BG62473B1 - Pharmaceutical preparation with monitored release - Google Patents

Abstract

The preparation is used in medicine as a pain killer for 12to 24 hours in a one or two daily doses, the single dose beingfrom 50 to 400 mg. It has monitored control and in the form of atablet or a capsule it contains spheroids and active substance:tranadol, built in a matrix or applied as a coating on thespheroid. The matrix has supervied (controlled) release andcontains, in wt.%, cellulose ether from 1 to 80 and aliphaticalcohols C12-C16 up to 60. The invention also relates to apharmaceutical preparation with monitored (controlled) release inthe form of a tablet or a capsule containing particles with sizesfrom 0.01 to 3.0 mm and tramadol as active component or its saltfrom 50 to 800 mg, included in a matrix. The matrix consists ofmeltable material selected from hydrogenerated vegetable oil,hydrogenerated beaver fat, microcrystalline wax, bee wax, carnubawax and glycerol monostereate, the quantity of the tramadol isfrom 10 to 90 wt.%.15 claims

Description

The invention relates to a controlled release pharmaceutical preparation, to a method for its preparation and its medical use. In particular, the invention relates to a controlled-release preparation comprising tramadol or a pharmaceutically acceptable salt thereof.

Tramadol, which has the chemical name (+) - trans-2 - / (dimethylamino) methyl / -1 (3-methoxyphenyl) -cyclohexanol, is an orally active opioid analgesic.

Conventional release preparations in the form of capsules, drops and suppositories containing tramadol, in particular its hydrochloride salt, are used for the treatment of moderate and severe pain. However, these preparations do not provide a controlled release of tramadol. Moreover, despite the long use of tramadol, no controlled-release preparations for oral administration containing tramadol as the active ingredient have been described anywhere in the literature.

It is an object of the invention to provide a controlled-release tramadol pharmaceutical formulation for oral administration suitable for at least twelve hours (e.g., up to 24 hours) of pain management.

According to the invention, a controlled release formulation comprising tramadol or a pharmaceutically acceptable salt thereof for oral administration has been devised.

Suitable pharmaceutically acceptable salts of tramadol for use according to the invention are those known in the art as pharmaceutically acceptable salts with acid impurities. The hydrochloride salt is particularly preferred.

The pharmaceutical composition of the invention is in unit dosage form, comprising a tablet or capsule containing spheroids and an active ingredient that is embedded in a matrix or coated on a spheroid. The preparation is suitable for dosing twice or once a day to provide pain relief for 12 or 24 hours, characterized in that the active ingredient is tramadol or a pharmaceutically acceptable salt thereof, the unit dosage form containing from 50 to 400 mg of active ingredient, calculated as tramadol hydrochloride, the matrix is a controlled release matrix comprising a cellulose ether of 1 to 80 wt. % of the preparation and from 0 to 60 wt. % of one or more C ₁₂ -C ₃₆ aliphatic alcohols relative to the final preparation. The spheroid is in the form of a normal-release matrix containing the active ingredient or an inert core having a coating containing the active ingredient and coated with a controlled-release outer coating containing water-insoluble cellulose, water-soluble hydroxyalkylcellulose or acrylic polymer.

It is appropriate tsululozniyat ether is C, -C ₆ alkyl cellulose, and most preferably Cj-C ₆ alkylcellulose is ethylcellulose.

In one embodiment, the pharmaceutical composition comprises from 1 to 20% of one or more alkyl celluloses.

In another embodiment, the formulation contains from 5 to 30% by weight. % of C ₈ -C ₅₀ fatty alcohol, the fatty alcohol being suitably selected from lauryl alcohol, myristyl alcohol and stearyl alcohol.

In another embodiment of the pharmaceutical preparation, the spheroids are coated with an exterior controlled release of ethyl cellulose.

For this embodiment, it is appropriate to coat the active ingredient as a coating on inert grains, with drug containing beads coated with a controlled release outer coating.

The invention also relates to a method of preparing a pharmaceutical preparation in tablet form, which comprises the following steps:

a) granulating a mixture containing tramadol or a pharmaceutically acceptable salt thereof, in an amount corresponding to 50 to 400 mg for each final unit dosage form, with one or more C ₍ -C ₆ alkyl celluloses in an amount corresponding to 1 to 80 wt. % of the final preparation;

b) mixing alkylcellulose containing granules with 0 to 60 wt. %, based on the final preparation, with one or more C ₁₂ -C ₃₆ aliphatic alcohols, and c) forming and compressing the granules obtained to form tablets, each containing from 50 to 400 mg of active ingredient.

