WO2018041281A1

WO2018041281A1 - A pharmaceutical composition comprising rosuvastatin and ezetimibe and a preparation method thereof

Info

Publication number: WO2018041281A1
Application number: PCT/CZ2017/050036
Authority: WO
Inventors: Alena Prokopova; Jaroslava SVOBODOVA; Ondrej Dammer; Petr Mikes
Original assignee: Zentiva, K.S.
Priority date: 2016-09-05
Filing date: 2017-08-31
Publication date: 2018-03-08
Also published as: CZ2016538A3; TW201821063A

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

A PHARMACEUTICAL COMPOSITION COMPRISING ROSUVASTATIN AND

EZETIMIBE AND A PREPARATION METHOD THEREOF

Field of the Invention An object of the invention is a two-layer tablet comprising the active ingredients 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, and ezetimibe of formula II, with the systematic name (3R,4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4- hydroxyphenyl)azetidin-2-one or its pharmaceutically acceptable salts, and pharmaceutically acceptable excipients, the shape of the two-layer tablet and a method of its production. The composition has excellent properties both from the point of view of its physical characteristics and as regards the release rate of the active substance or product stability.

Background Art Rosuvastatin or a pharmaceutically acceptable salt thereof is one of HMG-CoA reductase inhibitors that inhibit the synthesis of cholesterol to treatment dyslipidaemia. Crestor^® tablets (rosuvastatin calcium salts developed by AstraZeneca), including rosuvastatin as a main ingredient, have been widely used for the treatment of dyslipidaemia and dyslipidaemia- related disorders. In particular, research has been reporting on excellent effects of rosuvastatin in lowering LDL cholesterol levels in blood and increasing beneficial HDL cholesterol levels in the body, compared to the effects of atorvastatin or simvastatin, which is commercially available as a drug having the same mechanism as rosuvastatin. Accordingly, there is an increasing interest in rosuvastatin formulation. Ezetimibe {Ezetrof* tablets, Merck & Co.) is a selective cholesterol absorption inhibitor. HMG-CoA reductase inhibitors are generally used in a combination with a therapeutic agent for dyslipidaemia having a different mechanism from that of the HMG-CoA reductase inhibitors to enhance therapeutic effects. Among such combinations, due to good drug interaction between the HMG-CoA reductase inhibitor and ezetimibe as a drug inhibiting the re-absorption of cholesterol in the small intestine, composite formulations of these two ingredients are actively being studied. Through much research, combined treatment of ezetimibe with rosuvastatin is also reported as having excellent pharmaceutical effects. Rosuzet^® composite pack, containing both Ezetrol^® (ezetimibe) and MSD rosuvastatin tablets, was developed by Merck & 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 formulation in a tablet form, it is necessary to ensure high bioavailability of the active ingredients. A dissolution pattern of the active ingredients of a solid formulation for oral administration is closely related to the bioavailability of the formulation, wherein high dissolution rate is premised on high bioavailability.

WO2009024889 (Ranbaxy Laboratories) relates generally to combinations of HMG-CoA reductase inhibitors with ezetimibe and deals with the problem of degradation of ezetimibe in the presence of alkali metal salt additives. The issue is solved by addition of alkaline earth metal additives instead.

WO2011019326 (Bilgic Mahmut) relates to a process for preparation of a pharmaceutical formulation comprising ezetimibe and rosuvastatin. The said process includes dissolution of ezetimibe and preparation of ezetimibe by wet granulation. The examples of such formulations include only monolayer compositions comprising a phosphate and microcrystalline cellulose among other excipients.

WO2012064307 (Bilgic Mahmut) discloses rosuvastatin or its pharmaceutically acceptable salt formulations wherein the rosuvastatin particle size distribution d_(0.90) is coarser than 100 μηι. The examples are not disclosed sufficiently to be reproduced by a person skilled in the art.

WO2013066279 (Bilgic Mahmut) discloses examples of pharmaceutical formulations comprising ezetimibe and/or pharmaceutically acceptable salt thereof with a second active ingredient wherein the particle size of ezetimibe is between 10 to 50 μπι. The examples are not disclosed in an enabling manner.

