CZ2016538A3 - A pharmaceutical composition comprising two different active ingredients - Google Patents

Abstract

: The invention relates to a two-layer tablet containing two different active ingredients, namely rosuvastatin of formula I, with the systematic name (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2--yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe of formula II, with the systematic name (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3--hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one or its pharmaceutically acceptable salts, esters, hydrates or solvates, and suitable pharmaceutically acceptable excipients, in the shape of circular two-layer tablet. The composition has excellent properties both in terms of its physical characteristics and as regards the release rate of the active substances or product stability. (I) (II)

Description

Technical field

The present invention relates to a bilayer tablet containing the active substances rosuvastatin of the formula I, chemically (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -2- (N-methylmethanesulfonamido) -6- (propan-2-yl) pyrimidine -5-yl] -3,5-dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salts and ezetimibe of formula II, chemically (3R, 4S) -1- (4-fluorophenyl) -3 - [(3S) -3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-hydroxyphenyl) azetidin-2-one or a pharmaceutically acceptable salt thereof, and suitable pharmaceutically acceptable excipients, bilayer tablet shape and process for its preparation. The composition has excellent properties both in terms of physical properties and in terms of the release rate of the active ingredient or the stability of the product.

(AND)

BACKGROUND OF THE INVENTION

Rosuvastatin, or a pharmaceutically acceptable salt thereof, is one of the HMG-CoA reductase inhibitors that inhibit cholesterol synthesis in the treatment of dyslipidemia. Crestor® tablets (rosuvastatin calcium developed in AstraZeneca), including rosuvastatin as the main ingredient, have been widely used in the home and abroad to treat dyslipidemia and related problems. In particular, research has shown an excellent effect of rosuvastatin on lowering the level of LDL cholesterol in the blood and increasing the level of favorable HDL cholesterol in the body, compared to the effects of atorvastatin or simvastatin, which is commercially available as a drug with the same mechanism of action as rosuvastatin. As a result, there is an increasing interest in the formulation of rosuvastatin.

• · · · ·

Ezetimibe (Ezetrol® Tablets, Gauge & Co.) is a selective inhibitor of cholesterol absorption.

HMG-CoA reductase inhibitors are generally used in combination with a dyslipidemia treatment agent to enhance the therapeutic effect, since they have a different mechanism of action than HMG-CoA reductase inhibitors. Due to the good drug interactions between the HMG-CoA reductase inhibitor and ezetimibe as a small intestine cholesterol reabsorption inhibiting drug, the composite formulation of the two components between the combinations is actively studied.

According to many researches, combination therapy with ezetimibe and rosuvastatin also shows excellent pharmaceutical effects. Rosuzet® Composite Package, containing Ezetrol® (ezetimibe) and MSD tablets of rosuvastatin, was developed by Měrek & Co. for the treatment of primary hypercholesterolemia. Viazet® hard capsules, containing ezetimibe and rosuvastatin zinc, were developed by EGIS Pharmaceuticals PLC for the treatment of primary hypercholesterolemia. In order to prepare an effective fixed dose tablet formulation, it is necessary to ensure a high bioavailability of the active ingredients. The dissolution pattern of solid form active agents for oral administration is closely related to the bioavailability of the formulation, with a high degree of dissolution based on high bioavailability.

It is apparent from the prior art that Měrek & in their patent application WO2002058732 concerning compositions and therapeutic combinations of a peroxisome proliferator-activated receptor (PPAR) and a sterol absorption inhibitor (s), disclose an ezetimibe formulation comprising magnesium stearate in an amount of 1 wt. %. Examples of bilayer compositions containing ezetimibe together with rosuvastatin are not provided.

WO2009024889 (Ranbaxy Laboratories) relates to general combinations of HMG-CoA reductase inhibitors with ezetimibe and addresses the problem of ezetimibe degradation in the presence of alkali metal salts as an additive. This problem has been solved by adding alkaline earth metals instead of alkali metal salts. The idea of bilayer tablets, capsules and others is presented, although the relevant examples are not given. The only example is a monolayer coated tablet comprising a composition of ezetimibe and rosuvastatin and excipients, including calcium hydrogen phosphate, prepared by mixing the granules of ezetimibe and rosuvastatin. Thus, a two-layer formulation could refrain from using such a phosphate.

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WO2009074286 (Ratiopharm) relates to novel formulations containing ezetimibe alone as active ingredient. The specific composition described herein comprises 0.5 to 1 wt. % of the lubricant and the particle size distribution of ezetimibe at d (0.9) is 5-80 µm and the specific surface area is preferably less than Smgg ^-1 . Examples of bilayer compositions containing ezetimibe together with rosuvastatin are not disclosed.

WO2011012912 (Egis Pharmaceuticals) discloses a method for producing a granulate comprising microcrystalline ezetimibe used for pharmaceutical compositions, wherein ezetimibe is dissolved, precipitated with water, and the resulting granules are obtained by spray suspension to excipients. Examples of a two-layer composition comprising ezetimibe together with rosuvastatin are not disclosed.

WO2011019326 (Bilgic Mahmut) relates to a method of preparing a pharmaceutical composition comprising ezetimibe and rosuvastatin. The process comprises dissolving ezetimibe and preparing ezetimibe by wet granulation. Examples of such formulations include only monolayer compositions containing excipients, including, but not limited to, phosphate and microcrystalline cellulose. Examples of bilayer compositions containing ezetimibe together with rosuvastatin are not disclosed.

WO2011139256 (Bilgic Mahmut) discloses rosuvastatin formulations used in the treatment of hyperlipidemia which include a phosphate salt as a stabilizer. Dicalcium phosphate dihydrate is mentioned, and is used as a phosphate stabilizer in rosuvastatin formulations. Examples of bilayer compositions containing ezetimibe together with rosuvastatin are not disclosed.

WO2012064307 (Belgium Mahmut) discloses forms of rosuvastatin or a pharmaceutically acceptable salt thereof, wherein the particle size distribution of rosuvastatin at d (0.90) is coarser than 100 µm. A composition containing the above substances can also be used as a bilayer tablet phase. The application further describes one example of a bilayer tablet containing the active ingredients rosuvastatin and ezetimibe. The ezetimibe granulate is prepared by dissolving ezetimibe in a solvent. The composition of the bilayer tablet is not sufficiently described to be prepared by one skilled in the art.