The invention also relates to a method for the preparation of a pharmaceutical composition which comprises granulating a mixture comprising tramadol or a pharmaceutically acceptable salt thereof in an amount corresponding to 50 to 400 mg of each final unit dosage form, lactose and one or more alkyl celluloses in an amount corresponding to 1 to 80 wt. % by weight of the final preparation, from 0 to 60 wt. % based on the final preparation of one or more C ₂₃ -C ₃₆ aliphatic alcohols, and then shaping and compressing the granules to form tablets, each containing from 50 to 400 mg of the active ingredient.

The unit dosage form of the invention includes a tablet or capsule containing a plurality of particles ranging in size from 0.1 to 3.0 mm, the preparation also comprising an active ingredient which is included in a matrix of pharmaceutically acceptable excipients, that the active ingredient is tramadol or a pharmaceutically acceptable salt thereof, the unit dosage form containing between 50 and 800 mg of tramadol (calculated as tramadol hydrochloride), and the matrix consists essentially of a hydrophobic soluble material selected from idrogenirano vegetable oil, hydrogenated castor oil, microcrystalline wax, beeswax, carnauba wax and glycerol monostearate, wherein the total amount of active ingredient is from 10 to 90 wt. % of the preparation.

In this embodiment of the preparation, it is appropriate for the matrix to also include a release modification material selected from soluble soluble materials or pulverized soluble or insoluble organic material.

The tablet or the plurality of particles is suitably composed of hydrogenated vegetable oil and the active ingredient.

It is advantageous for the pharmaceutical preparation to be in the form of a tablet obtained by compressing the plurality of particles.

The method of preparing the pharmaceutical preparation described above involves placing in a high-speed mixer (of known construction) a mixture of tramadol or pharmaceutically acceptable salt thereof in crushed form and crushed hydrophobic soluble material selected from hydrogenated vegetable oil, hydrogenated bean mass, microcrystalline, microcrystalline beeswax, carnuba wax or glycerol monostearate, the amount of active ingredient used being from 10 to 90% by weight. % of the final preparation and provides 50 to 800 mg of active ingredient in each final unit dosage form, whereby the resulting mixture is mechanically treated in the high-speed mixer upon energy delivery through a heating jacket and / or microwave radiation to a temperature of 40 ° C or more, in which the mixture melts or softens and forms agglomerates having a cohesive granular structure and of irregular shape, appearance and size, crushing the agglomerates to obtain a mixture of dust and small particles, then continuing and machining in a high-speed mixer until particle sizes of 0.1 to 3.0 mm are obtained, which are either filled into capsules or compressed into tablets containing 50 to 800 mg of active ingredient.

Using such technology, it has been found that in order to achieve the desired release characteristics (both in vivo and in vitro) more quickly, the mixture to be treated must contain two essential ingredients, in particular:

a) tramadol or a salt thereof; and b) a hydrophobic fusible carrier or solvent, optionally together with another component;

c / a release control component containing water-soluble organic or inorganic material.

It has been found that the total amount of tramadol or a pharmaceutically acceptable salt thereof in the mixture may vary widely, for example from 10 to 90 wt. %.

The hydrophobic soluble component (b) must be a hydrophobic material such as natural or synthetic wax or oil, for example hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, beeswax, carnauba wax or glycerol monostearate, and have a suitable melting point of 35 to 140 ° C, preferably 45 to 110 ° C.

The release-modifying component (c), when a water-soluble soluble material is preferred, is usually polyethylene glycol, and when selecting the specific materials, it is usually a pharmaceutically suitable material such as dicalcium phosphate or lactose.

Another preferred method of manufacturing the preparation according to the invention involves the following steps:

a / mechanical treatment in a high-speed mixer of a mixture of tramadol or a pharmaceutically acceptable salt thereof in a crushed form and a fractured hydrophobic fusible carrier or solvent with a melting point of 35 to 140 ° C and optionally a controlled-release component comprising a water-soluble fusible material, or pulverized soluble or insoluble organic or inorganic material, at a rate and feed energy, allowing the carrier or solvent to melt or soften until agglomerates are formed;

b) crushing the large agglomerates to obtain controlled release grains, and c) continuing the machining process, optionally adding a small percentage of carrier or solvent;

d / optionally repeating step (c), possibly repeating step (b) one or more times.

By this method, it is possible to achieve high yields (over 80%) of particles of the desired size, with the desired release uniformity of tramadol or its salt.