WO2013166117 (Althera Life Sciences) discloses examples of solid dosage formulations comprising combinations of ezetimibe and rosuvastatin in one tablet that is expected to have the same area under curve (AUC) as two active ingredients taken individually orally. This patent application solves the issue of rosuvastatin degradation by addition of a basic milieu to the rosuvastatin layer; particularly the addition of dicalcium phosphate is mentioned. The process for preparation of the ezetimibe layer is very complex and thus also cost-demanding: two steps out of the five require usage of solvents (organic solvents and water, respectively), each of them followed by energy demanding drying. Furthermore, the proposed "mounting" of ezetimibe solution on lactose surface under very restricting and specific conditions makes the proposed process ineffective and not robust enough. WO2015044698 (Egis Pharmaceuticals) discloses examples of combined ezetimibe and rosuvastatin pharmaceutical composition wherein the interaction with the individual active ingredients is minimized. The solution to such a problem is a capsule containing a tablet comprising rosuvastatin zinc salt (2: 1) and a tablet comprising ezetimibe. WO2015102400 (HANMI Pharm. Co.) discloses examples of ezetimibe and rosuvastatin compositions in a form of a single-layered or a double-layered tablet or capsules. The only example of a double-layered tablet is a composition containing ezetimibe and rosuvastatin wherein the ezetimibe part of the composition includes magnesium stearate in the concentration of 1.3 wt.%.

WO2015199356 (HANMI Pharm. Co.) relates to a composite formulation including ezetimibe and rosuvastatin having improved dissolution rate and velocity of active ingredients. The main invention is the critical content of organic solvent for the preparation of ezetimibe wet-granules.

An object of the present invention is a two-layer tablet comprising as the active ingredients rosuvastatin or its pharmaceutically acceptable salts and ezetimibe or its pharmaceutically acceptable salts that will be stable even without the use of basic stabilizing excipients and that will at the same time have acceptable dissolution profiles of both active substances and whose industrial production will achieve a sufficient process robustness and uniformity of the contents of the active ingredients in individual layers.

Disclosure of the Invention

The invention relates to a stable pharmaceutical composition comprising, as the active ingredients, rosuvastatin or its pharmaceutically acceptable salts, hydrates, solvates or esters, and ezetimibe or its pharmaceutically acceptable salts, hydrates, solvates or esters, the pharmaceutical composition according to the invention having the form of a two-layer tablet wherein each layer of the tablet only contains one of these active ingredients.

An object of the invention is a two-layer oral tablet that has a circular horizontal cross-section with the diameter D and height h and where the D : h ratio is preferably from 1.50 : 1.00 to 2.50 : 1.00, more preferably from 1.70 : 1.00 to 2.46 : 1.00.

Another object of the invention is a production method of such a two-layer tablet.

Brief description of the Drawings Fig. 1: Schematic representation of a tablet with a circular horizontal cross-section with the height h and diameter D.

Fig. 2: Schematic representation of the circular horizontal cross-section of the tablet with the diameter D.

Fig. 3: Schematic representation of an oblong-shaped tablet with the dimensions A x B and height h. Detailed description of the Invention

An object of the invention is a pharmaceutical composition comprising 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, hydrates, solvates or esters, and ezetimibe of formula II, with the systematic name (3R,4S)-l-(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 it is in the form of a two-layer tablet with one layer comprising ezetimibe as the only active ingredient and one layer comprising rosuvastatin as the only active ingredient.

An advantage of the two-layer tablet is separation of individual ingredients, which prevents their interaction and also allows to independently adapt each tablet layer to the physicochemical characteristics of individual active ingredients. Thus, independent and free releasing of ezetimibe and rosuvastatin from individual layers of the tablet can be ensured. The two-layer tablets according to individual aspects of the present invention show further improved physico-chemical properties.

During the development of a two-layer tablet containing the active ingredients rosuvastatin and ezetimibe, it was observed that during production, breaking and/or crushing of the tablet layers occurred, or a large proportion of tablets fell apart into individual layers during further processing. Also observed was an undesired variability of the average contents of the active ingredients in individual layers as well as lack of uniformity of the contents, and these two parameters did not comply with the requirements as defined by the European Pharmacopoeia. As demonstrated in the examples, this problem was observed in tablets having oblong shape (i.e. with an oval horizontal cross-section, Fig. 3) and it was unexpectedly solved when the shape of the tablets was changed to tablets with a circular horizontal cross-section (Fig. 1 and 2). An adjustment of the weight ratio between the ezetimibe and rosuvastatin layer to a value in the range of 1:2 to 2: 1 (including the limit values) also proved to be advantageous.