WO2013066279 (Bilgic Mahmut) discloses examples of pharmaceutical formulations containing ezetimibe and / or a pharmaceutically acceptable salt thereof with a second active agent, wherein the particle size of the particles is ezetimibe. The ezetimibe is between 10 and 50 µm. The ezetimibe is between 10 and 50 µm. A composition composed of the above substances can also be used as a phase on bilayer tablets. The application further discloses bilayer tablets containing the active substances rosuvastatin and ezetimibe. However, the application does not provide any dissolution and stability data, nor are the compositions described sufficiently to be prepared by one skilled in the art.

WO2013166117 (Althera Life Sciences) discloses examples of solid dosage forms comprising combinations of ezetimibe and rosuvastatin in one tablet, which are expected to be the area under the curve (AUC) of two individually orally used active agents. the patent application solves the problem of the degradation of rosuvastatin by the addition of a basic medium, in particular the addition of calcium phosphate. In the formulation example, the magnesium stearate content is not specified, but it is mentioned that the ezetimibe layer has a magnesium stearate content of 0.2 to 5 wt. %. The process of preparing the ezetimibe layer is very complex, and hence cost-intensive: two steps out of five require the use of solvents (organic solvents and water, respectively), each of which is followed by vigorous drying. In addition, the proposed "assembly" of the ezetimibe solution on the lactose surface under very restrictive and specific conditions renders the proposed process inefficient and non-robust.

WO2015044698 (Egis Pharmaceuticals) describes examples of pharmaceutical compositions comprising ezetimibe and rosuvastatin, in which the interaction between the individual active substances is minimized. The solution to this problem is a capsule containing a tablet with a zinc salt of rosuvastatin (2: 1) and a tablet containing ezetimibe. The magnesium stearate content of ezetimibe is 0.9 wt. %.

WO2015102400 (HANMI Pharm. Co.) describes examples of ezetimibe and rosuvastatin compositions in the form of monolayer or bilayer tablets or capsules. The only example of a bilayer tablet is a composition comprising ezetimibe and rosuvastatin, wherein a portion of the ezetimibe composition comprises 1.3 wt% magnesium stearate. %.

WO2015199356 (HANMI Pharm. Co.) relates to a composite formulation comprising ezetimibe and rosuvastatin with improved dissolution rate and active ingredient rate. The main invention comprises a critical amount of an organic solvent for the preparation of the ezetimibe wet granulate.

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It is an object of the present invention to provide a bilayer tablet comprising as active ingredients rosuvastatin or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof, which will be stable without the use of basic stabilizing excipients, which will also have satisfactory dissolution profiles. production will not be a problem with the robustness of the process and the uniformity of active substance content in the individual layers

SUMMARY OF THE INVENTION

The invention relates to a stable pharmaceutical composition comprising as active substances rosuvastatin or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to the invention being in the form of a bilayer tablet, each tablet layer containing only one of these active ingredients.

The subject of the invention is a bilayer oral tablet having a circular plan with a diameter D and a height ha wherein the ratio Dh is from 1.50: 1.00 to 2.50: 1.00, preferably from 1.70: 1.00 to 2. , 46: 1.00. The present invention also provides a process for the manufacture of such a bilayer tablet.

List of figures in drawings

Giant. 1: Schematic representation of a tablet with a circular plan of height h and diameter D

Giant. 2: Schematic representation of a circular plan view of a tablet having a diameter D

Giant. 3: A schematic representation of a oblong tablet having dimensions A x B and height h

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical composition comprising rosuvastatin of formula I, chemically (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -2- (N-methylmethanesulfonamido) -6- (propan-2-yl) -pyrimidine -5-yl] -3,5-dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salts and ezetimibe of formula II, chemically (3R, 4S) -1- (4-fluorophenyl) -3 - [(3S) -3 - (4-fluorophenyl) -3-hydroxypropyl] -4- (4-hydroxyphenyl) azetidin-2-one or pharmaceutically acceptable salts thereof and suitable pharmaceutically acceptable excipients, characterized in that it is in the form of a bilayer tablet with a single layer of ezetimibe and one layer of rosuvastatin.

F _x ft N - 1 Ύ 0 H s = o ^HO xX II O OH OH (AND)

The advantage of the bilayer tablet is the separation of the individual active ingredients, thus avoiding their interaction, but it also allows each layer of the tablet to be independently adapted to the specific physicochemical properties of the individual active ingredients. Thus, ezetimibe and rosuvastatin can be independently and freely released from the individual tablet layers.

In the development of a bilayer tablet containing rosuvastatin and ezetimibe as active ingredients, a production problem has been observed in which the tablet layers are broken or crushed, or a large proportion of the tablets disintegrated into individual layers during further processing. There was also a problem with the variability of the average active ingredient contents in the individual layers and with the content uniformity as defined in the European Pharmacopoeia. As demonstrated by the examples, this problem was observed with oblong tablets (i.e., oval in plan view, Figure 3) and was unexpectedly resolved when the shape of the tablets was changed to circular plan view (figures 1 and 2). Adjusting the weight ratio between the ezetimibe layer and the rosuvastatin layer to a value in the range of 1: 2 to 2: 1 (including limit values) has also proven advantageous.

Pharmaceutical composition of the invention, which contains rosuvastatin of formula I, chemically (3α, 5S, 6E) -7- [4- (4-fluorophenyl) -2- (N-methylmethanesulfonamido) -6- (propan-2-yl) -pyrimidine -5-yl] -3,5-dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salts and ezetimibe of formula II, chemically (3R, 4S) -1- (4-fluorophenyl) -3 - [(3R) S) -3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-hydroxyphenyl) azetidin-2-one, or a pharmaceutically acceptable salt thereof, and a suitable pharmaceutically acceptable excipient, is in the form of a bilayer tablet with a circular plan view with a diameter D and height L 1 and wherein the ratio of Dh is from 1.50: 1.00 to 2.50: 1.00, preferably from 1.70: 1.00 to 2.46: 1.00.

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Surprisingly, the shape of the tablet has a very significant technological influence on the implementation of the invention. Surprisingly, the importance of a suitable tablet shape has been found in the practice of the invention. Only tablets with a circular footprint with a diameter D and a height h, where the D: h ratio is from 1.50: 1.00 to 2.50: 1.00, preferably from 1.70: 1.00 to 2, were suitable, 46: 1.00.