The resulting particles can be sieved to eliminate those larger or smaller in size, and then molded into the desired dosage units, for example, by encapsulation in hard gelatin capsules containing the required dose of the active substance or by compression into tablets .

Step (a) of process (a) can be performed in high speed ordinary type mixers with the standard stainless steel interior design, for example Collett Vactron mixer or the like. The mixture is treated to a temperature of about 40 ° C or higher, whereby the mixture acquires a cohesive (granular) granular structure with particle sizes in the range of 1-3 mm to fine powder in the case of non-agglomerated material. Such material, in the embodiments described below, appears to be a collection of agglomerates which, upon cooling below 40 ° C, have structural uniformity and resistance to tensile fracture between the fingers. At this stage of the process, the agglomerates are of different sizes, shapes and appearance.

It is preferable to allow the agglomerates to cool. The temperature to which they are cooled is of little importance and can be left at a temperature in the range of room temperature to 37 ° C.

The agglomerates are destroyed by any suitable means of grinding the dust of the large agglomerates to form a mixture of dust and small particles, preferably with a diameter of less than 2 mm. It is desirable to perform continuous classification using a Jackson Crockatt granulator with appropriately sized mesh openings or Comil with a properly sized mesh. It has been found that if a grille with too small a hole size is used in these apparatus, the agglomerates, which melt under the action of the blade or the stirrer, clog the grate and prevent the passage of the mixture through it, thereby reducing the yield of the finished product . A sieve of size 12 has been found to be most appropriate.

The sorted material is returned to the high-speed mixer and the process continues. This is thought to result in the adhesion of the refined particles into particles of the same size range.

In a preferred embodiment of the process according to the invention, the processing of the sorted material continues until the hydrophobic melt materials used begin to soften and then an additional hydrophobic melt material is optionally added. Stirring is continued until the mixture is transformed into particles of the desired size over a predetermined range.

In order to ensure an equal supply of ingredients in the high-speed mixer, it is preferable that at least some of the energy is supplied from microwave energy sources.

Energy can also be supplied from other sources such as the heat jacket or through the mixer mixer and grinding blades.

Once the particles are formed, they are cooled or allowed to cool and can then be sieved to remove larger or smaller sized ones.

The resulting particles can be used to prepare dosage units according to the invention in the form of, for example, tablets or capsules in known ways.

It has also been found that particles containing tramadol or a salt thereof produced by the fusion method as described in application PCT / SE 93/00225 and the method also described in UK application + 9324045.5 of 23. XI. 1993 and the methods according to the invention are particularly suitable for treating particles in the form of tablets.

It has been found that by properly sorting the materials used in the formation of the particles and for the preparation of the tablets, as well as the proportions in which they are used, it is possible to achieve a considerable degree of control over the maximum values of dissolution and release of tramadol or a salt thereof from the compressed tablets.

Typically, to form a tablet according to the invention, the particles prepared as described above are mixed with tablet excipients, for example one or more of the standard excipients, such as diluents, lubricants, binders, flowable excipients. , disintegrating agents, surfactants or water-soluble polymeric materials.

Suitable diluents are, for example, microcrystalline cellulose, lactose and dicalcium phosphate. Suitable lubricants are, for example, magnesium stearate and sodium stearyl fumarate. Suitable binders are, for example, hydroxypropylmethyl cellulose, polyvidone and methyl cellulose.

Suitable disintegrating agents are starch, sodium glycogen glycolate, crospovidone sodium and croscarmalose.

Suitable surfactants are Poloxamer 188, polysorbate 80 and sodium lauryl sulfate.

Suitable flowable auxiliaries are talc, colloidal anhydrous quartz.

Suitable water-soluble polymers are PEGs with a molecular weight in the range of 1000 to 6000.

For the manufacture of the tablets according to the invention, the particles can be mixed or mixed with the desired excipients (if any) using known procedures, for example, the crusher Y cone or mixing hopper. The resulting mixture can be compressed by the usual tabletting procedure using a suitable size tablet mold. The tablets may be manufactured using conventional tablet machines, the examples described below being manufactured on a standard F3 single-punch machine or on a Kilian rotary tablet machine RLE 15.

Even with such a highly water-soluble active agent as tramadol or a salt thereof, compression tablets produced by standard methods have been found to produce very low release values of the active ingredient, i. corresponding to the release for a period longer than 24 hours and even greater than 36 hours. It has been found that the release profile can be adjusted in many ways. For example, higher drug values are associated with an increase in release values; the use of larger proportions of the water-soluble fusible material in the particles or of the surfactants in a tablet formulation is also associated with an increased rate of release of the active ingredient. By controlling the relative values of these ingredients, it is possible to achieve a predetermined release profile of tramadol or its salt.

