EA040745B1 - PHARMACEUTICAL COMPOSITION CONTAINING TWO DIFFERENT ACTIVE INGREDIENTS AND METHOD FOR ITS PRODUCTION - Google Patents

Description

Field of invention

The present invention relates to a pharmaceutical composition containing the active ingredients: rosuvastatin of formula I, having the systematic name (3R,5S,6E)-7-[4-(4-fluorophenyl)-2(N-methylmethanesulfonamido)-6-(propane-2 -yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid, or pharmaceutically acceptable salts thereof, and ezetimibe of formula II, systematically named (3R,4S)-1-(4-fluorophenyl)-3 -[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one, or pharmaceutically acceptable salts thereof, as well as a method for producing this pharmaceutical composition.

(I)

(II)

State of the art

Rosuvastatin or a pharmaceutically acceptable salt thereof is one of HMG-CoA reductase inhibitors that inhibit cholesterol synthesis for the treatment of dyslipidemia. Crestor® tablets (rosuvastatin calcium developed by AstraZeneca) containing rosuvastatin as the main ingredient are widely used to treat dyslipidemia and dyslipidemia-related disorders. In particular, studies have reported superior effects of rosuvastatin in lowering blood levels of LDL cholesterol and increasing levels of good HDL cholesterol in the body compared to the effects of atorvastatin or simvastatin, which are commercially available as drugs having the same mechanism of action as and rosuvastatin. Thus, there is a growing interest in the composition of rosuvastatin.

Ezetimibe (Ezetrol® Tablets, Merck & Co.) is a selective cholesterol absorption inhibitor. HMG-CoA reductase inhibitors are commonly used in combination with a dyslipidemia therapeutic agent having a different mechanism of action from that of HMG-CoA reductase inhibitors to enhance therapeutic effects. Among these combinations, due to the good drug interaction between the HMG-CoA reductase inhibitor and ezetimibe as a cholesterol reabsorption inhibitor drug in the small intestine, combined formulations of the two ingredients are being actively investigated.

Through rigorous research, combination treatment with ezetimibe and rosuvastatin has also been described as having superior pharmaceutical effects. Rosuzet® combined packaging containing both Ezetrol® (ezetimibe) and rosuvastatin MSD tablets was developed by Merck & Co. for the treatment of primary hypercholesterolemia. Viazet® hard capsules containing ezetimibe and rosuvastatin zinc have been developed by EGIS Pharmaceuticals PLC for the treatment of primary hypercholesterolemia. In order to obtain an effective fixed dose formulation in the form of tablets, it is necessary to ensure high bioavailability of the active ingredients. The dissolution profile of active ingredients in a solid oral formulation is closely related to the bioavailability of the formulation, where a high dissolution rate is a prerequisite for high bioavailability.

WO 2009024889 (Ranbaxy Laboratories) refers mainly to combinations of HMG-CoA reductase inhibitors with ezetimibe, and they have the problem of degradation of ezetimibe in the presence of alkali metal salt additives. The problem is solved by adding additives in the form of alkaline earth metal salts instead.

WO 2011019326 (Bilgic Mahmut) relates to a process for the preparation of a pharmaceutical formulation containing ezetimibe and rosuvastatin. Said method includes dissolving ezetimibe and making ezetimibe by wet granulation. Examples of such formulations include only monolayer formulations containing phosphate and microcrystalline cellulose in addition to other excipients.

WO 2012064307 (Bilgic Mahmut) describes formulations of rosuvastatin or a pharmaceutically acceptable salt thereof, wherein the particle size distribution of rosuvastatin d(o, _9o > is greater than 100 µm. The composition of a bilayer tablet is not described sufficiently to be prepared specialist in this field.

WO 2013066279 (Bilgic Mahmut) describes examples of pharmaceutical formulations containing ezetimibe and/or a pharmaceutically acceptable salt thereof with a second active ingredient, wherein the particle size of ezetimibe is between 10 and 50 µm.

WO 2013166117 (Althera Life Sciences) describes examples of solid dosage formulations containing combinations of ezetimibe and rosuvastatin in one tablet, which are expected to have the same area under the curve (AUC) as the two active ingredients taken orally separately. This patent application solves the problem of rosuvastatin degradation by providing an alkaline environment for the rosuvastatin layer; in particular, calcium hydrogen phosphate is mentioned. The method for preparing the ezetimibe layer is very complex and thus also costly: two of the five steps require the use of solvents (organic solvents and water, respectively), each followed by energy-intensive drying. Moreover, the proposed fixing of the ezetimibe solution on the surface with lactose under very strict and specific conditions makes the proposed method inefficient and not sufficiently reliable.

WO 2015044698 (Egis Pharmaceuticals) describes examples of a combined pharmaceutical composition of ezetimibe and rosuvastatin where interaction with individual active ingredients is minimized. The solution to this problem is a capsule containing a tablet containing rosuvastatin zinc salt (2:1) and a tablet containing ezetimibe.

WO 2015102400 (HANMI Pharm. Co.) describes exemplary compositions of ezetimibe and rosuvastatin in the form of a single-layer and a double-layer tablet or capsule. A single example of a bilayer tablet is a composition containing ezetimibe and rosuvastatin, wherein the ezetimibe composition portion comprises magnesium stearate at a concentration of 1.3% by weight.

WO 2015199356 (HANMI Pharm. Co.) relates to a combined formulation comprising ezetimibe and rosuvastatin having improved dissolution rate and efficiency of the active ingredients. The main part of the invention is the critical content of the organic solvent for the preparation of wet ezetimibe granules.

The object of the present invention is to provide a stable bilayer tablet containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts and ezetimibe or its pharmaceutically acceptable salts.

Description of the invention

The invention relates to a stable pharmaceutical composition containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts, hydrates, solvates or esters, and ezetimibe or its pharmaceutically acceptable salts, hydrates, solvates or esters, and the pharmaceutical composition according to the invention has the form of a bilayer tablet where each tablet layer contains only one of these active ingredients.

According to the invention, the weight ratio of the rosuvastatin layer to the ezetimibe layer in the bilayer tablet is preferably between 1:2 and 2:1, including limit values.

According to the invention, the ezetimibe layer preferably contains from 0.15 to 0.5% by weight of a glidant, relative to the total weight of the ezetimibe layer, said glidant being preferably selected from stearic acid or its pharmaceutically acceptable salts.

According to the invention, the ezetimibe layer is preferably free of cellulose and its derivatives, i. the ezetimibe layer contains pharmaceutically acceptable excipients other than cellulose and its derivatives. In another embodiment, the ezetimibe layer contains cellulose and/or its derivatives (preferably microcrystalline cellulose) in an amount of up to 10.5% by weight, including limits, relative to the total weight of the ezetimibe layer, while cellulose and/or its derivatives are present. only in the extragranular phase.

