CZ2008740A3 - Solid pharmaceutical composition with atorvastatin and telmisartan active ingredients - Google Patents

Abstract

The solid pharmaceutical composition with the active ingredients telmisartan and atorvastatin is characterized in that they are both alkaline or alkaline earth salts and the composition further comprises an organic or inorganic base selected from meglumine, sodium hydroxide or potassium hydroxide, calcium hydroxide, oxide or carbonate or magnesium or sodium or potassium, and further polyvinylpyrrolidone and a filler. The filler is selected either: (a) from a water-soluble mono- or oligosaccharide, or from an alcoholic sugar, wherein 95% by weight of all of the filler particles which may be present in the composition either alone or combined into larger granules of which 99% by weight. less than 1.0 mm, lies between 0.025 and 0.355 mm; or (b) from a water-insoluble polysaccharide, of which 95% by weight of all the filler particles which may be present in the composition either alone or combined into larger granules of which 75% by weight is less than 0,50 mm; 25 mm.

Description

SOLID PHARMACEUTICAL COMPOSITION WITH ACTIVE SUBSTANCES

ATORVASTATIN AND TELMISARTAN

Technical field

The invention relates to a solution to the problem of a pharmaceutical composition wherein two substances are common; atorvastatin, a potent inhibitor of HMG Co A reductase, and telmisartan, an ATII receptor blocker. Both have been reported to have a number of positive effects for the treatment and prevention of cardiovascular problems. Initially, however, atorvastatin is used to treat hypercholesterolemia, while telmisartan is used in the hypertension area. It is clear that the combination of treatment of these two best known risk factors will significantly improve the prognosis of the development of various cardiovascular diseases. Pharmaceutical compositions containing both in a single dose will then improve compliance over administration of each form separately.

BACKGROUND OF THE INVENTION

Possibilities of co-administration of HMG Co A reductase inhibitors and ΑΤΠ receptor blockers have been known for some time. For example, in WO 95/26188 treatment of atherosclerosis, lowering of cholesterol, and possibly lowering of blood pressure by the combination has been suggested.

Further, EP 1 514 543 discloses combinations of atorvastatin with various ΑΤΠ blockers. Again, the effect of this combination is focused on the treatment and prevention of cardiovascular diseases and the reduction of two risk factors.

WO 2004/62557 relates to the use of atorvastatin in combination with telmisartan for the treatment of cardiovascular, cardiopulmonary and cardiorenal disorders. According to the application, this composition is particularly useful for metabolic disorders associated with a sugar body disorder. However, this application does not disclose any composition in which both substances are together.

Several patent applications are known to address telmisartan with another agent. Namely, they are hydrochlorothiazide (WO 2003 / 059327AI and WO 2007 / 060170A2) or amlodipine (WO 2006 / 048208AI). In all cases it is a layered tablet.

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In WO-2004 / 096215AI, a composition of telmisartan with hydrochlorothiazide together in a single layer is described.

Atorvastatin is known to be a poorly stable substance and its composition should always be addressed in this respect.

The composition of the two different active substances must not only be stable, but also have an adequate release rate of both substances. For this reason, the knowledge of the behavior of one composition cannot simply be transferred to another.

The task was therefore to develop a composition of telmisartan and atorvastatin that would meet all the demands placed on it and thus improve the satisfaction of both patients and doctors with combination therapy.

SUMMARY OF THE INVENTION

The present invention provides a solid pharmaceutical composition of telmisartan and atorvastatin in the form of an alkali salt or an alkali metal salt of min, containing a basic reactant, together either:

(a) a water - soluble mono- or oligosaccharide and, where appropriate, an alcohol sugar; or

b) insoluble polysaccharide (collectively carbohydrate) ·

The solid carbohydrate particles may be present alone or in granules. In any case, virtually all carbohydrate particles are smaller than 0.355 mm.

When combined into granules, virtually all granules must be less than 1 mm and, in the case of insoluble polysaccharides, even less than 0.5 mm.

In a preferred embodiment, sorbitol is selected as the soluble saccharide. Here it has proven advantageous to select 50 to 80 wt. a total number of all particles less than 160 µm.