In order to clarify the invention, the following examples are given which are merely illustrative.

Example 1.

Tablets according to the invention with the following composition in mg:

mg / tablet

Tramadol hydrochloride 100 Lactose Ph. Eur. 68,0 Ethylcellulose (Surelease R 25% solids) 15 Chemically purified water Ph. Eur. 13,3 * Cetostearyl alcohol Ph. Eur. (paraffin dehydrator o) 42.00 Magnesium stearate Rn. Eur. 2.00 Purified talc Rn. Eur. 3.00 * removed during processing 230,00

Tramadol hydrochloride (100 mg) and lactose (68 mg) were granulated, then fed to a fluid mass granulator and sprayed with ethylcellulose (15 mg) and water. The granules were dried at 60 ° C and passed 5 through a 1 mm mesh screen.

Melted cetostearyl alcohol (42 mg) was added to the heated tramadol containing granules and the whole mixture was stirred very carefully. The granules were allowed to cool for 10 days and sieved through a sieve with a mesh size of 1.6 mm. Chemically purified water and magnesium stearate are then added, which is mixed with the granules. The granules are then compressed into tablets. 15

The tablets are film coated with the following composition in mg:

mg / tablet

Hydropropylmethyl whole- the vine Ph. Eur. 15. eps. (Methocel E 15) Hydroxyprimethyl is 0.770 20 lulose Rn. Eur. 5 cps (Methocel E 5) 3.87 Obasiree M-1-7111 V 25 (33% claimed it hard) 2.57 Polyethylene glycol 400 USNF 0.520 Purified talc Rn. Eur. Chemically purified 0.270 water Ph. Eur. 55.52 * 30

* removed during processing Example 2.

Tablets according to the invention with the following composition in mg:

mg / tablet 35

Tramadol hydrochloride 100.00

Lactose Ph. Eig.58.00

Ethylcellulose US NF15,00 (Ethnos! 45 CP)

Cetostearyl alcohol Ph. Eig. 52.00 (Dehydag)

Magnesium stearate Rn. Eig 2,00

Purified talc Rn. Eig 3,00

The mixture of tramadol hydrochloride (100 mg), lactose (58 mg) and ethylcellulose (15 mg) was granulated, while the molten cetostearyl alcohol (52 mg) was added and everything was mixed very carefully. The granules were then allowed to cool and sieved through a sieve with a mesh size of 1.6 mm. Purified talc and magnesium stearate are added, which are mixed with the granules. The granules are then compressed into tablets coated with a film similar to that of Example 1.

Example 3.

Film-coated tablets by the method described in Example 2, having the following composition in mg:

mg / tablet

Tramadol hydrochloride 100.00

Lactose Ph. Eig.70.00

Hydroxyethyl cellulose Ph. Eig. 12.50 Cetostearyl alcohol Ph. Eig. 42.00

Magnesium stearate Rn. Eig 2,00

Purified talc Rn. Eig 3,00

In vitro dissolution studies

In vitro dissolution studies were performed on tablets prepared as described above. The results are given in Table 1.

TABLE 1 % By weight of tramadol released Time (n) Example 1 Example 2 ^x Example 3 1 39 35 43 2 52 47 60 4 67 62 84 8 82 78 97 12 90 86 -

* measured at the core of the tablet.

In an experiment involving 12 healthy volunteers, the serum levels of tramadol after taking one tablet prepared according to Example 2 were found to be similar to those shown in Figure 1.

Examples 4 and 5. Particles having the compositions given in Table II below are prepared by the following processes:

I. Place the ingredients (A) and (C) (total batch weight 0.7 kg) in the tank with a capacity of 10 l of a Collette Gral mixer (or similar mixer) equipped with variable speed mixing and granulating blades.

II. The ingredients are agitated at a speed of 150-1000 rpm and heat is applied simultaneously to agglomerate the contents of the tank.

III. Sort the agglomerated material by passing it through Comil and / or Jakson Crockatt to obtain controlled release grains.

IV. The sorted material is heated and stirred in a 10-liter Collette Gral tank until uniform conglomerates are formed with sizes falling within a predetermined range in a yield greater than 80%. The process takes approximately 5 min.

V. Remove the conglomerates from the mixer and sieve through sieves of 0.5 and 2 mm openings to separate the conglomerates of the appropriate size.