According to the invention, the rosuvastatin layer is free from the main stabilizing excipients.

Another objective of the invention is a reliable method for obtaining such a composition.

Detailed description of the invention

The objective of the invention is a pharmaceutical composition containing rosuvastatin of formula I with the systematic name (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan2-yl)pyrimidin-5 -yl]-3,5-dihydroxyhept-6-enoic acid or pharmaceutically acceptable salts, hydrates, solvates or esters thereof, 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, hydrates, solvates or esters, and pharmaceutically acceptable excipients, characterized in that that it is in the form of a bilayer tablet in which one layer contains ezetimibe as the only active ingredient and the other layer contains rosuvastatin as the only active ingredient.

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Oh OH he (I)

(II)

The advantage of a bilayer tablet is the separation of the individual ingredients, which prevents their interaction and allows each layer of the tablet to be independently adapted to the physicochemical characteristics of the individual active ingredients. Thus, independent and free release of ezetimibe and rosuvastatin from the individual layers of the tablet can be ensured. Bilayer tablets in accordance with individual aspects of the present invention, in addition, show improved physico-chemical properties.

As used herein and unless otherwise indicated, the term ezetimibe refers to ezetimibe or its pharmaceutically acceptable inorganic or organic salt, ester, hydrate, solvate, enantiomer, racemate, polymorph, crystalline form and amorphous form, and/or combinations thereof. According to one aspect of the invention, the bilayer tablet preferably contains an amount corresponding to 10 mg of free ezetimibe, i. e. ezetimibe is not in the form of an inorganic or organic salt, ester, hydrate or solvate.

As used herein and unless otherwise indicated, the term rosuvastatin refers to rosuvastatin or its pharmaceutically acceptable inorganic or organic salt, ester, hydrate, solvate, enantiomer, racemate, crystalline form and amorphous form, and/or combinations thereof. Among the pharmaceutically acceptable salts, inorganic salts are preferred, for example calcium, magnesium, sodium, potassium, lithium, zinc, copper, manganese or cadmium salts. Particularly preferred are the calcium, magnesium, zinc and copper salts, with the calcium and magnesium salts being most preferred, especially the calcium salts. The single layer tablet according to the invention preferably contains an amount corresponding to 2.5-40 mg of free rosuvastatin, i.e. rosuvastatin is not in the form of an inorganic or organic salt, ester, hydrate or solvate.

The term ezetimibe layer refers to one of the two layers of a bilayer tablet that contains the active substance ezetimibe as the only active substance in this layer and pharmaceutically acceptable excipients.

Preferably, the ezetimibe layer contains 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 relative to the total weight of this layer.

Preferably, the ezetimibe layer may contain at least one pharmaceutically acceptable excipient selected from an excipient or a combination of excipients selected from the group of lactose, glucose, cellulose and its derivatives, calcium carbonate, calcium phosphate, starch, mannitol and other sugar alcohols, and other excipients. , a disintegrant or a combination of disintegrants selected from the group of croscarmellose sodium, carboxymethyl starch sodium, crospovidone and alginates, a binder or a combination of binders selected from the group of water-soluble polymers such as polyvinylpyrrolidone, preferably polyvinylpyrrolidone with average molecular weight up to 1500000, preferably up to 60000, water-soluble cellulose derivatives, preferably methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sugar alcohols, preferably mannitol, sorbitol, surface-a active substance or combination of surfactants selected from the group of block copolymers of ethylene oxide and propylene oxide (referred to as poloxamers, where the term poloxamer means a polymer of formula HO(C ₂ H ₄ ) _a (C3H ₆ O)b(C ₂ H ₄ O) _a H, where a and b indicate the number of elements of oxyethylene and oxypropylene), alkyl sulfates, preferably sodium lauryl sulfate, sodium stearyl sulfate, sodium dioctylsulfosuccinate, alkylarylsulfonates, preferably sodium dodecylbenzenesulfonate, polyethylene glycols and polysorbates.

Preferably, the ezetimibe layer contains at least one first pharmaceutically acceptable excipient and at least one second pharmaceutically acceptable excipient.

More preferably, the ezetimibe layer contains a granulate containing ezetimibe and at least one first pharmaceutically acceptable excipient and an extragranular phase containing at least one second pharmaceutically acceptable excipient.

Preferably, the second pharmaceutically acceptable excipient comprises a glidant selected from the group consisting of stearic acid or its pharmaceutically acceptable salts in an amount of 0.15 to 0.5% by weight based on the total weight of the ezetimibe layer.

In a preferred embodiment, the ezetimibe layer contains a granulate and an extra-granular phase, where the granulate is substantially free of cellulose and its derivatives. The extragranular phase may be free of cellulose and its derivatives, or may contain cellulose and/or its derivatives in an amount of up to 10.5% by weight, including the limit value, relative to the total weight of the ezetimibe layer. Those. the ezetimibe layer either contains pharmaceutically acceptable excipients other than cellulose and its derivatives, or contains cellulose and/or its derivatives (preferably microcrystalline cellulose) at a concentration of up to 10.5% by weight, including the limit value, relative to the weight of the ezetimibe layer, only in extragranular phase.

The term rosuvastatin layer refers to one of the two layers of a bilayer tablet which contains the active substance rosuvastatin as the only substance in the layer, preferably in an amount corresponding to 2.5-40 mg of rosuvastatin, and at least one pharmaceutically acceptable excipient. The rosuvastatin layer is preferably free of major stabilizing excipients.

Pharmaceutically acceptable minor excipients in the rosuvastatin layer may include an excipient or a combination of excipients selected from the group of lactose, glucose, cellulose and its derivatives, starch, mannitol and other sugar alcohols, and other minor excipients known in the art, a binder or a combination of binders substances selected from the group of water-soluble polymers such as polyvinylpyrrolidone, preferably polyvinylpyrrolidone with an average molecular weight up to 1500000, preferably up to 60000, water-soluble cellulose derivatives, preferably methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sugar alcohols, preferably mannitol , sorbitol, glidant, or a combination of glidants such as colloidal silicon dioxide, corn starch, magnesium or calcium stearate, stearic acid, sodium stearyl fumarate, talc, polyethylene oxide and other glidants known in the art, a disintegrant, or a combination of disintegrants selected from the group of croscarmellose sodium, carboxymethyl starch sodium, crospovidone, and alginates.

Basic stabilizing excipients are excipients which, after dispersion of the pharmaceutical composition in an aqueous medium, raise the pH above pH 9. Such substances include, for example, carbonates such as calcium carbonate, alkali metal and alkaline earth metal hydroxides such as calcium hydroxide hydroxide, calcium phosphate or calcium hydrogen phosphate, basic amino acids, or meglumine.