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The insoluble carbohydrate is preferably a microcrystalline cellulose, the size of which is preferably limited to a maximum of 30% by weight. % of all particles larger than 75 µm and at least 50 wt. If the microcrystalline cellulose particles are combined into granules, preferably about 75 wt. % of all granules is less than 0.5 mm and about 40 wt. All granules fall within the range of 0.1 to 0.25 mm in size.

The pharmaceutical composition is composed of two mixtures, usually specially made, one of which is telmisartan and the other atorvastatin.

The weight of both mixtures ranges from 50 to 600 mg / tablet for the telmisartan layer and 140 to 1000 mg / tablet for the atorvastatin layer.

In the simplest embodiment of the invention, these mixtures can only be homogenized and compressed into a tablet.

A more preferred, but laborious solution is to form a tablet of two layers, each containing one of the mixtures.

The invention also includes advantageous technical parameters of the product. These are the particle sizes of the active ingredients, the size of the granules in which the active ingredients may be incorporated, and other pharmaceutical ingredients.

DETAILED DESCRIPTION OF THE INVENTION

The solution to the problem of the stability of the composition and the desired release of both active substances can best be achieved with tablets consisting of two layers, one containing atorvastatin and the other a telmisartan mixture.

If it is necessary for technical reasons to solve the problem with a tablet containing both active substances in a single layer, it seems advantageous to use the alkali salt of telmisartan in the form of particles obtained by spray drying.

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Spray drying is preferably carried out as follows: Telmisartan is dissolved in water, preferably in a water / ethanol mixture, in the presence of a base such as NaOH, KOH, meglumine and the like, preferably only NaOH, and a binder, e.g. not only serves as a binder, but also as a solution stabilizer. This solution is spray dried.

After drying, the spray mixture is mixed with a soluble filler selected from carbohydrates or sugar alcohols, atorvastatin salt, which may be in the form of a granulate, and other excipients. The choice of excipients is essentially the same as those described below for the atorvastatin layer. In the case of the addition of atorvastatin which is not in the form of granules, additives for direct tableting of atorvastatin are selected. If atorvastatin is in the form of a granulate, the following intergranular admixtures are used.

The release rate in this case is controlled by the particle size of the telmisartan spray dried mixture and the excipient.

In the case of the choice of a two-layer tablet it is considerably easier to model the desired release profiles of the active ingredients, but production is technically more demanding; requires less conventional tabletting equipment.

The first layer contains telmisartan, which slowly dissolves from the matrix, the second layer contains atorvastatin; this layer, on the other hand, disintegrates rapidly, resulting in rapid release of atorvastatin. Different decay rates, respectively. By washing the individual layers, different dissolution profiles important for optimum absorption of both active substances can be achieved.

It has been found that, in order to achieve the desired effect, it is necessary to produce a composition which, under the conditions described in Pharm.Eur., By the paddle method at 75 min, achieves the following values when released in phosphate buffer at pH 7.5:

for atorvastatin:

Time dissolved active substance [min] [% 1 15 Dec > 70 30 > 90

for telmisartan:

. dissolved active substance [min] ·· 2. [%] ' 15 Dec > 30 30 > 60 60 > 80

Either a water-soluble carbohydrate filler such as glucose, sucrose, anhydrous lactose or lactose monohydrate and sugar alcohols such as sorbitol, mannitol, xylitol, or insoluble carbohydrates such as microcrystalline cellulose are used to prepare the first telmisartan-containing layer, to form a soluble layer. next. For the telmisartan layer composition, sorbitol was preferred. microcrystalline cellulose.

Among the other excipients, an organic or inorganic base such as sodium or potassium hydroxide, meglumine, arginine and the like can be used as the basic component. Preferably, a combination of sodium hydroxide and meglumine is used in an appropriate ratio.

The binder used is a polyvinylpyrrolidone (PVP) group, such as various types of povidones, povidone 25, povidone 30, resp. povidone 90, copolymers of vinylpyrrolidones with other vinyl derivatives, such as povidone VA 64, microcrystalline cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and pregelatinized Starch. Among these, the use of povidones and hydroxypropylcellulose is preferred.