In a preferred embodiment of the invention, the bilayer tablet is a circular plan with a diameter D and a height h wherein the D: h ratio is between 1.70: 1.00 and 2.10: 1.00 for tablets of rosuvastatin and ezetimibe strengths 40 and 10. mg or an equivalent amount of an individual pharmaceutically acceptable salt, from 1.85: 1.00 to 2.36: 1.00 for tablets having the strength of rosuvastatin and ezetimibe 20 and 10 mg or an equivalent amount of an individual pharmaceutically acceptable salt, and from 1.90: 1.00 to 2.46: 1.00 for tablets of 10 and 10 mg strength of rosuvastatin and ezetimibe or the corresponding amount of each pharmaceutically acceptable salt.

The height of the tablet is another essential parameter of the present invention. A bilayer oral tablet comprising rosuvastatin or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, with a circular footprint of diameter D and height h, wherein the height h is from 3.5 to 6.5 mm, more preferably from 3.7 mm to

6,3 mm.

In a preferred embodiment, the bilayer tablet is a circular plan with a diameter D and a height h, wherein the height h is 5.8 ± 0.5 mm for tablets of 40 and 10 mg strength of rosuvastatin and ezetimibe or an equivalent amount of each pharmaceutically acceptable salt. 7 ± 0.5 mm for tablets with the strength of rosuvastatin and ezetimibe 20 and 10 mg or the corresponding amount of each pharmaceutically acceptable salt and 4.2 ± 0.5 mm for tablets with the strength of rosuvastatin and ezetimibe 10 and 10 mg or the corresponding amount of individual pharmaceutically acceptable salts.

The diameter of the tablet is another parameter of the present invention. A bilayer oral tablet containing rosuvastatin or pharmaceutically acceptable salts thereof and ezetimibe or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, with a circular footprint of diameter D and height h, wherein the diameter D has a value in the range of 8.0 to 12.0 mm, preferably from

8.5 to 11.5 mm, most preferably from 8.9 to 11.1 mm.

In a preferred embodiment, the bilayer tablet is a circular plan with a diameter D and a height h, wherein the diameter D has a value of 11 ± 0.1 mm for tablets of rosuvastatin and ezetimibe strength of 40 and 10 mg or equivalent amounts of individual pharmaceutically acceptable salts. 8 ± 0.1 mm for tablets with the strength of rosuvastatin and ezetimibe 20 and 10 mg or the corresponding amount of each pharmaceutically acceptable salt and 9.0 ± 0.1 mm for tablets with the strength of rosuvastatin and ezetimibe 10 and 10 mg or the corresponding amount of individual pharmaceutically acceptable salts.

In another preferred embodiment, the bilayer tablet is provided with a coating which occupies 0.1 to 1% by weight of the core, more preferably 0.5 to 10% by weight of the core and most preferably 1 to 5% by weight of the core.

The advantages of the circular plan tablet and these parameters are significant in achieving satisfactory values of homogeneity and variability in the content of the active pharmaceutical agent or active pharmaceutical agents in the tablet according to Ph. Eur.

Further, the height of the tablet is surprisingly unusually high and largely outside the usual range of tablet height, i.e. from 3.5 to 6.5 mm, more preferably from 3.7 mm to 6.3 mm. The usual height of the tablets is between 2.0 and 4.0 mm. Among other things, the height of the tablets also has a significant influence on the selection of suitable tablet packs, whether in blisters of different materials or in plastic containers. Further, the diameter of the prepared tablets is within the selected narrower range of the conventional diameter, i.e., in the range of 8.0 to 12.0 mm, preferably 8.5 to 11.5 mm, most preferably 8.9 to 11 mm, 1 mm.

In the implementation of the invention in the form of a different tablet shape, for example oblong shape (see Figure 3) or other shapes, there were significant problems not only with the homogeneity and variability of the content of active pharmaceutical substances in the tablet, but also with disintegration, brittleness and friability of prepared tablets.

The 'height' (thickness) h of a tablet is defined as the perpendicular distance of two parallel tangents to the round surface of the tablet perpendicular to its vertical axis (see Figure 1).

The "diameter" (diamond, symbol 0) D of a circular tablet is defined as the length of a line that passes through the center of the tablet and whose two extreme points lie on a circle forming the perimeter of the circular tablet (see Figures 1 and 2).

'Tablet strength' and / or 'bilayer tablet strength' means the dosage strength of the active substance in a tablet, which is defined by the weight content of the active substance or active substances in the tablet.

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The present invention provides three tablet strengths: tablets of 40 mg rosuvastatin and 10 mg ezetimibe or the corresponding amount of each pharmaceutically acceptable salt, tablets of 20 mg rosuvastatin and ezetimibe 10 mg or the corresponding amount of individual pharmaceutically acceptable salt, and tablets of rosuvastatin 10 mg and ezetimibe 10 mg or an equivalent amount of each pharmaceutically acceptable salt.

The term "ezetimibe" for the purposes of this document means ezetimibe or a pharmaceutically acceptable inorganic or organic salt, hydrate, solvate, enantiomer, racemate, ester, polymorph, crystalline form, and amorphous form and / or combinations thereof. One bilayer tablet according to the invention contains an amount corresponding to 10 mg of free ezetimibe, i.e. ezetimibe, which is not in the form of an inorganic or organic salt, hydrate or solvate.

The term "rosuvastatin" for the purposes of this document means rosuvastatin or a pharmaceutically acceptable inorganic or organic salt, hydrate, solvate, enantiomer, racemate, ester, crystalline form, and amorphous form, and / or combinations thereof. Of the pharmaceutically acceptable salts, inorganic salts are preferred, for example calcium, magnesium, sodium, potassium, lithium, zinc, copper, manganese, or cadmium. Particularly preferred are the calcium, magnesium, zinc and copper salts, of which calcium and magnesium salts, especially calcium salt, are most preferred. One bilayer tablet according to the invention contains an amount corresponding to 2.5-40 mg of free rosuvastatin, i.e. rosuvastatin, which is not in the form of an inorganic or organic salt, ester, hydrate or solvate.

The term "stable formulation" and / or "stable bilayer tablet" means a formulation and / or tablet which, when subjected to a stress test storage at 40 ° C and 75% relative humidity for 6 months, contains

less than 1 wt.%, preferably less than 0.7 wt.%, most preferably less than 0.55 wt. rosuvastatin impurities, based on the declared amount of rosuvastatin; and

less than 1 wt.%, preferably less than 0.5 wt.%, most preferably less than 0.2 wt.%. impurities derived from ezetimibe based on the declared amount of ezetimibe.