The definitions of the ezetimibe layer and the rosuvastatin layer essentially indicate that the claimed bilayer tablet consists of an ezetimibe layer and a rosuvastatin layer. This bilayer tablet may preferably be coated. Moreover, the tablet coating contains film-forming agents such as hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol and optionally other excipients selected from the group of emollients such as triethyl citrate, dibutyl sebacate or polyethylene glycol, surfactants such as sodium lauryl sulfate, dyes, for example, such as iron oxides and titanium dioxide, and anti-caking agents such as talc. If a tablet is mentioned in the description, this should be understood as referring to a bilayer tablet in accordance with the invention.

Reference to Ph. Eur. or European Pharmacopoeia more specifically refers to its 9th edition (released in 2016, version 9.0).

The terms stable formulation and/or stable bilayer tablet refer to a formulation and/or tablet which after stability testing contains less than 1% by weight, preferably less than 0.7% by weight, most preferably less than 0.55% by weight of impurities formed from rosuvastatin, relative to the stated amount of rosuvastatin, and less than 1% by weight, preferably less than 0.5% by weight, most preferably less than 0.2% by weight of impurities formed from ezetimibe, relative to the declared amount of ezetimibe.

In the present description and unless otherwise indicated, the term particle size d( _x ) means that 100xx% of the volume of the particles have a diameter less than, greater than or equal to, respectively, the specified value

- 4 040745 diameter d, when measured by the method of scattering of laser radiation. Those. if, for example, d(o,9o> rosuvastatin is more than 100 µm, then this means that 90% of the particle volume of rosuvastatin or its pharmaceutically acceptable salt exceeds 100 µm when determined by the method of laser light scattering. On the contrary, if, for example, the particle size d( ₀ , ₉₀ ) is 15 µm or less, which means that 90% of the particle volume of ezetimibe or a pharmaceutically acceptable salt thereof is 15 µm or less in size as determined by the laser light scattering method.

Preferably the d( _0.90 ) of ezetimibe _{is 25 µm or less, more preferably the d(0.90 ) is} 20 µm or less, _{and most preferably the d(0.90 )} is 15 µm or less as determined by the laser light scattering method.

Preferably d( _0.90 ) of rosuvastatin is in the range of 100-225 µm _, more preferably d( _0.90 ) is in the range _of 130-200 µm and most preferably d( _0.90 ) is in the range of 150-175 _µm as determined by the laser scattering method. radiation.

During the development of a bilayer tablet containing rosuvastatin and ezetimibe as active ingredients, it was found that during preparation, fragmentation or destruction of the tablet layers occurred and a significant part of the tablets disintegrated into individual layers during further processing. There was also undesirable variability in the average content of active ingredients in individual layers, as well as a lack of uniformity of content, and these two parameters did not meet the requirements defined in the European Pharmacopoeia. As shown in the examples, it turned out that the efficiency and reliability of the method depends on the mass ratio between the ezetimibe layer and the rosuvastatin layer. Testing various ratios showed that this technological problem was solved if the mass ratio of the individual layers was adjusted to a value in the range from 1:2 to 2:1 (including limit values). Such tablets exhibited attrition, as determined using the method according to European Pharmacopoeia, of less than 0.2%.

Another problem that had to be solved in the development of a bilayer tablet of ezetimibe and rosuvastatin was to achieve a sufficient release rate of ezetimibe from the tablet. Ezetimibe is practically insoluble in water, which reduces the dissolution rate in the aquatic environment, as well as, for example, in digestive juice. This may lead to low bioavailability of ezetimibe, i.e. its lack of effectiveness. Thus, the development of a formulation that provides high bioavailability of ezetimibe and a high rate of release of ezetimibe from a tablet is highly desirable in the pharmaceutical industry.

Glidants such as stearic acid and its salts have a negative effect on the release rate of active ingredients from pharmaceutical formulations. Glidants repel water, reducing the rate of dissolution of the active ingredients in the formulation. The reference literature indicates that stearic acid or its pharmaceutically acceptable salts, preferably magnesium stearate and aluminum stearate, can be used in pharmaceutical formulations in an amount of from 0.2 to 2% by weight. However, it is well known in the art that the usual content of stearic acid or its pharmaceutically acceptable salt, preferably magnesium stearate, calcium stearate and/or aluminum stearate, for pharmaceutical processing is about 1% by weight or higher for tablets, so that they can in principle be was to receive. If an insufficient amount of glidants is used, technological problems can be expected during the preparation of tablets, such as sticking of the material to the punch or to the mold.

Surprisingly, it was found that a sufficient amount of stearic acid or its pharmaceutically acceptable salt, preferably magnesium stearate, calcium stearate and/or aluminum stearate, in the ezetimibe layer to obtain bilayer tablets in accordance with the present invention, is from 0.15 to 0.5% by weight (including limit values, relative to the total weight of the ezetimibe layer). The low content of stearic acid or its pharmaceutically acceptable salts, preferably magnesium stearate, calcium stearate and/or aluminum stearate, is advantageous for faster dissolution and release of ezetimibe from the tablet.

Thus, the present invention, which is a bilayer tablet, provides the above-described advantages of a low content of a glidant, which is stearic acid or an acceptable salt thereof, preferably magnesium stearate, calcium stearate and/or aluminum stearate, in the ezetimibe layer to release ezetimibe , and at the same time, these tablets are easy to obtain, despite the low content of a substance that promotes sliding.

Cellulose and its derivatives, especially microcrystalline cellulose, also affect the release rate of ezetimibe from the tablet. Testing of many variants (comparative example C provided for illustration) showed that the presence of cellulose and its derivatives, especially microcrystalline cellulose, in the intragranular phase of the ezetimibe layer, reduced the release of ezetimibe from the tablet. Cellulose and its derivatives can be used in the extragranular phase, but only at concentrations up to 10.5% by weight, including limit values, relative to the weight of the ezetimibe layer, with the limit and advantageous embodiment being a bilayer tablet which contains no cellulose or derivatives at all. cellulose.

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Thus, the bilayer oral tablet of the invention is characterized in that the ezetimibe layer contains pharmaceutically acceptable excipients other than cellulose and its derivatives. Alternatively, the ezetimibe layer may contain cellulose and its derivatives, preferably microcrystalline cellulose, at a concentration of up to 10.5% by weight, including limits, relative to the weight of the ezetimibe layer, only in the extragranular phase.

More than 85% by weight of the claimed content of ezetimibe is released from the bilayer tablets of the invention within 30 minutes in dissolution tests. In a preferred embodiment, more than 90% by weight of the claimed content of ezetimibe and in a particularly preferred embodiment, more than 95% of the claimed content of ezetimibe are released within 30 minutes in dissolution tests.