TABLE II EXAMPLE 4 5 (a) Tramadol HCI (wt.%) 50 75 (c) Hydrogenated vegetable oil 50 25 (wt.%)

Example 6. Particle samples, semi-tooling, to form in Example 4, were mixed with magnesium stearate capsules on a single-matrix purifying talc machine, using the Y-cone of F 3 Manesty to form tablets. crusher or mixing hopper. The mixture after containing 200, 300 and 400 mg of tramadol HCL.

this is compressed using (1) 14x6 The single dose ingredients are as follows:

mm, (2) 16 x 7 mm or (3) 18.6 x 7.5 mm

Table III.

Tablet Ingredient mg / tablet 1 2 3 Tramadol HC1 200 300 400 Hydrogenated vegetable 200 300 400 butter Intermediate total weight 400 600 800 Purified talc 12,63 18.95 25,26 Magnesium stearate 8.42 12,63 16,84

The tablets are evaluated in terms of reconstitution using pH. Eur. blade method, 100 rpm 01 N HCL.

For the evaluation of uncompressed particles Ph. Eur. the blade is replaced by pH. Eur.

5Q network.

The results are shown in Table IV:

TABLE IV · Hours after STARTING ΗΛ TEST PARTICLES TABLE 1 TABLE2 TABLETKAS % TRIMADOL HCI% 1 54 16 15 15 2 68 23 20 21 3 76 28 25 25 4 82 32 28 28 6 89 40 35 35 8 93 46 41 40 10 96 50 45 45 12 98 55 49 49 16 100 63 57 56 20 NR 70 63 NR

These results confirm the effectiveness of tableting in reducing the rate of release.

Example 7. Samples of the particles obtained in Example 5 were tableted as described in Example 3, with single dose ingredients being as follows:

TABLE V TABLE INGREDIENT MGH / TABLE 4 5 6 Tramadol HCI 200 300 400 Hydrogenated Vegetable OIL 66.7 100 133 Intermediate total weight 266.7 400 533 Purified TLC 7.63 11.44 15.25 Magnesium stearate 5.16 7.63 10.17

Tablets and samples of uncompressed conglomerates (each sample containing 400 mg 50 tramadol hydrochloride) were evaluated by the dissolution method described above. The results are shown in Table VI:

TABLE VI Hours after start- BATH TO TEST Człstii GdbLETklA TblTetkdB TLbLETklb % Tramadol HCI is released 1 77 43 40 '42 2 92 64 55 56 3 98 75 65 66 4 100 83 72 73 6 102 94 83 84 8 102 100 91 91 10 102 NR 96 97

These results show that by increasing the content of the highly water-soluble tramadol hydrochloride (75% w / w in this example compared to 50% w / w in example 6), a significantly higher rate of release of the active ingredient.

Example 8.

Repeat Example 4, but for the following composition in mg:

mg / tablet

Tramadol HCL200

Hydrogenated vegetable oil163

The resulting conglomerates were mixed as described in Example 6 with:

mg / tablet

Purified talc 11.5

Magnesium stearate 7,66

The mixture was then compressed as in Example 6, but using 15 mm x 6.5 mm normal flat / flat molds with recesses for the capsules.

The tablets obtained were evaluated by the dissolution method described above.

The results are shown in Table VII.

In an experiment involving five healthy volunteers, the plasma profile obtained after single administration of the tablet is shown in Figure 2, as shown by comparing the intake of commercially available 100 mg tramadol pills.

TABLE VII

HOURS AFTER TFCTA START ^% Tramadol HCI is released 1 20 2 27 3 32 4 37 6 44 8 50

Sequel

10 55 12 60 16 67 20 73 24 77

Claims (15)