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A lubricant such as sodium stearyl fumarate, stearic acid, calcium stearate, magnesium stearate, talc may be used. Of this group of substances, magnesium stearate is particularly preferred.

The second layer, which contains atorvastatin calcium, disintegrates rapidly and thus rapidly releases the active ingredient. Fillers from the group of substances such as pregelatinized starch, microcrystalline cellulose, cellulose, mannitol, sorbitol, xylitol, anhydrous lactose, lactose monohydrate, calcium phosphate, hydrogen or calcium phosphate dihydrogen and the like can be used for this second layer. a mixture of lactose monohydrate and microcrystalline cellulose.

Among the other excipients, an organic or inorganic base such as sodium or potassium hydroxide, meglumine, argmine, hydroxide, oxide, carbonate or bicarbonate of calcium, magnesium, sodium or potassium and the like can be used as the basic component. magnesium oxide.

The binders used are polyvinylpyrrolidones, such as various types of povidones, povidone 25, povidone 30, resp. povidone 90, copolymers of vinylpyrrolidones with other vinyl derivatives, such as povidone VA 64, microcrystalline cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and pregelatinized starch. Of this class of substances, the use of hydroxypropylcellulose is preferred.

For rapid disintegration, disintegrants from the group of maize starch, pregelatinized starch, low substituted hydroxypropylmethylcellulose, microcrystalline cellulose and super disintegrants such as sodium croscarmellose, sodium carboxymethyl starch type A, B or C are used, or crospovidone. For this layer, a mixture of low substituted hydroxypropylcellulose and croscarmellose sodium is preferred.

Substances from the group of substances such as colloidal silicon dioxide, talc and the like are preferably used to improve flow properties. Preferably, colloidal silicon dioxide is used.

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As a lubricant, a substance such as sodium stearyl fumarate, stearic acid, calcium stearate, magnesium stearate, talc, cutin may be used. Of this group of substances, magnesium stearate is particularly preferred.

Purified water or a mixture of water and ethanol or methanol in various proportions are used as solvents. Preferred solvents are purified water and ethanol. These solvents are removed from the pulp by drying during the manufacturing process.

Film-forming agents, lubricants, pigments, plasticizers are used to coat the tablets.

The bilayer tablets of the invention may comprise:

- 80 mg telmisartan and 10 - 80 mg atorvastatin, as a calcium salt. Preferably, 20.40 and 80 mg of telmisartan and 10.20.40 and 80 mg of atorvastatin calcium salt.

The Telmisartan layer can be prepared by the following procedures:

Several different methods of preparing telmisartan tablet can be used. Telmisartan is in amorphous form in the tablet.

Spray drying - Telmisartan is dissolved in water, preferably water / ethanol in the presence of bases such as NaOH, KOH, meglumine and the like, preferably only NaOH, and binders, such as povidone, which serves not only as a binder but also solution stabilizer. This solution is spray dried. After drying, the spray mixture is mixed with a soluble filler, such as sorbitol, e.g. an insoluble filler, microcrystalline cellulose of a suitable particle size, and other excipients such as meglumine or magnesium stearate.

Fluid granulation - Telmisartan is dissolved in water, preferably in a water / ethanol mixture in the presence of bases such as NaOH, KOH, meglumine and the like, preferably only NaOH, and binders, eg povidone, which serves not only as a binder but also solution stabilizer. With this solution, a soluble filler such as sorbitol or monosaccharides or an insoluble filler such as polysaccharides such as microcrystalline cellulose is fluidically granulated. The dried and sieved granulate is mixed with a portion of a soluble or insoluble filler of suitable particle size and other excipients such as meglumine or magnesium stearate.

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The particle size of the soluble filler may be in the range of 0 - 355 microns, preferably 100 microns. The particle size of the insoluble filler may be in the range of 0-250 microns, preferably 50 microns. The use of a fine filler results in the formation of fine granules in the fluidized bed granulation, with an even distribution of the active substance telmisartan. When using larger filler grain sizes, telmisartan is applied to the surface of the filler particles and the homogeneity of the granulate is less.