More than 75% by weight of the claimed content of ezetimibe is released from the bilayer tablets of the invention within 20 minutes in the dissolution test. In a preferred embodiment, more than 80% by weight of the claimed content of ezetimibe in a particularly preferred embodiment, more than 86% of the claimed content of ezetimibe is released within 20 minutes in the dissolution test.

The third aspect of the present invention is the absence of the main excipients in the rosuvastatin layer. From the reference literature it is well known that rosuvastatin and its salts are unstable in an acidic environment. Therefore, reference literature recommends the use of basic stabilizing agents such as calcium carbonate, calcium hydroxide, or phosphates, especially calcium hydrogen phosphate, which is found in the commercial preparation of rosuvastatin Crestor®, to stabilize pharmaceutical formulations of rosuvastatin.

However, dissolution of a formulation containing basic stabilizing excipients may unnaturally increase the normal acidic pH in the stomach, which adversely affects the gastric mucosa. This effect is particularly detrimental to patients suffering from diseases of the stomach and stomach wall, with particular caution required in patients on long-term rosuvastatin therapy. The presence of basic substances in the composition can also have a negative impact on the stability and dissolution of ezetimibe from the total composition of ezetimibe and rosuvastatin.

During development and comparative testing, it was unexpectedly found that for the bilayer tablet according to the invention it was not necessary to use the main stabilizing substances in the rosuvastatin layer.

In a preferred embodiment, the bilayer tablet contains in the ezetimibe layer an ezetimibe granulate with lactose, croscarmellose sodium and/or sodium carboxymethyl starch, sodium lauryl sulfate and/or sodium lauryl stearate, and hydroxypropyl methylcellulose and/or polyvinylpyrrolidone with a molecular weight of less than 60,000. the tablet contains in the ezetimibe layer an extragranular phase with from 0.15 to 0.5% by weight of magnesium stearate or calcium stearate or aluminum stearate (relative to the weight of the ezetimibe layer), croscarmellose sodium and/or carboxymethyl starch sodium, and optionally with microcrystalline cellulose in concentrations up to 10.5% by weight (relative to the weight of the ezetimibe layer).

In a preferred embodiment, the bilayer tablet contains in the rosuvastatin layer: rosuvastatin, lactose, microcrystalline cellulose, croscarmellose sodium and/or carboxymethyl starch sodium, colloidal silicon dioxide, and magnesium stearate and/or calcium stearate and/or aluminum stearate.

In a particularly preferred embodiment, the bilayer tablet contains in the ezetimibe layer an ezetimibe granulate with lactose, croscarmellose sodium, lauryl sulfate sodium and polyvinylpyrrolidone with a molecular weight of less than 35,000, and an extragranular phase containing from 0.15 to 0.5% by weight of magnesium stearate ( relative to the weight of the ezetimibe layer), croscarmellose sodium and optionally microcrystalline cellulose at a concentration of up to 10.5% by weight (relative to the weight of the ezetimibe layer).

In a particularly preferred embodiment, the bilayer tablet contains in the rosuvastatin layer: rosuvastatin, lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

The tablet in accordance with the present invention can be obtained using methods that are well known to the person skilled in the art.

The tableting mixture to form the ezetimibe layer is preferably prepared using known granulation techniques, with wet granulation being preferred. The tabletting mix to form the rosuvastatin layer can preferably be prepared using dry methods, direct mixing and direct compression being preferred. The preferred production method is a combination of wet granulation for the ezetimibe layer and direct mixing and pressing for the rosuvastatin layer. The composition of the rosuvastatin layer according to the invention, which allows direct mixing and pressing, is highly advantageous in terms of time and economy. The pressure ratio for compressing tabletting mixtures into a bilayer tablet is preferably 1:2 to 1:10, the first value referring to the pressure for compressing the first layer (generally the thicker layer) and the second value referring to the pressure for compressing the second layer and the entire pills.

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

The tablet according to the present invention can be obtained by a production method comprising the following steps:

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

b) the obtained ezetimibe granules are mixed with at least one second pharmaceutically acceptable excipient,

c) rosuvastatin or a pharmaceutically acceptable salt thereof is mixed with at least one pharmaceutically acceptable excipient, where the pharmaceutically acceptable excipient(s) is not the main one,

d) the resulting mixture of ezetimibe and rosuvastatin for tableting is compressed into bilayer tablets,

e) the resulting bilayer tablets are optionally coated.

A preferred embodiment includes a method of preparation, where the mixture of ezetimibe with at least one first pharmaceutically acceptable excipient in step a) is wetted using water and the resulting mixture is processed into a granulate by liquid granulation. At least one first pharmaceutically acceptable excipient in step a) is selected from the group consisting of filler, binder, disintegrant, surfactant, or any combination thereof, as described above.

In a preferred embodiment, at least one second excipient in step b) is a glidant selected from the group consisting of stearic acid or acceptable salts thereof, which is used in the ezetimibe layer at a concentration of 0.15 to 0.5% by weight relative to the total weight of this layer, and optionally additional excipients such as a filler, a binder, a disintegrant, or a combination of these substances, as described above.

In a preferred embodiment, at least one second excipient in step b) may include microcrystalline cellulose at a concentration of up to 10.5% by weight (relative to the weight of the ezetimibe layer).

As pharmaceutically acceptable excipients, the rosuvastatin layer may contain at least one pharmaceutically acceptable non-primary excipient as defined for the rosuvastatin layer described above. The first pharmaceutically acceptable excipient and the second pharmaceutically acceptable excipient are as defined for the ezetimibe layer described above.

Individual preferred aspects of the invention are the following embodiments.

1. A two-layer tablet containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, where each layer of the tablet contains only one of these active substances and the ratio of the masses of the individual layers is from 1:2 to 2:1 (including limit values).

2. A bilayer tablet containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, where the layer of ezetimibe contains from 0.15 to 0. 5% by weight of a glidant which is stearic acid or acceptable salts thereof.

3. A bilayer tablet containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, wherein the ezetimibe layer is substantially free of cellulose and its derivatives , or where the ezetimibe layer contains cellulose and its derivatives only in the extragranular phase (preferably microcrystalline cellulose) at a concentration of up to 10.5% by weight, including the limit value, relative to the weight of the ezetimibe layer.

4. A bilayer tablet containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutical

- 7 040745 ceutically acceptable salts, esters, hydrates or solvates, wherein the rosuvastatin layer is substantially free of basic stabilizing excipients.

5. A two-layer tablet containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, where each tablet layer contains only one of these active substances and the weight ratio of the individual layers is from 1:2 to 2:1 (including limits) and where the ezetimibe layer contains a glidant, which is stearic acid or its acceptable salts, at a concentration of from 0.15 to 0.5% by weight relative to the weight of the ezetimibe layer.