For the purpose of this document, the term "particle size d ^" means that the% of the volume of the particles has a diameter smaller than or equal to the stated diameter d as measured by the laser scattering method. Thus, if, for example, 90 90 ros rosuvastatin is greater than 100 µm, it means that 90% by volume of the particles of rosuvastatin or a pharmaceutically acceptable salt thereof is greater than 100 µm, as measured by laser scattering method. Conversely, for example, if the particle size of ezetimibe d (o 90) is equal to or less than 15 µm, this means that 90% of the volume of ezetimibe or a pharmaceutically acceptable salt thereof is equal to or less than 15 µm, as measured by laser scattering method ).

Rosuvastatin or a pharmaceutically acceptable salt thereof should have a particle size d (o 90) of greater than 100 µm, more preferably greater than 150 µm, and most preferably a particle size d (o 90) of greater than 175 pm, measured by laser scattering method.

Ezetimibe or a pharmaceutically acceptable salt thereof should have a particle size d (.9 90) of less than or equal to 15 µm, preferably less than or equal to 10 µm, as measured by laser scattering method, to carry out such a suitable embodiment of the invention.

Preferably, the d (o 90) of ezetimibe is less than or equal to 25 pm, more preferably d (o 90) is less than or equal to 20 pm and most preferably d (o 90) is less than or equal to 15 pm as measured by laser scattering method .

Preferably, the d (o 90) rosuvastatin is in the range 100-225 pm, more preferably the d (o 90) in the range 130-200 pm and most preferably d (o 90) in the range 150-175 pm as measured by laser scattering method).

The term 'layer of ezetimibe' means one of two layers of a bilayer tablet containing the active substance ezetimibe as the only active ingredient in that layer, and pharmaceutically acceptable excipients. Among the other pharmaceutically acceptable excipients, the ezetimibe layer comprises a glidant selected from the group consisting of stearic acid or its acceptable salts, which is used in the ezetimibe layer at a concentration of 0.15 to 0.5% by weight based on the total weight of the layer. As additional excipients, the ezetimibe layer may contain:

- a filler or combination of fillers selected from the group of lactose, glucose, cellulose and its derivatives, calcium carbonate, calcium phosphate, starch, mannitol and other sugar alcohols and other fillers known in the art,

- a disintegrant or combination of disintegrants selected from croscarmellose sodium, carboxymethyl starch sodium, crospovidone and alginates, • disintegrant or a combination of disintegrants selected from croscarmellose sodium, crospovidone and alginates; ···········································

- a binder or combination of binders selected from the group of water-soluble polymers such as polyvinylpyrrolidone, preferably polyvinylpyrrolidone having an average molecular weight of up to 1,500,000, preferably up to 60,000, water-soluble cellulose derivatives, preferably methyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sugar alcohols, preferably mannitol, sorbitol,

- a surfactant or a combination of surfactants selected from the group of block copolymers of ethylene oxide and propylene oxide (the so-called poloxamers, where the term "poloxamer" refers to a polymer of the formula HO (C2H4) and (C3H6O) and (C2H4O) and H; "Refers to the number of oxyethylene and oxypropylene units), alkyl sulfates preferably sodium lauryl sulfate, sodium stearyl sulfate, sodium dioctylsulfosuccinate, alkyl aryl sulfonates preferably sodium dodecylbenzenesulfonate, polyethylene glycols and polysorbates.

In a preferred embodiment, the ezetimibe layer comprises pharmaceutically acceptable excipients other than cellulose and its derivatives or comprises cellulose and its derivatives, preferably microcrystalline cellulose at a concentration of up to 10.5 wt%. including limit values, based on the weight of the ezetimibe layer, only in the extragranular phase.

The term 'rosuvastatin layer' means one of two layers of a bilayer tablet containing the active substance rosuvastatin as the only active ingredient in this layer in an amount corresponding to 2.5-40 mg of rosuvastatin and a pharmaceutically acceptable excipient, which layer is free of basic stabilizing aids substances. As pharmaceutically acceptable non-basic excipients, the rosuvastatin layer may comprise:

- a filler or combination of fillers selected from the group of lactose, glucose, cellulose and its derivatives, starch, mannitol and other sugar alcohols and other non-basic fillers known in the art,

- a binder or combination of binders selected from the group of water-soluble polymers such as polyvinylpyrrolidone, preferably polyvinylpyrrolidone having an average molecular weight of up to 1,500,000, preferably up to 60,000, water-soluble cellulose derivatives, preferably methyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sugar alcohols, preferably mannitol, sorbitol,

- a glidant or combination of glidants such as colloidal silicon dioxide, corn starch and glidants such as magnesium or calcium stearate, stearic acid, sodium stearyl fumarate, talc, polyethylene oxide and other known glidants,

a disintegrant or combination of disintegrants selected from croscarmellose sodium, carboxymethyl starch sodium, crospovidone and alginates.

· · · · · · · • · · · • · • · · · · · · · · · · · · "Basic stabilizing excipients" are excipients which, when the pharmaceutical composition is dispersed in an aqueous medium, increase the pH above pH 9. Such substances are, for example, carbonates such as calcium carbonate, alkali and alkaline earth metal hydroxides such as calcium hydroxide, dicalcium phosphate or dicalcium phosphate, basic amino acids or meglumines.

It is inherent from the definitions of the ezetimibe layer and the rosuvastatin layer that the claimed "bilayer tablet" consists of an ezetimibe layer and a rosuvastatin layer. Preferably, the bilayer tablet may be coated. The tablet coating then comprises film-forming agents such as hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, and optionally other excipients selected from the group of plasticizers such as trieyl citrate, dibutyl sebacate or polyethylene glycol, surfactants such as sodium lauryl sulfate, dyes such as iron oxide and titanium dioxide and anti-sticking ingredients such as talc. The coating occupies 0.1 to 15% by weight of the core, more preferably 0.5 to 10% by weight of the core and most preferably 1 to 5% by weight of the core. Thus, if the coating is, for example, 1% by weight of the core, then the coated core constitutes 101% by weight of the core.

When referring to a " tablet ", it is always understood that it is a " bilayer tablet " according to the invention.