An example of the use of a soluble carbohydrate as a filler is sorbitol with a particle size of max. all particles larger than 315 µm; 20 to 50 wt. greater than 160 pm; % and at least 80 wt. greater than 40 pm.

Another way of characterizing is by using percentiles such as D50 greater than 125 µm.

Percentiles, or quantities, can be defined as D (X) representing a size (micrometer) that is greater (lying above) than the X% size of the test lot particles.

For insoluble carbohydrate as filler, microcrystalline cellulose with a maximum of 1 wt. particles larger than 250 µm; 30 wt. % greater than 75 µm and at least 50 wt. greater than 32 pm.

Otherwise, the particle size used can be characterized by percentiles, D10 less than 30 µm; D50 between 40-60 pm and D90 greater than 80 pm.

The use of meglumine as a basic component in a telmisartan solution can cause the granulate to harden after drying, making it difficult to process. This hardening also occurs after mixing with tableting ingredients, for example magnesium stearate. Surprisingly, it was found that when meglumine is added up to the extragranulation phase, this effect does not occur and the granulate, respectively. tabletting is considerably better processed.

Description of atorvastatin layer preparation:

Several different methods of preparing atorvastatin tablet can be used. Atorvastatin calcium is present in tablets in amorphous form, or a crystal modification may be used.

v a) Kneading granulation - Atorvastatin in the form of a calcium salt is mixed with other ingredients such as microcrystalline cellulose, lactose, hydroxypropylcellulose and, if appropriate, a mixture of the two. parts of croscarmelosa, resp. magnesium oxide or calcium carbonate. This mixture is granulated with aqueous and / or water. with meglumine alcoholic solution, resp. only with water or water / ethanol. The resulting granulate is fluidized or sheet dried. The dried granulate is screened to a suitable granule size, which is subsequently mixed with extragranular excipients such as magnesium stearate and colloidal silica, respectively. part of croscarmelosa.

b) Dry granulation - Atorvastatin calcium salt is mixed with other ingredients such as microcrystalline cellulose, lactose, hydroxypropylcellulose and, if necessary, b. Parts of croscarmelosa, resp. magnesium oxide, respectively. megluminem. The resulting mixture is compacted in a suitable compactor or compressed on a tablet press using large punches. The resulting compacts are screened to a suitable granule size, which are then mixed with extragranular excipients such as magnesium stearate and colloidal silica, respectively. part of croscarmelosa.

c) Direct blending - Atorvastatin calcium salt is mixed with other ingredients such as microcrystalline cellulose, lactose, hydroxypropylcellulose and, if necessary. parts of croscarmelosa, resp. magnesium oxide, respectively. megluminem. Extragranular excipients such as magnesium stearate and colloidal silicon dioxide, respectively. part of croscarmelosa.

Compression, coating and packaging of tablets

The tablets thus prepared are compressed into bilayer tablets which are coated with a film-forming material coating containing plasticizers, pigments and other fillers.

The coated tablets are preferably adjusted in Al / Al blisters, optionally under an inert atmosphere.

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Examples of composition:

Telmisartan 80 mg / Atorvastatin 10 mg - 2 core layer

Ingredients AND Al mg / tbl. mg / tbl. Telmisartan 80,000 80,000 Sodium hydroxide 6,800 6,800 Povidone 40,000 40,000 Sorbitol 324,400 Microcrystalline cellulose - 324,400 Meglumin 24,000 24,000 Magnesium stearate 4,800 4,800 Total 1st layer 480,000 480,000 Atorvastatin Ca 10,340 10,340 Meglumin 4,200 4,200 Microcrystalline cellulose 70,000 70,000 Lactose 35,760 35,760 Croscarmeiosa Na 4,500 4,500 Hydroxypropyl cellulose 14,000 14,000 Colloidal silica 0.500 0.500 Magnesium stearate 0.700 0.700 Total 2, layer 140,000 140,000 Total core weight 620,000 620,000