6. A two-layer tablet containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, where each layer of the tablet contains only one of these active substances and the mass ratio of the individual layers is from 1:2 to 2:1 (including limit values), and where the ezetimibe layer is essentially free of cellulose and its derivatives, or where the ezetimibe layer contains cellulose and its derivatives only in the extragranular phase (preferably microcrystalline cellulose) at a concentration of up to 10.5% by weight, including the limit value, relative to the weight of the ezetimibe layer.

7. A two-layer tablet containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, where each layer of the tablet contains only one of these active substances and the weight ratio of the individual layers is from 1:2 to 2:1 (including limit values), and where the layer of rosuvastatin is essentially free from the main stabilizing excipients.

8. A two-layer tablet containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, where each layer of the tablet contains only one of these active substances and the weight ratio of the individual layers is from 1:2 to 2:1 (including limits), and where the ezetimibe layer contains a glidant, which is stearic acid or its acceptable salts, at a concentration of from 0.15 to 0.5 % by weight relative to the weight of the ezetimibe layer, and where the ezetimibe layer is essentially free of cellulose and its derivatives, or where the ezetimibe layer contains cellulose and its derivatives only in the extragranular phase (preferably microcrystalline cellulose) at a concentration of up to 10.5% by weight , including the limit value, relative to the weight of the ezetimibe layer.

9. A two-layer tablet containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, where each layer of the tablet contains only one of these active substances and the weight ratio of the individual layers is from 1:2 to 2:1 (including limits), and where the ezetimibe layer contains a glidant, which is stearic acid or its acceptable salts, at a concentration of from 0.15 to 0.5 % by weight, based on the weight of the ezetimibe layer, and wherein the rosuvastatin layer is substantially free of major stabilizing excipients.

10. A two-layer tablet containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, where each layer of the tablet contains only one of these active substances and the weight ratio of the individual layers is from 1:2 to 2:1 (including limit values), and where the ezetimibe layer is essentially free of cellulose and its derivatives, or where the ezetimibe layer contains cellulose and its derivatives only in the extragranular phase (preferably microcrystalline cellulose) at a concentration of up to 10.5% by weight, including the limit value, relative to the weight of the ezetimibe layer, and where the rosuvastatin layer is essentially free of major stabilizing excipients.

11. A two-layer tablet containing as active ingredients rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, where each tablet layer contains only one of these active substances and the weight ratio of the individual layers is from 1:2 to 2:1 (including limits), and where the ezetimibe layer contains a glidant, which is stearic acid or its acceptable salts, at a concentration of from 0.15 to 0.5 % by weight, relative to the weight of the ezetimibe layer, and where the ezetimibe layer is essentially free of cellulose and its derivatives, or where the ezetimibe layer contains cellulose and its derivatives only in the extragranular phase (preferably microcrystalline cellulose) at a concentration of up to 10.5% by weight. weight, including the limiting value, relative to the weight of the ezetimibe layer, and where the rosuvastatin layer is essentially free from the main s stabilizing excipients.

12. The method of obtaining a bilayer tablet according to any of the embodiments of the invention

- 8 040745 tenia 1-11.

13. A method for producing a bilayer tablet according to any of the embodiments of the invention 1-12, wherein the ezetimibe layer is obtained by wet granulation with water as a wetting agent and the rosuvastatin layer is obtained by direct mixing and direct compression, and the compression pressure ratio is in the ratio range from 1 :2 to 1:10.

These embodiments provide the unexpected effect of stability of the composition and improvement in the rate of release and bioavailability of active substances from the composition, solving problems regarding uneven content of individual active substances in tablet layers and undesirable attrition of tablets during manufacture.

Brief description of the drawings

Fig. 1. Dissolution profile for the release of ezetimibe from a bilayer tablet of the invention (Example 13) compared to a tablet according to Comparative Example A.

Fig. 2. Dissolution profile for the release of ezetimibe from a bilayer tablet of the invention (Example 13) compared to a tablet according to Comparative Example C.

Examples

The exemplary embodiments below are provided only to illustrate and explain the invention, and are in no way intended to limit the scope of protection, which is limited only by the wording of the patent claims. Any other modifications to the composition or methods of preparation are possible, as long as they are carried out while maintaining the stability of the composition and the dissolution profile of both active substances.

Examples of stable ezetimibe layer composition

In all of Examples 1-6, the tablet mix for the ezetimibe layer was prepared by wet granulation with water as the granulation wetting agent.

Example 1

Substance name Function Composition (mg/tablet) granulate ezetimibe active ingredient 100 Lactose monohydrate Filler 141.0 sodium salt croscarmellose baking powder 12.0 Sodium lauryl sulfate superficially active substance 4.0 Povidone 25 binder substance 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20.0 sodium salt croscarmellose baking powder 4.0 magnesium stearate glidant 10 Layer-total: 200.0

- 9 040745

Example 2

Substance name Function Composition (mg/tablet) granulate ezetimibe active ingredient 100 Lactose monohydrate filler 137.0 sodium salt carboxymethyl starch baking powder 14.0 Sodium stearyl sulfate superficially active substance 4.0 Hydroxypropyl methylcellulose (Methocel E5) binder substance 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20, 4 sodium salt carboxymethyl starch baking powder 6.0 magnesium stearate glidant 0.6 Layer-total: 200.0

Example 3

Substance name Function Composition (mg/tablet) granulate ezetimibe active ingredient 100 Mannitol filler 141.0 sodium salt croscarmellose baking powder 12.0

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Sodium lauryl sulfate superficially active substance 4.0 Povidone 25 binder substance 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20.7 sodium salt croscarmellose baking powder 4.0 calcium stearate glidant 0.3 Layer-total: 200.0

Example 4

Substance name Function Composition (mg/tablet) granulate ezetimibe active ingredient 100 Lactose monohydrate filler 161.4 sodium salt croscarmellose baking powder 12.0 Sodium lauryl sulfate superficially active substance 4.0 Hydroxypropyl methylcellulose (Methocel E5) binder substance 8.0 Extragranular phase Microcrystalline cellulose filler, binder sodium salt croscarmellose baking powder 4.0 aluminum stearate glidant 0.6 Layer-total: 200.0

- 11 040745

Example 5

Substance name Function Composition (mg/tablet) granulate ezetimibe active ingredient 10.0 Mannitol filler 141.0 sodium salt croscarmellose baking powder 12.0 Sodium lauryl sulfate superficially active substance 4.0 Povidone 25 binder substance 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20.0 sodium salt croscarmellose baking powder 4.0 Stearic acid glidant 10 Layer-total: 200.0

Example 6

Substance name Function Composition (mg/tablet) granulate ezetimibe active ingredient 100

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Lactose monohydrate filler 161.0 sodium salt croscarmellose baking powder 12.0 Sodium lauryl sulfate superficially active substance 4.0 Povidone 25 binder substance 8.0 Extragranular phase Microcrystalline cellulose filler, binder sodium salt croscarmellose baking powder 4.0 magnesium stearate glidant 10 Layer-total: 200.0

Examples of a stable composition for a layer of rosuvastatin

In all of Examples 7-12, the tablet mix for the rosuvastatin layer was prepared by direct mixing.