The pharmaceutical composition according to the invention, which comprises 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, hydrates, solvates or esters, and ezetimibe of formula II, with the systematic name (3R,4S)-l-(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, is in the form of a two-layer tablet with a circular horizontal cross-section with the diameter D and height h, and where the D : h ratio is preferably from 1.50 : 1.00 to 2.50 : 1.00, more preferably from 1.70 : 1.00 to 2.46 : 1.00.

The shape of the tablet surprisingly has a very significant technological effect when working the invention. During the working of the invention, the importance of a suitable shape of the tablet was surprisingly established. Two-layer tablets comprising a rosuvastatin layer and an ezetimibe layer having a circular horizontal cross- section with the diameter D and height h, wherein preferably the D : h ratio is from 1.50 : 1.00 to 2.50 : 1.00, more preferably from 1.70 : 1.00 to 2.46 : 1.00, show an improved hardness, an improved resistance against crushing and breaking during the production process, an improved stability of the active ingredients, and an improved homogeneity and variability parameters of the contents.

In a preferred embodiment of the invention, a two-layer tablet is provided having a circular horizontal cross-section with the diameter D and height h, wherein the D : h ratio is in the range from 1.70 : 1.00 to 2.10 : 1.00 for tablets with the strength of rosuvastatin and ezetimibe of 40 and 10 mg, respectively; from 1.85 : 1.00 to 2.36 : 1.00 for tablets with the strength of rosuvastatin and ezetimibe of 20 and 10 mg, respectively; and from 1.90 : 1.00 to 2.46 : 1.00 for tablets with the strength of rosuvastatin and ezetimibe of 10 and 10 mg, respectively. Another aspect of the present invention relates to the height of the tablet. A two-layer oral tablet comprising rosuvastatin or its pharmaceutically acceptable salts, hydrates, solvates or esters, and ezetimibe or its pharmaceutically acceptable salts, hydrates, solvates or esters, and pharmaceutically acceptable excipients, with a circular horizontal cross-section with the diameter D and height h, preferably has the height h in the range from 3.5 to 6.5 mm, more preferably from 3.7 mm to 6.3 mm.

In a preferred embodiment, a two-layer tablet is provided having a circular horizontal cross- section with the diameter D and height h, wherein the height h has a value of 5.8 + 0.5 mm for tablets with the strength of rosuvastatin and ezetimibe of 40 and 10 mg, respectively; 4.7 + 0.5 mm for tablets with the strength of rosuvastatin and ezetimibe of 20 and 10 mg, respectively; and 4.2 + 0.5 mm for tablets with the strength of rosuvastatin and ezetimibe of 10 and 10 mg, respectively. Yet another aspect of the present invention relates to the diameter of the tablet. A two-layer oral tablet comprising rosuvastatin or its pharmaceutically acceptable salts, hydrates, solvates or esters, and ezetimibe or its pharmaceutically acceptable salts, hydrates, solvates or esters, and pharmaceutically acceptable excipients, with a circular horizontal cross-section with the diameter D and height h, preferably has the diameter D in the range from 8.0 to 12.0 mm, preferably from 8.5 mm to 11.5 mm, most preferably from 8.9 to 11.1 mm.

In a preferred embodiment, a two-layer tablet is provided having a circular horizontal cross- section with the diameter D and height h, wherein the diameter D has a value of 11 + 0.1 mm for tablets with the strength of rosuvastatin and ezetimibe of 40 and 10 mg, respectively; 9.8 + 0.1 mm for tablets with the strength of rosuvastatin and ezetimibe of 20 and 10 mg, respectively; and 9.0 + 0.1 mm for tablets with the strength of rosuvastatin and ezetimibe of 10 and 10 mg, respectively;.