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Telmisartan 80 mg / Atorvastatin 10 mg - 2 'Core layer

Ingredients A2 A3 mg / tbl. mg / tbl. Telmisartan 80,000 80,000 Sodium hydroxide 6,800 6,800 Povidone 40,000 40,000 Microcrystalline cellulose 324,400 Sorbitol 324,400 Meglumin 24,000 24,000 Magnesium stearate 4,800 4,800 Total 1st layer 480,000 480,000 Atorvastatin Ca 10,340 10,340 Meglumin 4,200 4,200 Polysorbatum 80 3,500 3,500 Microcrystalline cellulose 67,750 67,750 Lactose 34,510 34,510 Croscarmelosa Na 4,500 4,500 Hydroxypropyl cellulose 14,000 14,000 Colloidal silica 0.500 0.500 Magnesium stearate 0.700 0.700 Total 2nd layer 140,000 140,000 Total core weight 620,000 620,000

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Examples of composition:

Telmisartan 80 mg / Atorvastatin 10 mg - 2; core layer

Ingredients A4 A5 A6 A7 mg / tbl. mg / tbl. mg / tbl. mg / tbl. Telmisartan 80,000 80,000 80,000 80,000 Sodium hydroxide 6,800 6,800 6,800 6,800 Povidone 40,000 40,000 40,000 40,000 Sorbitol 324,400 Microcrystalline cellulose - 324,400 312,400 300,400 Meglumin 24,000 24,000 24,000 24,000 CroscarmelosaNa 12,000 24,000 Magnesium stearate 4,800 4,800 4,800 4,800 Total 1st layer 480,000 480,000 480,000 480,000 Atorvastatin Ca 10,340 10,340 10,340 10,340 Magnesium oxide 14,000 14,000 14,000 14,000 Microcrystalline cellulose 70,000 70,000 70,000 70,000 Lactose 26,000 26,000 26,000 26,000 Croscarmelosa Na 4,500 4,500 4,500 4,500 Hydroxypropyl cellulose 14,000 14,000 14,000 14,000 Colloidal silica 0.500 0.500 0.500 0.500 Magnesium stearate 0.700 0.700 0.700 0.700 Total 2nd layer 140,000 140,000 140,000 140,000 Total core weight 620,000 620,000 620,000 620,000

The release rate of the individual components was monitored in a dissolution apparatus by a paddle method in phosphate buffer pH 7.5.

Under these conditions, for example, composition A7 released the following amounts of active ingredients in percent:

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15 min 30 min 60 min (%) (%) (%) Atorvastatin 98, l 100.9 - Telmisartan 58.7 84.2 98.2

Examples of composition:

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Telmisartan 80 mg / Atorvastatin 20 mg - 2 {core layers

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Ingredients (B) BI B2 mg / tbl. mg / tbl. mg / tbl. Telmisartan 80,000 80,000 80,000 Sodium hydroxide 6,800 6,800 6,800 Povidone 40,000 40,000 40,000 Sorbitol 324,400 - Microcrystalline cellulose 324,400 324,400 Meglumin 24,000 24,000 24,000 Magnesium stearate 4,800 4,800 4,800 Total 1st layer 480,000 480,000 480,000 Atorvastatin Ca 20,680 20,680 20,680 Meglumin 8,400 8,400 8,400 Microcrystalline cellulose 140,000 140,000 62,960 Lactose 71,520 71,520 28,251 Croscarmelosa Na 9,000 9,000 4,500 Hydroxypropyl cellulose 28,000 28,000 14,000 Colloidal silica 1,000 1,000 0.500 Magnesium stearate 1,400 1,400 0.700 Total 2nd layer 280,000 280,000 140,000 Total core weight 760,000 760,000 620,000