Example 7

Substance name Function Compo Zicia (mg/tablet) Rosuvastatin layer calcium salt rosuvastatin active ingredient 41.6 Lactose monohydrate filler, binder 244.0 Microcrystalline cellulose filler, binder 94.0 colloidal dioxide silicon substance that promotes 2.4 slip sodium salt croscarmellose baking powder 12.0 magnesium stearate glidant 6.0 Layer-total: 400.0

- 13 040745

Example 8

Substance name Function Composition (mg/tablet) Rosuvastatin layer calcium salt rosuvastatin active ingredient 41.6 Lactose monohydrate filler, binder 244.0 Microcrystalline cellulose filler, binder 94.0 Talc/powder talc glidant 2.4 sodium salt croscarmellose baking powder 12.0 magnesium stearate glidant 6.0 Layer-total: 400.0

Example 9

Substance name Function Composition (mg/tablet) Rosuvastatin layer calcium salt rosuvastatin active ingredient 41.6 Mannitol filler, binder 244.0 2 4 Microcrystalline cellulose filler, binder 94.0 colloidal dioxide silicon glidant 2.4 sodium salt croscarmellose baking powder 12.0 aluminum stearate glidant 6.0 Layer-total: 400.0

- 14 040745

Example 10

Substance name Function Composition (mg/tablet) Rosuvastatin layer calcium salt rosuvastatin active ingredient 41.6 Mannitol filler, binder 240.0 Microcrystalline cellulose filler, binder 94.0 colloidal dioxide silicon glidant 2.4 sodium salt carboxymethyl starch baking powder 16.0 calcium stearate glidant 6.0 Layer-total: 400.0

Example 11.

Substance name Function Composition (mg/tablet) Rosuvastatin layer calcium salt rosuvastatin active ingredient 20, 8 Lactose monohydrate filler, binder 122.0 Microcrystalline cellulose filler, binder 47.0 colloidal dioxide silicon glidant 1.2 sodium salt croscarmellose baking powder 6.0 magnesium stearate glidant thirty Layer-total: 200.0

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Example 12.

Substance name Function Composition (mg/tablet) Rosuvastatin layer calcium salt rosuvastatin active ingredient 10, 4 Lactose monohydrate Microcrystalline cellulose filler, binder filler, binder 61.0 23.5 colloidal dioxide silicon glidant 0.6 sodium salt croscarmellose baking powder thirty magnesium stearate glidant 1.5 Layer-total: 100.0

Stable composition of a bilayer tablet containing an ezetimibe layer and a rosuvastatin layer

Examples 13-15.

Substance name Composition (mg/tablet) Example 13 Example 14 Example 15 Ezetimibe layer 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 Tablet core - total: 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 pigment - 0.03 - Tablet-total: 615.0 410.0 307.48

Abrasion determined using the method according to European Pharmacopoeia was less than 0.2% for examples 13-15.

In a dissolution test, more than 90% by weight of the stated amount of ezetimibe was released from the tablet after 30 minutes.

Trial Example 13 Example 14 Example 15 Time decay 3 min 4 min 3 min

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bilayer tablet Release of ezetimibe after 30 min (% by weight, average for 10 tablets) 98.3% 94.7 97.6% Release of ezetimibe after 30 minutes (% by weight, minimum measured value for 10 tablets) 96.5% 90.7% 94.3 Release of rosuvastatin after 30 minutes (% by weight, average value for 10 tablets) 97.6% 99.6% 99.6% Release of rosuvastatin after 30 minutes (% by weight, minimum measured value for 10 tablets) 95.6% 98.3% 95.7% Trial Example 13 Example 14 Example 15 Content of ezetimibe after manufacturing, average value for 10 tablets (minimum and maximum measured value) 10.2 mg (9.9-10.3 mg) 10.1 mg (10.0-10.2 mg) 10.2 mg (9.9-10.2 mg) Content rosuvastatin after manufacturing, average value for 10 40.2 mg (39.3-40.4 mg) 2 0.1 mg (19.8-20.2 mg) 10.2 mg (9.8-10.3 mg) tablets (minimum and maximum measured value)

- 17 040745

Examples 16-18.

Substance name Composition (mg/tablet) Example 16 Example 17 Example 18 Ezetimibe layer 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 Tablet core - total: 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 pigment - 0.03 - Tablet-total: 615.0 410.0 307.48

Attrition, determined using the method according to European Pharmacopoeia, was less than 0.2% for examples 16-18.

Trial Example 16 Example 17 Example 18 Decay time bilayer tablet 3 min 3 min 4 min Ezetimibe release after 30 minutes (% by mass, average value for 10 tablets) 96.2% 93.4 97.1% Ezetimibe release after 30 minutes (% by mass, minimum measured 86.5% 85.3% 93.2% value for 10 tablets) Release of rosuvastatin after 30 minutes (% by weight, average value for 10 tablets) 97.1% 97.1% 97.5% Release of rosuvastatin after 30 minutes (% by weight, minimum measured value for 10 tablets) 96.3% 93.1% 96.7%

- 18 040745

Examples 19-21.

Substance name Composition (mg/tablet) Example 19 Example 2 0 Example 21 Ezetimibe layer 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 Tablet core - total: 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 pigment - 0.03 - Tablet-total: 615.0 410.0 307.48

Abrasion, determined using the method according to European Pharmacopoeia, was less than 0.2% for examples 19-21.

Trial Example 19 Example 2 0 Example 21 Time decay 5 minutes 3 min 4 min

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bilayer tablet Ezetimibe release after 30 minutes (% by mass, average value for 10 tablets) 96.2% 98.2% 97.4% Ezetimibe release after 30 minutes (% by mass, minimum measured value for 10 tablets) 86.5% 95.8% 90.9% Release of rosuvastatin after 30 minutes (% by weight, average value for 10 tablets) 97.1% 97.4% 98.2% Rosuvastatin release after 30 minutes (% by mass, minimum measured value for 10 tablets) 96.3% 94.7% 96.4%

Comparative examples

In all of Comparative Examples A-D, the tablet mix for the ezetimibe layer was prepared in the same manner as in Examples 1-6, ie. by wet granulation with water as the granulation wetting agent, and a tablet mixture for the rosuvastatin layer was obtained in the same way as in examples 7-12, i.e. through direct mixing. After compression, the bilayer tablets were coated in the same manner as in Example 13.

