drug in a profile with a lag phase from 60 minutes to 840 minutes, preferably from 60 minutes to 540 minutes, follows while the lag phase Share of 5 wt .-% or less of the active ingredient is released. Pellet according to one of claims 1 to 14, wherein after a Lag phase within 60 minutes at least 80 wt .-% of the still remaining active ingredient are released. Pellet according to one of claims 1 to 14, wherein the active ingredient is released from the pellet with a profile, such that after a lag phase, the release of the drug between 3 and 25 % By weight per hour, preferably between 3 and 15% by weight per hour, in particular between 3 and 6.5% by weight per hour. Collective of pellets, where at least 90% of the Definition according to a correspond to the preceding claims. A collective according to claim 17, wherein the pellets comprise a such particle size distribution show that 90% of the pellets have a diameter of mean diameter by no more than half the mean diameter differs. Collective of nuclei, whereby at least 90% of the Requirements for the cores according to a the claims 2 to 5 meet. Process for the preparation of a pellet after a of the preceding claims 1 to 16, the method comprising the steps of: (A) Provision of an active substance-containing pellet core with a length-to-width ratio of less than about 1.4 and a mean roughness of less than 10 μm and / or a relative mean roughness of less than 2%; (B) spray on an aqueous or organic solution or dispersion containing a film former that releases the drug pH-independent controls. Process for the preparation of a tablet, the following Steps includes: (a) Mixing pellets according to any one of claims 1 to 7 with one or more constituents selected from fillers, binders, disintegrants, flow regulators and lubricants to form a mixture; and (b) pressing of the mixture to form a tablet. The method of claim 21, wherein during the Stage of compression a portion of the pellets is destroyed so the release of the drug from the tablet does not lag the phase shows. Tablet producible by a method according to claims 21 or 22.