Telmisartan 80 mg / Atorvastatin 20 mg - 2nd core layer

Ingredients B3 B4 B5 mg / tbl. mg / tbl. mg / tbl. Telmisartan 80,000 80,000 80,000 Sodium hydroxide 6,800 6,800 6,800 Povidone 40,000 40,000 40,000 Sorbitol 324,400 - Microcrystalline cellulose 324,400 324,400 Meglumin 24,000 24,000 24,000 Magnesium stearate 4,800 4,800 4,800 Total 1st layer 480,000 480,000 480,000 Atorvastatin Ca 20,680 20,680 20,680 Meglumin 8,400 8,400 8,400 Polysorbatum 80 7,000 7,000 7,000 Microcrystalline cellulose 135,500 135,500 55.720 Lactose 69,020 69,020 28,500 Croscarmelosa Na 9,000 9,000 4,500 Hydroxypropyl cellulose 28,000 28,000 14,000 Colloidal silica 1,000 1,000 0.500 Magnesium stearate 1,400 1,400 0.700 Total 2nd layer 280,000 280,000 140,000 Total core weight 760,000 760,000 620,000

Telmisartan 80 mg / Atorvastatin 20 mg - 2 Core layers

Ingredients B6 B7 B8 B9 mg / tbl. mg / tbl. mg / tbl. mg / tbl. Telmisartan 80,000 80,000 80,000 80,000 Sodium hydroxide 6,800 6,800 6,800 6,800 Povidone 40,000 40,000 40,000 40,000 Sorbitol 324,400 Microcrystalline cellulose 324,400 312,400 300,400 Croscarmelosa Na - - 12,000 24,000 Meglumin 24,000 24,000 24,000 24,000 Magnesium stearate 4,800 4,800 4,800 4,800 Total 1st layer 480,000 480,000 480,000 480,000 Atorvastatin Ca 20,680 20,680 20,680 20,680 Magnesium oxide 28,000 28,000 28,000 28,000 Microcrystalline cellulose 140,000 140,000 140,000 140,000 Lactose 52,000 52,000 52,000 52,000 Croscarmelosa Na 9,000 9,000 9,000 9,000 Hydroxypropyl cellulose 28,000 28,000 28,000 28,000 Colloidal silica 1,000 1,000 1,000 1,000 Magnesium stearate 1,400 1,400 1,400 1,400 Total 2nd layer 280,000 280,000 280,000 280,000 Total core weight 760,000 760,000 760,000 760,000

The release rate of the individual components was monitored in a dissolution apparatus by a paddle method in phosphate buffer pH 7.5.

Under these conditions, for example, composition B9 released the following amount of active ingredients:

15 min 30 min 60 min (%) (%) (%) Atorvastatin 98.1 100.9 * Telmisartan 58.7 84.2 98.2

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Claims (36)