A controlled release pharmaceutical preparation in the form of a tablet or capsule containing spheroids and an active ingredient embedded in a matrix or coated on a spheroid, wherein the preparation is suitable for dosing twice or once daily to provide pain relief for 12 or 24 h, characterized in that the active ingredient is tramadol or a pharmaceutically applicable salt thereof, the unit dosage form containing from 50 to 400 mg of the active ingredient calculated as tramadol hydrochloride, and the matrix is m Rizza controlled release comprising a cellulose ether from 1 to 80 wt. % up to 60 wt. % one or more C ₁₂ -C ₃₆ aliphatic alcohols relative to the final preparation, and the spheroid is in the form of a normal release matrix containing the active ingredient or an inert core with a coating containing the active ingredient and with an additional controlled release outer coating containing water-insoluble cellulose, water-soluble hydroxyalkyl cellulose or acrylic polymer or copolymer. Pharmaceutical preparation according to claim 1, characterized in that the cellulose ether is C ₂ -C ₆ alkyl cellulose. 3. A pharmaceutical preparation according to claim 2, characterized in that the _{C] -C6} alkyl cellulose is ethyl cellulose. Pharmaceutical preparation according to claim 2 or 3, characterized in that it contains from 1 to 20% of one or more alkyl celluloses. Pharmaceutical preparation according to one of Claims 1 to 4, characterized in that it contains from 5 to 30% by weight. % Of C ₈ -C _J0 fatty alcohol. Pharmaceutical preparation according to claim 5, characterized in that the fatty alcohol is selected from lauryl alcohol, myristyl alcohol and stearyl alcohol. Pharmaceutical preparation according to claim 1, characterized in that the spheroids have a controlled release outer coating containing ethyl cellulose. Pharmaceutical preparation according to claim 7, characterized in that the active ingredient is coated on inert grains, with the tramadol-containing grains having a controlled release outer coating. A method for preparing a pharmaceutical preparation according to any one of claims 1 to 6 in tablet form, comprising the following steps: a) granulating a mixture containing tramadol or a pharmaceutically acceptable salt thereof, in an amount corresponding to 50 to 400 mg for each final unit dosage form, with one or more C ₂ -C ₆ alkyl celluloses in an amount corresponding to 1 to 80 wt. . % of the final preparation; b) blending alkyl cellulose containing granules with 0-60 wt. % based on the final preparation with one or more C ₁₂ -C ₃₆ aliphatic alcohols, and c) molding and compressing the resulting granules to form tablets, each containing 50 to 400 mg of active ingredient. A method for preparing a pharmaceutical preparation according to any one of claims 1 to 6, which comprises granulating a mixture comprising tramadol or a pharmaceutically acceptable salt thereof in an amount corresponding to 50 to 400 mg of each final unit dosage form, lactose and one or more alkyl celluloses in an amount corresponding to 1 to 80% by weight. % by weight of the final preparation, from 0 to 60 wt. % of one or more C ₂₃ -C ₃₆ aliphatic alcohols based on the final preparation and then forming and pressing the granules to form tablets, each containing 50 to 400 mg of the active ingredient. 11. A pharmaceutical composition comprising a tablet or capsule comprising a plurality of particles ranging in size from 0.1 to 3.0 mm, the preparation also comprising an active ingredient included in a matrix, the preparation being dosed once or twice daily and provides pain relief for 12 or 24 hours, characterized in that the active ingredient is tramadol or a pharmaceutically acceptable salt thereof, with the unit dosage form containing between 50 and 800 mg of tramadol (calculated as tramadol hydrochloride) and the matrix consisting essentially of hydrophobic melt the mat rial selected from hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, beeswax, carnauba wax and glycerol monostearate, wherein the total amount of active ingredient is from 10 to 90 wt. % of the preparation. Pharmaceutical preparation according to claim 11, characterized in that the matrix also includes a release modifying material selected from soluble soluble materials or fractured soluble or insoluble organic or inorganic material. Pharmaceutical preparation according to claim 11 or 12, characterized in that the tablet or the plurality of particles consists of a hydrogenated vegetable oil and an active ingredient. A pharmaceutical preparation according to claim 11,12 or 13, characterized in that it is in the form of a tablet treated by compression of the multiple particles. 15. A method for the preparation of a pharmaceutical preparation according to claims 11, 12, 13 or 14, which comprises placing in a known high-speed mixer a mixture of tramadol or a pharmaceutically applicable salt thereof in crushed form and fractured hydrophobic melt material selected from hydrogenated vegetable oil, hydrogenated bean oil, microcrystalline wax, beeswax, carnuba wax or glycerol monostearate, the amount of active ingredient used being from 10 to 90 wt. % of the final preparation and provides 50 to 800 mg of active ingredient in each final unit dosage form, whereby the resulting mixture is mechanically treated in the high-speed mixer upon energy delivery through a heating jacket and / or microwave radiation to a temperature of 40 ° C or more, in which the mixture melts or softens and forms agglomerates having a cohesive granular structure and irregular shape, appearance and size, then the agglomerates are crushed to obtain a mixture of dust and small particles, then mechanically this treatment is continued in the high-speed mixer until particle sizes of 0.1 to 3.0 mm are obtained, which are either filled into capsules or compressed into tablets containing 50 to 800 mg of active ingredient.