- 20 040745

Comparative example A: content of magnesium stearate 1% by mass and 1.5% by mass.

Substance name Composition A1 (mg/tablet tablet) Composition A2 (mg/tablet tablet) Ezetimibe granulate: ezetimibe 100 100 Lactose monohydrate 140.0 139.0 sodium salt croscarmellose 12.0 12.0 Sodium lauryl sulfate 4.0 4.0 Povidone 25 8.0 8.0 Extragranular phase: Microcrystalline cellulose 20.0 20.0 sodium salt croscarmellose 4.0 4.0 magnesium stearate 2.0 thirty Ezetimibe layer-total: 200.0 200.0 Rosuvastatin layer: calcium salt rosuvastatin 41.6 41.6 Lactose monohydrate 244.0 244.0 Microcrystalline cellulose 94.0 94.0 colloidal dioxide silicon 2.4 2.4 sodium salt croscarmellose 12.0 12.0 magnesium stearate 6.0 6.0 Rosuvastatin layer- total: 400.0 400.0 Tablet-total: 600.0 600.0

Trial Comparative example A1 Comparative example A2 Decay time two-layer 4 min 5 minutes

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pills Release of ezetimibe after 30 min (% by mass, average value for 10 tablets) 84.7% 81.1% Ezetimibe release after 30 minutes (% by mass, minimal measured value for 10 tablets) 79.1% 77.3% Rosuvastatin release after 30 min (% w/w, mean for 10 tablets) 97.1% 97.4% Release rosuvastatin after 30 min (% by mass, minimal measured value for 10 tablets) 96.3% 94.7%

The dissolution profiles of tablet A2 and the tablet according to example 13 are shown in FIG. 1.

Comparative example B: layer ratio 1:3 and 3:1.

Substance name Composition B1 (mg/tablet tablet) Composition B2 (mg/tablet tablet) Ezetimibe granulate: ezetimibe 100 100 Lactose monohydrate 90.5 224.8 sodium salt 8.0 16.0

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croscarmellose Sodium lauryl sulfate 2.7 5, 3 Povidone 25 5, 3 10.6 Extragranular phase: Microcrystalline cellulose 13.3 26.6 sodium salt croscarmellose 2.7 5, 3 magnesium stearate 0.6 1.3 Ezetimibe layer-total: 133.1 299.9 Rosuvastatin layer: calcium salt rosuvastatin 41.6 10.4 Lactose monohydrate 244.0 61.0 Microcrystalline cellulose 94.0 23.5 colloidal dioxide silicon 2.4 0.6 sodium salt croscarmellose 12.0 thirty magnesium stearate 6.0 1.5 Rosuvastatin layer- total: 400.0 100.0 Tablet-total: 533.1 399.9

Attrition, determined using the method according to European Pharmacopoeia, was 4% for composition B1 and 6% for composition B2.

Trial Comparative example B1 Comparative example B2 Content of ezetimibe after manufacture (average value for 10.2 mg (9.3-10.6 mg) 10.1 mg (9.1-10.7 mg) 10 tablets, minimum and maximum measured value) Content rosuvastatin after manufacturing (average value for 10 tablets, minimum and maximum measured value) 39.9 mg (37.6-42.4 mg) 40.2 mg (38.0-42.7 mg)

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Comparative Example C: Microcrystalline cellulose in the intragranular phase of the ezetimibe layer.

Substance name Function Composition (mg/tablet) granulate ezetimibe active ingredient 10.0 Lactose monohydrate filler 131.0 Microcrystalline cellulose filler, binder 10.0 sodium salt croscarmellose baking powder 12.0 Sodium lauryl sulfate superficially active substance 4.0 Povidone 25 binder substance 8.0 Extragranular phase Microcrystalline cellulose filler, binder 20.0 sodium salt baking powder 4.0 croscarmellose magnesium stearate glidant 10 Layer-total: 200.0

- 24 040745

Substance name Function Composition (mg/tablet) Rosuvastatin layer calcium salt rosuvastatin active ingredient 41.6 Lactose monohydrate filler, binder 244.0 Microcrystalline cellulose filler, binder 94.0 colloidal dioxide silicon glidant 2.4 sodium salt croscarmellose baking powder 12.0 magnesium stearate glidant 6.0 Layer-total: 400.0 Trial Comparative example C Decay time bilayer tablet 7 min Release of ezetimibe after 30 min 82.6%

- 25 040745

Substance name Function (% by mass, average value for 10 tablets) Ezetimibe release after 30 minutes (% by mass, minimal measured value for 10 tablets) 77.3% Release rosuvastatin after 30 min (% by weight, average for 10 tablets) 98.2% Release rosuvastatin after 30 min (% by mass, minimal measured value for 10 tablets) 96.4

Composition (mg/tablet tablet)

The dissolution profile for the release of ezetimibe was quantified and compared with the dissolution profile of the tablet according to Example 13 and 21. The dissolution profiles of the tablet according to Comparative Example C and the tablet according to Example 13 and 21 are shown in FIG. 2.

Comparative Example D: Stabilization of the Rosuvastatin Layer with Calcium Hydrogen Phosphate.

Substance name Composition (mg/tablet) Ezetimibe granulate: ezetimibe 100

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Lactose monohydrate 141.0 sodium croscarmellose salt 12.0 Sodium lauryl sulfate 4.0 Povidone 25 8.0 Extragranular phase: Microcrystalline cellulose 20.0 sodium croscarmellose salt 4.0 magnesium stearate 10 Ezetimibe layer-total: 200.0 Rosuvastatin layer: calcium rosuvastatin salt 41.6 Lactose monohydrate 224.0 Calcium hydrogen phosphate 20 Microcrystalline cellulose 94.0 colloidal silicon dioxide 2.4 sodium croscarmellose salt 12.0 magnesium stearate 6.0 Rosuvastatin layer-total: 400.0 Coating layer: Hydroxypropyl methylcellulose 10.45 Polyethylene glycol 6000 1.50 Titanium dioxide 1.20 Talc 1.80 Red iron oxide 0.05 Yellow iron oxide pigment - Tablet-total: 615.0

Bilayer tablets according to Comparative Example D stabilized with calcium hydrogen phosphate and bilayer tablets according to Example 13 were subjected to a stability test at 40° C. and 75% relative humidity for 6 months. The results show that the bilayer tablet according to the invention is as stable as the calcium hydrogen phosphate stabilized bilayer tablet.