A tablet according to the present invention may be prepared by a manufacturing process comprising the following steps:

a) ezetimibe or a pharmaceutically acceptable salt thereof is granulated together with at least one pharmaceutically acceptable excipient, preferably using a wetting agent,

b) mixing the obtained ezetimibe granules with at least one other pharmaceutically acceptable excipient,

c) mixing rosuvastatin or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable non-basic excipient;

(d) compressed ezetimibe and rosuvastatin tablet into two-layer tablets;

(e) optionally, coating the bilayer tablets obtained with a coating.

A tablet according to the present invention may be prepared by a manufacturing process consisting of the following steps:

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a) ezetimibe or a pharmaceutically acceptable salt thereof is granulated together with at least one pharmaceutically acceptable excipient, preferably using a wetting agent,

b) mixing the obtained ezetimibe granules with at least one other pharmaceutically acceptable excipient,

c) mixing rosuvastatin or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable non-basic excipient;

(d) compressed ezetimibe and rosuvastatin tablet into two-layer tablets;

(e) optionally, coating the bilayer tablets obtained with a coating.

As pharmaceutically acceptable excipients, the rosuvastatin layer may comprise substances as defined in the "rosuvastatin layer" above. As additional excipients, the ezetimibe layer may contain substances as defined in the “ezetimibe layer” above.

A preferred embodiment comprises a preparation process wherein the mixture of ezetimibe with at least one pharmaceutically acceptable excipient according to a) is wetted with water and the resulting mixture is processed to granulate by fluid granulation. Another preferred embodiment comprises a process wherein at least one pharmaceutically acceptable excipient according to a) is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant, or any combination thereof. In a preferred embodiment, the at least one pharmaceutically acceptable excipient other than cellulose and its derivatives according to a) is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant or any combination thereof.

Another preferred embodiment comprises a process wherein at least one pharmaceutically acceptable excipient of (b) in the extragranular phase is a filler, binder or disintegrant, or a combination thereof. Another preferred embodiment comprises a process wherein after adding at least one pharmaceutically acceptable excipient according to b) in the extragranular phase and at least one subsequent homogenization, a glidant or combination of glidants is added and the resulting mixture is again homogenized. In yet another preferred embodiment, the at least one pharmaceutically acceptable excipient of (b) is in the extragranular phase, the glidant being stearic acid or its acceptable salts, preferably magnesium stearate, calcium stearate or aluminum stearate, at a concentration of 0.15 to 0. 5 wt. including limit values based on the weight of the ezetimibe layer, and at least one other pharmaceutically acceptable excipient selected from the group consisting of a filler, a binder and a disintegrant. In another preferred embodiment, the selected pharmaceutically acceptable excipients according to point b) extragranulámí phase other than cellulose and 13 ·· »♦ ·· ·· ·· · _e · • · ta ·» · »• * · · · · * · *. * *.......

Or derivatives thereof, or the cellulose and its derivatives, preferably microcrystalline cellulose, are present in a total concentration of up to 10.5% by weight. including limit values based on the weight of the ezetimibe layer.

More than 80% by weight of the bilayer tablets according to the invention are released in the dissolution tests over 30 minutes. declared content of ezetimibe. Preferably, more than 90 wt. the declared content of ezetimibe, and in a particularly preferred embodiment more than 95 wt. declared content of ezetimibe.

More than 75% by weight of the bilayer tablets according to the invention are released in the dissolution tests in 20 minutes. declared content of ezetimibe. Preferably, more than 80 wt. the declared content of ezetimibe, and in a particularly preferred embodiment more than 86 wt. declared content of ezetimibe.

The disintegration time of the bilayer tablets of the invention is less than 15 minutes, preferably less than 8 minutes, most preferably less than 5 minutes, as measured by the European Pharmacopoeia method. The strength of the bilayer tablets of the invention is at least 60 N, preferably more than 110 N and most preferably more than 140 N, as measured by the European Pharmacopoeia method.

Particular aspects of the invention are the following embodiments:

An embodiment of the invention is a bilayer tablet containing rosuvastatin of formula I, chemically (3R, 5S ^, 6R) -7- [4- (4-fluorophenyl) -2- (N-methylmethanesulfonamido) -6- (propane-2) -yl) -pyrimidin-5-yl] -3,5-dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salts and ezetimibe of formula II, chemically (3R, 4S) -1- (4-fluorophenyl) -3- [ (3 S) -3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-hydroxyphenyl) azetidin-2-one or a pharmaceutically acceptable salt thereof, and a suitable pharmaceutically acceptable excipient having a circular plan view of diameter D and height and wherein the D: h ratio is from 1.50: 1.00 to 2.50: 1.00, preferably from 1.70: 1.00 to 2.46: 1.00.

2. A preferred embodiment of the invention is a bilayer tablet comprising as active ingredients rosuvastatin or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof, with a circular plan view with a diameter D and a height ha wherein the D: h ratio is in the range of 1.70: 1; 00 to 2.10: 1.00 for tablets of 40 and 10 mg strength of rosuvastatin and ezetimibe or the corresponding amount of each pharmaceutically acceptable salt, from 1.85: 1.00 to 1.00: 1.00 to 1.00: 1.00 * · E · r «9 9 9 9 99 199 9 »

2.36: 1.00 for rosuvastatin and ezetimibe 20 and 10 mg tablets or the corresponding amount of each pharmaceutically acceptable salt, and from 1.90: 1.00 to 2.46: 1.00 for rosuvastatin and ezetimibe tablets 10 and 10 mg or an equivalent amount of each pharmaceutically acceptable salt.

3. Another embodiment of the invention is a bilayer oral tablet comprising rosuvastatin or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, with a circular plan view of diameter D and height h, wherein height h is from 3.5 to 6 5 mm, more preferably from 3.7 mm to 6.3 mm. A preferred embodiment is a bilayer tablet containing rosuvastatin or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof, with a circular plan view with a diameter D and a height h, wherein the height h is 5.8 ± 0.5 mm for tablets of thickness rosuvastatin and ezetimibe 40 and mg, or an equivalent amount of the individual pharmaceutically acceptable salts, 4.7 ± 0.5 mm for tablets with the strength of rosuvastatin and ezetimibe 20 and 10 mg, or the corresponding amount of each pharmaceutically acceptable salt, and 4.2 ± 0.5 mm for tablets of 10 and 10 mg rosuvastatin and ezetimibe strength or the corresponding amount of each pharmaceutically acceptable salt.