PATENT CLAIMS A solid pharmaceutical composition comprising a. The active substances telmisartan and atorvastatin, which are in the form of alkali or alkaline earth salts; and b. an organic or inorganic base selected from meglumine, sodium or potassium hydroxide, calcium, magnesium or sodium or potassium hydroxide, oxide or carbonate; and c. polyvinylpyrrolidone PVP, characterized in that it contains a filler selected from: a) from a water-soluble mono- or oligosaccharide or an alcohol sugar, the size being 95 wt. % of all filler particles that may be present in the composition either alone or be grouped into larger granules, of which 99 wt. less than 1,0 mm, lies in the range 0,025 to 0,355 mm, or b) a water insoluble polysaccharide, wherein the size is 95 wt. % of all filler particles which may be present in the composition either alone or be grouped into larger granules, of which 75% by weight; less than 0.50 mm is less than 0.25 mm. Pharmaceutical composition according to claim 1, characterized in that a soluble filler is selected, wherein 70 to 80 wt. % of the optional filler granules are in the range of 0.1 to 0.8 mm and 60 to 70% by weight. all filler particles are in the size range of 0.025 to 0.125 mm. Pharmaceutical composition according to claim 1, characterized in that an insoluble filler is selected, wherein 50 to 70 wt. % of the optional filler granules are between 0.1 and 0.8 mm and 80 wt. it is less than 0.25 mm and the size of all free filler particles is within the size range: max. 1%> 250 gm (60 mesh), max. 30%> 75 gm (200 mesh), min. 50% > 32 gm (469 mesh), or D10 < 30 gm, D50 = 40-60 gm, D90 < 80 gm. Pharmaceutical composition according to claim 1 or 2, characterized in that the soluble filler sorbitol is selected. . »♦,>> ..11 · >><«<· · · ¹ · ¹¹ Pharmaceutical compositions according to claim 1 or 3, characterized in that the insoluble filler is microcrystalline cellulose. Pharmaceutical composition according to claims 1 to 5, characterized in that it is composed of two mixtures, the first of which comprises telmisartan sodium or potassium salt, a) a soluble filler according to claim 1, 2 or 4, or b) an insoluble filler according to claim 1, 3 or 5, PVP and sodium or potassium hydroxide, meglumine, croscarmellose sodium, optionally other pharmaceutically useful substances; and a second atorvastatin calcium or magnesium salt, magnesium, calcium or magnesium or calcium carbonate or meglumine and optionally other pharmaceutically useful substances. Pharmaceutical composition according to claim 6, characterized in that the two mixtures are either pressed together in a single layer of the tablet or separated in two different layers. Pharmaceutical composition according to any one of the preceding claims, characterized in that the telmisartan mixture consists of a granulate which is joined by a solution of telmisartan salt and PVP and a base formed by sodium or potassium hydroxide, optionally in admixture with meglumine. Pharmaceutical composition according to claim 8, characterized in that type 25 PVP is used for the binder function; 30 or 90 in an amount of 5 to 10% by weight, based on the telmisartan mixture. Pharmaceutical composition according to claim 9, characterized in that the amount of PVP type 25 is chosen to be 8.3 ± 0.5% by weight, based on the telmisartan mixture. Pharmaceutical composition according to claims 1 to 10, characterized in that it contains telmisartan salt with a particle size of 0.5 to 5 µm, which does not form clusters larger than 50 µm. . * * ‘« 3 i · 1 <«i» t <· < .4 4'4 14 · · ** IQ ι i ····· 1/13 ·· «« »·» · Pharmaceutical composition according to claim 11, characterized in that it contains telmisartan salt with a particle size of 2 to 3 µm. Pharmaceutical composition according to claims 6 to 12, characterized in that the telmisartan mixture comprises sodium or potassium hydroxide inside the granules, while meglumine outside the granules. Pharmaceutical composition according to claims 6 to 13, characterized in that it comprises from 0.5 to 15 3 wt. % sodium or potassium hydroxide, 1 to 10 wt. meglumine, 10 to 20 wt. % telmisartan and 0.5 to 3 wt. magnesium stearate, based on the weight of the telmisartan mixture. Pharmaceutical composition according to claim 14, characterized in that it contains 1 to 2 wt. sodium or potassium hydroxide, 4 to 8 wt. % meglumine, 10 to 20 wt. % telmisartan and 0.8 to 2.5 wt. magnesium stearate, based on the telmisartan mixture. Pharmaceutical composition according to any one of the preceding claims, characterized in that it comprises atorvastatin calcium in amorphous form with a particle size of 95% by weight. less than 50 pm. Pharmaceutical composition according to any one of the preceding claims, characterized in that it contains atorvastatin calcium salt in crystalline form having a particle size of 0 to 40 pm. Pharmaceutical composition according to any one of the preceding claims, characterized in that the atorvastatin component is a granulate comprising 50 to 80% by weight of atorvastatin. % of granules of 0.1 to 1.5 mm and 20 to 50 wt. dust fractions below 0.1 mm, wherein the