-

Claims (8)

27 040745 Trial Comparative Example 2 Example 13 Total impurities of ezetimibe (average value for 10 tablets, minimum and maximum measured value) 0.06% (<0.05-0.06%) <0.05% (<0.05- 0.06%) Total impurity content of rosuvastatin (average value for 10 tablets, minimum and maximum measured value) 0.28% 0.20-0.32 0.31 (0.24-0.37%) Used methods Unless otherwise indicated, methods according to Ph. Eur (European Pharmacopoeia). Variability in the content of active ingredients, uniformity of content, friability, disintegration time, dosage according to Ph. Eur (European Pharmacopoeia). Definition of dissolution Device with agitators according to Ph. Eur. (European Pharmacopoeia) 900 ml phosphate buffer pH 7.0 ± 0.05 with 0.5% sodium lauryl sulfate, 75 rpm. HPLC chromatography with UV or PDA column detector, Kinetex 2.6 µ, C18, 30x4.60 mm column or equivalent, 0.1% phosphoric acid:methanol (42:58 v/v) mobile phase. ), solvent acetonitrile:water (60:40, v/v), detection at 242 nm. Stability, stability test: storage at 40°C and 75% relative humidity for 6 months. HPLC gradient elution method with UV(RPA) detector, Gemini C6-Phenyl column, 3 µm, 150x4.6 mm or equivalent, mobile phase of 1.0 ml of phosphoric acid per 1000 ml of water (component A) and methanol (component B) according to the gradient program indicated in the table below, detection at 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 Uniformity, content variability HPLC chromatography with column oven and UV detector, Gemini C6-Phenyl, 3 µm, 150x4.6 mm column (Phenomenex) or equivalent, mobile phase 0.085% phosphoric acid:methanol (35:65, v/v .), detection at 245 nm. CLAIM 1. A two-layer oral tablet containing rosuvastatin or its pharmaceutically acceptable salts, and ezetimibe or its pharmaceutically acceptable salts, and pharmaceutically acceptable excipients, characterized in that it consists of one layer of ezetimibe and one layer of rosuvastatin, where the specified layer of ezetimibe consists of granulate and extragranular phase, wherein said extragranular phase contains, as a glidant, stearic acid or its acceptable salts in a concentration of 0.15 to 0.5% by weight, including limit values, relative to the weight of the ezetimibe layer, and at least one additional a pharmaceutically acceptable excipient selected from the group consisting of a filler, a binder and a disintegrant, where the mass ratio of the ezetimibe layer and the rosuvastatin layer is in the range from 1:2 to 2:1, including limit values, and the ezetimibe layer granulate is free from microcrystalline cellulose. 2. The bilayer oral tablet according to claim 1, wherein said glidant is magnesium stearate, calcium stearate and/or aluminum stearate. - 28 040745 3. A bilayer oral tablet according to any one of the preceding claims, characterized in that the ezetimibe layer granulate contains ezetimibe or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient selected from the group consisting of filler, binder, disintegrant and surfactant . 4. A bilayer oral tablet according to any one of claims 1 to 3, characterized in that the extragranular phase of the ezetimibe layer contains microcrystalline cellulose at a concentration of up to 10.5% by weight, including the limit value, relative to the weight of the ezetimibe layer. 5. A bilayer oral tablet according to any one of claims 1 to 4, characterized in that the ezetimibe layer contains an excipient or a combination of excipients selected from the group including lactose, glucose, calcium carbonate, calcium phosphate, starch and sugar alcohols, preferably mannitol and/ or lactose, in particular selected from the group of mannitol and/or lactose, especially lactose monohydrate; and/or a binder or combination of binders selected from the group consisting of water-soluble polymers, preferably polyvinylpyrrolidone, especially polyvinylpyrrolidone with an average molecular weight of up to 1,500,000, preferably up to 60,000; water-soluble cellulose derivatives, preferably methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, in particular selected from the group consisting of polyvinylpyrrolidones, especially polyvinylpyrrolidone with an average molecular weight up to 60,000, and/or hydroxypropylmethylcellulose; and/or a disintegrant or combination of disintegrants selected from the group consisting of croscarmellose sodium, carboxymethyl starch sodium, crospovidone and alginates, preferably croscarmellose sodium; and/or a surfactant or combination of surfactants selected from the group consisting of block copolymers of ethylene oxide and propylene oxide; alkyl sulfates, preferably sodium lauryl sulfate, sodium stearyl sulfate and sodium dioctylsulfosuccinate; alkylarylsulfonates, preferably sodium dodecylbenzenesulfonate; polyethylene glycols and polysorbates, preferably selected from the group consisting of alkyl sulfates, preferably sodium lauryl sulfate or sodium stearyl sulfate, especially sodium lauryl sulfate. 6. A two-layer oral tablet according to any one of the preceding claims, characterized in that the rosuvastatin layer consists of rosuvastatin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, where the specified pharmaceutically acceptable excipient(s) is not the main one, and at least one pharmaceutically acceptable non-basic excipient in the rosuvastatin layer is specifically selected from the group consisting of an excipient or a combination of excipients selected from the group consisting of lactose or its monohydrate, glucose, cellulose and its derivatives, starch and sugar alcohols, preferably from the group comprising lactose monohydrate, microcrystalline cellulose and/or mannitol, a binder or combination of binders selected from the group consisting of polyvinylpyrrolidone; microcrystalline cellulose, water-soluble cellulose derivatives, preferably methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose; and sugar alcohols, preferably mannitol and sorbitol, in particular selected from the group consisting of microcrystalline cellulose, lactose monohydrate and/or mannitol, a disintegrant or a combination of disintegrants selected from the group consisting of croscarmellose sodium, carboxymethyl starch sodium, crospovidone and alginates, preferably croscarmellose sodium and/or sodium carboxymethyl starch, glidant or combination of glidants selected from the group consisting of colloidal silicon dioxide, corn starch, talc, polyethylene oxide, sodium stearyl fumarate and stearic acid or its acceptable salts, preferably stearate calcium, aluminum stearate and magnesium stearate, in particular selected from the group consisting of colloidal silicon dioxide, talc and stearic acid or its acceptable salts, preferably calcium stearate, aluminum stearate and magnesium stearate; and any combination of them. 7. A bilayer oral tablet according to any one of the preceding claims, characterized in that it contains 10 mg of ezetimibe or an appropriate amount of a pharmaceutically acceptable salt thereof and 5-45 mg of rosuvastatin or an appropriate amount of a pharmaceutically acceptable salt thereof. 8. A method for preparing a two-layer oral tablet containing rosuvastatin or its pharmaceutically acceptable salts and ezetimibe or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients and consisting of one layer of ezetimibe and one layer of rosuvastatin, characterized in that it includes steps from a) to d): a) ezetimibe or a pharmaceutically acceptable salt thereof, together with at least one first pharmaceutically acceptable excipient other than microcrystalline cellulose, is granulated using water as a wetting agent, -