4. Another embodiment of the invention is a bilayer oral tablet comprising rosuvastatin or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, with a circular plan view of diameter D and height h, wherein diameter D is in the range of 8.0 to 12.0 mm, preferably from 8.5 to 11.5 mm, most preferably from 8.9 to 11.1 mm. A preferred embodiment is a bilayer tablet comprising as active ingredients rosuvastatin or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof, with a circular plan view with a diameter D and height h, wherein the diameter D is ± 0.1 mm for tablets of rosuvastatin and ezetimibe strength 40 and 10 mg or an equivalent amount of each pharmaceutically acceptable salt, 9.8 ± 0.1 mm for tablets of 20 and 10 mg strength of rosuvastatin and ezetimibe or 9.0 ± 0.1 mm for tablets of 0 the strengths of rosuvastatin and ezetimibe 10 and 10 mg, or the corresponding amounts of the individual pharmaceutically acceptable salts.

In preferred embodiments, the bilayer tablet containing as active ingredients rosuvastatin or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof is provided with a coating which occupies 0, 1 to 15% by weight of the core, more preferably 0.5 to 10% by weight of the core, and most preferably 1 to 5% by weight of the core.

These embodiments bring about an unexpected effect on the stability of the composition and on the release of the active ingredients from the composition, while solving the problem of uniformity of content of the individual active ingredients in the tablet layers and abrasion of the tablets in manufacture.

Examples

The following examples are intended to illustrate and explain the invention, and are not intended to limit the scope of protection as defined by the claims. Any other modification of the composition or production methods is possible provided that it is made in accordance with the preservation of the stability of the composition and the dissolution profile of both active substances.

Examples of stable ezetimibe layer formulation

In all Examples 1 to 6, a tablet for the ezetimibe layer was prepared by wet granulation.

Example 1

Substance name Function Ingredients (mg / tbl) Granulate Ezetimibe active substance 10.0 Lactose monohydrate filler 141.0 Croscarmellose sodium disintegrant 12.0 Sodium lauryl sulfate surfactant 4.0 Povidone 25 binder 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20.0 Croscarmellose sodium disintegrant 4.0 Magnesium stearate glidant 1.0 Total layer: 200.0

• ·

Example 2

Substance name Function Ingredients (mg / tbl) Granulate Ezetimibe active substance 10.0 Lactose monohydrate filler 137.0 Carboxymethyl starch sodium disintegrant 14.0 Sodium stearyl sulfate surfactant 4.0 Hydroxypropyl methylcellulose (Methocel E5) binder 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20.4 Carboxymethyl starch sodium disintegrant 6.0 Magnesium stearate glidant 0.6 Total layer: 200.0

Example 3

Substance name Function Ingredients (mg / tbl) Granulate Ezetimibe active substance 10.0 Mannitol filler 141.0 Croscarmellose sodium disintegrant 12.0 Sodium lauryl sulfate surfactant 4.0 Povidone 25 binder 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20.7 Croscarmellose sodium disintegrant 4.0 Calcium stearate glidant 0.3 Total layer: 200.0

Example 4 ·

Substance name Function Ingredients (mg / tbl) Granulate Ezetimibe active substance 10.0 Lactose monohydrate filler 161.4 Croscarmellose sodium disintegrant 12.0 Sodium lauryl sulfate surfactant 4.0 Hydroxypropyl methylcellulose (Methocel E5) binder 8.0 Extragranular phase Microcrystalline cellulose filler, binder - Croscarmellose sodium disintegrant 4.0 Aluminum stearate glidant 0.6 Total layer: 200.0

Example 5

Substance name Function Ingredients (mg / tbl) Granulate Ezetimibe active substance 10.0 Mannitol filler 141.0 Croscarmellose sodium disintegrant 12.0 Sodium lauryl sulfate surfactant 4.0 Povidone 25 binder 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20.0 Croscarmellose sodium disintegrant 4.0 Stearic acid glidant 1.0 Total layer: 200.0

Example 6

Substance name Function Ingredients (mg / tbl) Granulate Ezetimibe active substance 10.0 Lactose monohydrate filler 161.0 Croscarmellose sodium disintegrant 12.0 Sodium lauryl sulfate surfactant 4.0 Povidone 25 binder 8.0 Extragranular phase Microcrystalline cellulose filler, binder - Croscarmellose sodium disintegrant 4.0 Magnesium stearate glidant 1.0 Total layer: 200.0

Examples of stable formulation of rosuvastatin layer

In all Examples 7-12, a tablet for the ezetimibe layer was prepared by direct mixing.

Example 7

Substance name Function Ingredients (mg / tbl) Rosuvastatin tablet Rosuvastatin calcium salt active substance 41.6 Lactose monohydrate filler, binder 244.0 Microcrystalline cellulose filler, binder 94.0 Colloidal silica glidant 2.4 Croscarmellose sodium disintegrant 12.0 Magnesium stearate glidant 6.0 Total layer: 400.0

• ·

Example 8

Substance name Function Ingredients (mg / tbl) Rosuvastatin tablet Rosuvastatin calcium salt active substance 41.6 Lactose monohydrate filler, binder 244.0 Microcrystalline cellulose filler, binder 94.0 Talc / slide glidant 2.4 Croscarmellose sodium disintegrant 12.0 Magnesium stearate glidant 6.0 Total layer: 400.0

Example 9

Substance name Function Ingredients (mg / tbl) Rosuvastatin tablet Rosuvastatin calcium salt active substance 41.6 Mannitol filler, binder 244.0 Microcrystalline cellulose filler, binder 94.0 Colloidal silica glidant 2.4 Croscarmellose sodium disintegrant 12.0 Aluminum stearate glidant 6.0 Total layer: 400.0

Example 10

Substance name Function Ingredients (mg / tbl) Rosuvastatin tablet Rosuvastatin calcium salt active substance 41.6 Mannitol filler, binder 240.0 Microcrystalline cellulose filler, binder 94.0 Colloidal silica glidant 2.4 Carboxymethyl starch sodium disintegrant 16.0 Calcium stearate glidant 6.0 Total layer: 400.0