atorvastatin substance is inside these granules. Pharmaceutical composition according to any one of claims 1 to 17, characterized in that the atorvastatin mixture comprises a filler having a particle or granule size of 0.025 to 3 mm, the atorvastatin salt being outside the particles or granules. Pharmaceutical composition according to any one of the preceding claims, characterized in that the atorvastatin mixture comprises a base selected from calcium or magnesium or sodium carbonates or calcium or magnesium or sodium oxide or meglumine. Pharmaceutical composition according to claim 20, characterized in that the base is selected from magnesium oxide, calcium carbonate or meglumine or a combination thereof. Pharmaceutical composition according to any one of the preceding claims, characterized in that it contains tween (polysorbate) in an amount of 0.5 to 10% by weight, based on the atorvastatin mixture. 23. A pharmaceutical composition according to claim 22 comprising tween in an amount of 1 to 4% by weight based on the atorvastatin composition. The pharmaceutical composition of claims 20 to 23, wherein the atorvastatin composition further comprises a filler selected from microcrystalline cellulose, lactose or sorbitol, or a mixture thereof, a binder selected from PVP, hydroxypropylcellulose, hydroxypropylmethylcellulose or starch, a disintegrant selected from croscarmellose, crospovidone , a carboxymethyl cellulose or a salt thereof, and a lubricant selected from stearic acid or a salt thereof. 25. The pharmaceutical composition of claim 24, wherein the atorvastatin mixture comprises a filler mixture of microcrystalline cellulose and lactose, a binder of hydroxypropyl cellulose, croscarmellose as a disintegrant, and a magnesium acid salt. stear as a lubricant. 26. The pharmaceutical composition of claim 25 wherein the atorvastatin composition comprises 5-15% atorvastatin based on free acid, 10-40% lactose, 30-60% microcrystalline cellulose, 2.5-10% croscarmellose, and 5-10% lactose. 20% hydroxypropylcellulose, each based on the atorvastatin mixture. «* I. «T ♦» t 'lata · · »‘ Pharmaceutical composition according to any one of the preceding claims, characterized in that the weight ratio of atorvastatin to telmisartan mixture is between 2: 1 and 1:10. 28. The pharmaceutical composition of claim 27 wherein the weight ratio of atorvastatin to telmisartan mixture is from 1: 1 to 1: 5. A method for producing a composition according to any one of the preceding claims, characterized in that the atorvastatin and telmisartan mixtures are first prepared separately, the mixtures are mixed in a homogenizer and finally compressed in a tabletting machine and optionally coated with a tablet. A method for producing a composition according to claims 1 to 28, characterized in that atorvastatin and telmisartan mixtures are prepared, which are separately fed to a tabletting machine, wherein the telmisartan layer is first compressed and the second atorvastatin layer is compressed. A method according to claim 29 or 30, comprising preparing a telmisartan mixture comprising injecting a solution of telmisartan in water or a mixture of water and ethanol, sodium hydroxide, PVP and optionally meglumine onto a fluidized bed of a filler selected from a soluble mono- or oligosaccharide or a sugar alcohol according to claim 1 or 2, or an insoluble polysaccharide according to claim 1 or 3, after which the dried granulate is mixed with a further proportion of saccharide, a lubricant and, optionally, a meglumine. Process according to claim 31, characterized in that the meglumine is mixed until the granulate is prepared. A method according to claim 29 or 30, comprising preparing a telmisartan mixture by spray drying a solution of telmisartan, sodium hydroxide and optionally meglumine, and mixing the resulting solid mixture with a filler selected from 1 »»; «I ι» ri 'lil i · ¹ »i» »V» r, ti * « From soluble mono- or oligosaccharide or sugar alcohol or insoluble polysaccharide and other excipients and optionally meglumine. 34. The method of claim 33, wherein the meglumine is mixed until the spray dried mixture is prepared. Process according to claim 29 or 30, characterized in that it comprises preparing an atorvastatin mixture by kneading the active substance, filler, binder or part of the disintegrant and optionally carbonate or calcium or magnesium oxide with water, a mixture of water and ethanol or a solution of meglumine in water. of the mixture, after which the resulting mixture is granulated, dried and further processed by grinding or sieving and mixed with the disintegrant or its remaining part, a lubricant and a flow aid. Process according to claim 29 or 30, characterized in that for the preparation of the atorvastatin mixture, the active substance in the form of a salt is mixed with a filler, a binder, optionally a disintegrant and, if appropriate, an appropriate base and compacted in a special compactor or tabletting machine with large the resulting compact is sieved into granules of appropriate size, which are further blended with the disintegrant or the remainder thereof and the lubricant.