Example 11

Substance name Function Ingredients (mg / tbl) Rosuvastatin tablet Rosuvastatin calcium salt active substance 20.8 Lactose monohydrate filler, binder 122.0 Microcrystalline cellulose filler, binder 47.0 Colloidal silica glidant 1,2 Croscarmellose sodium disintegrant 6.0 Magnesium stearate glidant 3.0 Total layer: 200.0

Example 12

Substance name Function Ingredients (mg / tbl) Rosuvastatin tablet Rosuvastatin calcium salt active substance 10.4 Lactose monohydrate filler, binder 61.0 Microcrystalline cellulose filler, binder 23.5 Colloidal silica glidant 0.6 Croscarmellose sodium disintegrant 3.0 Magnesium stearate glidant 1.5 Total layer: 100.0

A stable bilayer tablet formulation comprising an ezetimibe layer and a rosuvastatin layer according to the preceding examples

Example 13-15

Substance name Ingredients (mg / tbl) Ingredients (mg / tbl) Ingredients (mg / tbl) Layer of ezetimibe according to Example 1 according to Example 1 according to Example 1 Rosuvastatin layer according to Example 7 according to example 11 according to Example 12 Total tablet core: 600.0 400.0 300.0 Coating layer Hydroxypropyl methylcellulose 10.45 6.97 5.23

• ·

Substance name Ingredients (mg / tbl) Ingredients (mg / tbl) Ingredients (mg / tbl) Polyethylene glycol 6000 1.50 1 0.75 Titanium dioxide 1.20 0.8 0.6 Talc 1.80 1,2 0.9 Red iron oxide 0.05 - - Yellow iron oxide - 0.03 - Total tablet: 615.0 410.0 307.48 Diameter (D) of the tablet 11 ± 0.1 mm 9.8 ± 0.1 mm 9.0 ± 0.1 mm Height (/ z) of the tablet 5.8 ± 0.5 mm 4.7 ± 0.5 mm 4.2 ± 0.5 mm

Example 16-18

Substance name Ingredients (mg / tbl) Ingredients (mg / tbl) Ingredients (mg / tbl) Layer of ezetimibe according to Example 2 according to Example 4 according to Example 5 Rosuvastatin layer according to Example 8 according to example 11 according to Example 12 Total tablet core: 600.0 400.0 300.0 Coating layer Hydroxypropyl methylcellulose 10.45 6.97 5.23 Polyethylene glycol 6000 1.50 1 0.75 Titanium dioxide 1.20 0.8 0.6 Talc 1.80 1,2 0.9 Red iron oxide 0.05 - - Yellow iron oxide - 0.03 - Total tablet: 615.0 410.0 307.48 Tablet diameter (D) 11 ± 0.1 mm 9.8 ± 0.1 mm 9.0 ± 0.1 mm Height (h) of the tablet 5.8 ± 0.5 mm 4.7 ± 0.5 mm 4.2 ± 0.5 mm

Example 19-21

Substance name Ingredients (mg / tbl) Ingredients (mg / tbl) Ingredients (mg / tbl) Layer of ezetimibe according to Example 1 according to Example 3 according to Example 6 Rosuvastatin layer according to Example 9 according to example 11 according to Example 12 Total tablet core: 600.0 400.0 300.0 Coating layer

Substance name Ingredients (mg / tbl) Ingredients (mg / tbl) Ingredients (mg / tbl) Hydroxypropyl methylcellulose 10.45 6.97 5.23 Polyethylene glycol 6000 1.50 1 0.75 Titanium dioxide 1.20 0.8 0.6 Talc 1.80 1,2 0.9 Red iron oxide 0.05 - - Yellow iron oxide - 0.03 - Total tablet: 615.0 410.0 307.48 Diameter (D) of the tablet 11 ± 0.1 mm 9.8 ± 0.1 mm 9.0 ± 0.1 mm The height (//) of the tablet 5.8 ± 0.5 mm 4.7 ± 0.5 mm 4.2 ± 0.5 mm

Comparative examples

Comparative Example A - C

The formulation was prepared in the form of a bilayer oblong tablet (see Figure 3).

Substance name Ingredients (mg / tbl) Ingredients (mg / tbl) Ingredients (mg / tbl) Ezetimibe granulate: Ezetimibe 10.0 10.0 10.0 Lactose monohydrate 141.0 141.0 141.0 Croscarmellose sodium 12.0 12.0 12.0 Sodium lauryl sulfate 4.0 4.0 4.0 Povidone 25 8.0 8.0 8.0 Extragranular phase: Microcrystalline cellulose 20.0 20.0 20.0 Croscarmellose sodium 4.0 4.0 4.0 Magnesium stearate 1.0 1.0 1.0 Total ezetimibe: 200.0 200.0 200.0 Rosuvastatin layer: Rosuvastatin calcium salt 41.6 20.8 10.4 Lactose monohydrate 244.0 122.0 61.0 Microcrystalline cellulose 94.0 47.0 23.5 Colloidal silica 2.4 1,2 0.6

• 999 • 9999 9 9 999 999 9

Substance name Ingredients (mg / tbl) Ingredients (mg / tbl) Ingredients (mg / tbl) Croscarmellose sodium 12.0 6.0 3.0 Magnesium stearate 6.0 3.0 1.5 Total rosuvastatin layer: 400.0 200.0 100.0 Total tablet: 600.0 400.0 300.0 Size (A x B) of the tablet (14 x 7) ± 0.1mm (12.1 x 6.1) ± 0.1 mm (11.1 X 5.6) ± 0.1 mm Height (/ z) of the tablet 5.0 ± 0.5 mm 4.3 ± 0.5 mm 3.4 ± 0.5 mm

Surprisingly, the following problems with these parameters, which did not meet the pharmacopoeial specification (Ph. Eur.), Occurred for the tablets thus prepared:

unsatisfactory uniformity of active substance content (see comparative example D below)

- unsatisfactory disintegration, brittleness and friability (abrasion was higher than 1%)

- unsatisfactory homogeneity

Comparative example

The content of rosuvastatin and ezetimibe in tablets of various shapes

Limit by Ph. Eur. Tablet shape Oblong shape Circular floor plan Tablet size (mm) 13,9x6,9 Q 11 Tablet height (mm) 5.3 5.7 Rosuvastatin content in the tablet (mg) 38.0-42.0 W36.9 39.35 The content of ezetimibe in the tablet (mg) 9,5-10,5 10.7 10.15

Methods used

Unless otherwise specified, Ph.Eur methods were used. (European Pharmacopoeia).

Variability of active substance contents, content uniformity, abrasion, disintegration time, strength

- according to Ph.Eur. (European Pharmacopoeia)

Measurement of Dissolution ··· · ······························ 0 · ·· ·· ·· ··· ·

- Apparatus with stirrers according to Ph.Eur. (European Pharmacopoeia)

- 900 ml, phosphate buffer pH 7,0 ± 0,05 with 0,5% sodium lauryl sulphate, 75 rpm

- HPLC chromatography with column thermostat and UV or PDA detector, Kinetex column

2,6 μ, C18, 30 x 4,60 mm or equivalent, mobile phase 0,1% phosphoric acid:

methanol (42:58 v / v), solvent acetonitrile: water (60:40, v / v), detection 242 nm

Stability

- stress test, storage at 40 ° C and 75% relative humidity for 6 months

- gradient HPLC elution method with UV (PDA) detector, Gemini C6-Phenyl column, 3 pm, 150 x 4.6 mm or equivalent, mobile phase 1.0 ml phosphoric acid per 1000 ml water (component A), and methanol (component B) in the gradient program according to the table below, detection 245 nm

Time (min) Component A (% v / v) Component B (% v / v) 0 45 55 11.0 40 60 14.0 25 75 19.0 25 75 19.5 45 55 23.0 45 55

Content uniformity, content variability

- HPLC chromatography with column thermostat and UV detector, Gemini C6-Phenyl column, pm, 150 x 4.6 mm (Phenomenex) or equivalent, mobile phase 0.085% phosphoric acid: methanol (35: 65, v / v), detection 245 nm

Claims (17)

PATENT CLAIMS A bilayer oral tablet comprising rosuvastatin or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, characterized in that it consists of one layer of ezetimibe and one layer of rosuvastatin. The bilayer oral tablet according to claim 1, characterized in that the tablet has a circular plan view with a diameter D and a height ha wherein the ratio D: h is from 1.50: 1.00 to 2.50: 1.00, preferably from 1.70: 1.00 to 2.46: 1.00. The bilayer oral tablet according to claim 2, wherein the tablet has a circular plan view with a diameter D and a height h and wherein the D: h ratio is in the range of: from 1.70: 1.00 to 2.10: 1.00 for tablets having the strength of rosuvastatin and ezetimibe 40 and 10 mg or the corresponding amount of each pharmaceutically acceptable salt, from 1.85: 1.00 to 2.36: 1, 00 for tablets of 20 and 10 mg strength of rosuvastatin or ezetimibe or the corresponding amount of each pharmaceutically acceptable salt, and from 1.90: 1.00 to 2.46: 1.00 for tablets of 10 and 10 mg strength of rosuvastatin and ezetimibe or the corresponding the amount of each pharmaceutically acceptable salt. The bilayer oral tablet according to claims 1 and / or 2, characterized in that the height h has a value of from 3.5 to 6.5 mm, preferably from 3.7 mm to 6.3 mm. The bilayer oral tablet according to claim 4, characterized in that the height h has a value of: 5.8 ± 0.5 mm for tablets of 40 and 10 mg strength of rosuvastatin and ezetimibe or an equivalent amount of each pharmaceutically acceptable salt, 4,7 ± 0,5 mm for tablets of 20 and 10 mg strength of rosuvastatin and ezetimibe or an equivalent amount of each pharmaceutically acceptable salt, and 4.2 ± 0.5 mm for tablets of 10 and 10 mg rosuvastatin and ezetimibe strength or the corresponding amount of each pharmaceutically acceptable salt. The bilayer oral tablet according to claims 1 and / or 2, characterized in that the diameter D has a value in the range from 8.0 to 12.0 mm, preferably from 8.5 to 11.5 mm, · · * * * * * * · · · · · · · · · · · · · · · · · * · The bilayer oral tablet according to claim 6, wherein the diameter D has a value in the range from 8.9 to 11.1 mm. The bilayer oral tablet according to claims 6 and 7, characterized in that the diameter D has a value of: 11 ± 0.1 mm for tablets of 40 and 10 mg strength of rosuvastatin and ezetimibe or an equivalent amount of each pharmaceutically acceptable salt, 9.8 ± 0.1 mm for tablets of 20 and 10 mg strength of rosuvastatin and ezetimibe or an equivalent amount of each pharmaceutically acceptable salt; and 9.0 ± 0.1 mm for tablets of 10 and 10 mg rosuvastatin and ezetimibe strength or the corresponding amount of each pharmaceutically acceptable salt. The bilayer oral tablet according to any one of claims 1 to 8, wherein the weight ratio between the ezetimibe layer and the rosuvastatin layer has a value in the range of 1: 2 to 2: 1, including limit values. A bilayer oral tablet according to any one of claims 1 to 9, characterized in that it is coated. The bilayer oral tablet according to claim 10, characterized in that the tablet coating occupies 0.1 to 15% by weight of the core, more preferably 0.5 to 10% by weight of the core, most preferably 1 to 5% by weight of the core. The bilayer oral tablet according to claims 10 and / or 11, characterized in that a film-forming agent or a combination of film-forming agents selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose and polyvinyl alcohol is used in the coating. The bilayer oral tablet according to claims 10 to 12, characterized in that a plasticizer or plasticizer combination selected from the group consisting of trieyl citrate, dibutyl sebacate and polyethylene glycols is further used in the coating. The bilayer oral tablet according to any one of claims 1 to 13, characterized in that it has a hardness value of at least 60 N, preferably more than 110 N and most preferably more than 140 N under the conditions defined by Ph. Eur. • • • • The bilayer oral tablet according to any one of claims 1 to 14, characterized in that the disintegration value is less than 15 min, preferably less than 8 min, most preferably less than 5 min under the conditions defined by Ph. Eur. The bilayer oral tablet according to any one of claims 1 to 15, characterized in that the particle size d (o 90) of rosuvastatin or a pharmaceutically acceptable salt thereof in the rosuvastatin layer is greater than 100 µm, more preferably greater than 150 µm, and most preferably particle d (o 90) should be greater than 175 µm. The bilayer oral tablet according to any one of claims 1 to 16, characterized in that the particle size d (o 90) of ezetimibe or a pharmaceutically acceptable salt thereof in the ezetimibe layer is equal to or less than 15 µm, preferably equal to or less than 15 µm. 10 pm.