In another preferred embodiment, the two-layer tablet is fitted with coating, which preferably takes up 0.1 to 15 % of the core weight, more preferably 0.5 to 10 % of the core weight and most preferably 1 to 5 % of the core weight. The advantages of the tablet having a circular horizontal cross-section are significant to achieve acceptable values of homogeneity and variability of the contents of the active pharmaceutical ingredient(s) in the tablet in accordance with Ph. Eur. Furthermore, the height of the tablet is surprisingly unusually high and to a great extent it exceeds the usual range of tablet heights. The height of the tablet of the present invention is preferably from 3.5 to 6.5 mm, more preferably from 3.7 mm to 6.3 mm or from 4.2 to 6.5 mm. The usual height of tablets typically varies in the range of 2.0 to 4.0 mm. The height of tablets has, among other things, a material influence on the selection of suitable packing of tablets, both in blister packs of various materials and in plastic containers. Further, the diameter size of finished tablets is in a selected narrower range of the usual diameter size, i.e. in the range from 8.0 to 12.0 mm, preferably from 8.5 to 11.5 mm, most preferably from 8.9 to 11.1 mm. When the tablet was produced with another shape than that described in the present invention, e.g. in an oblong shape (see Fig. 3) or other shapes, significant problems occurred regarding homogeneity and variability of the contents of active pharmaceutical substances in the tablet, as well as concerning the values of disintegrability, brittleness and friability of finished tablets.

The references to Ph. Eur. or European Pharmacopoeia relate more specifically to its 9^th Edition (released in 2016, version 9.0).

The "horizontal cross-section" is a shape obtained by cutting the tablet by a plane passing through the tablet, parallel to its base.

The tablet of the invention, having a circular horizontal cross-section, may have an overall cylindrical shape, optionally with rounded edges and/or substantially rounded or lentil-shaped bases.

The "height" (thickness) ft of a tablet is defined as the vertical distance of two parallel tangents to the surface of the tablet, the tangents being directed perpendicularly to its vertical axis (see Fig. 1). The "diameter" (symbol 0) D of a tablet with a circular horizontal cross-section is defined as the length of an abscissa that passes through the center of the tablet and whose terminal points lie on the circle delimiting the perimeter of the circular tablet (see Fig. 1 and 2).

"Tablet strength" and/or "two-layer tablet strength" refers to the dosage strength of the active ingredients in the tablet which is defined by the strength content of the active ingredient(s) in the tablet. The strength of an ingredient refers to an amount of free active ingredient. When the active ingredient is present in the form of a salt, ester, hydrate or solvate, the amount of the salt, ester, hydrate or solvate is such that it corresponds to the amount of free active ingredient indicated as "strength". E.g., the strength of ezetimibe of 10 mg corresponds to 10 mg of free ezetimibe, or a corresponding amount of ezetimibe salt, ester, hydrate or solvate. This invention relates in particular to three tablet strengths: tablets with the strength of rosuvastatin of 40 mg and ezetimibe of 10 mg; tablets with the strength of rosuvastatin of 20 mg and ezetimibe of 10 mg; and tablets with the strength of rosuvastatin of 10 mg and ezetimibe of 10 mg.

In this text and unless indicated otherwise, 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 combination thereof. According to the invention, a two-layer tablet preferably contains the amount corresponding to 10 mg of free ezetimibe, i.e. ezetimibe that is not in the form of an inorganic or organic salt, ester, hydrate or solvate. In this text and unless indicated otherwise, 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 combination thereof. Among the pharmaceutically acceptable salts, inorganic salts, e.g. calcium, magnesium, sodium, potassium, lithium, zinc, copper, manganese or cadmium salts are preferred. Calcium, magnesium, zinc and copper salts are especially preferred, with the calcium and magnesium salts being most preferred, especially the calcium salt. One two-layer tablet according to the invention preferably contains the amount corresponding to 2.5 - 40 mg of free rosuvastatin, i.e. rosuvastatin that is not in the form of an inorganic or organic salt, ester, hydrate or solvate. The term "stable formulation" and/or "stable two-layer tablet" refers to such a formulation and/or tablet that, subjected to a stability test, contains

- less than 1 % by weight, preferably less than 0.7 % by weight, most preferably less than 0.55 % by weight of impurities derived from rosuvastatin, relative to the declared quantity 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 derived from ezetimibe, relative to the declared quantity of ezetimibe.

In this text and unless indicated otherwise, the term "particle size d_(x)" means that lOOx x % of the particle volume have a diameter that is smaller than, larger than or equal to, respectively, the said diameter value d, measured with the laser scattering method. I.e. if e.g. d_(0.90) of rosuvastatin is larger than 100 μιη, it means that 90 % of the volume of particles of rosuvastatin or its pharmaceutically acceptable salt are larger than 100 μιη, measured with the laser scattering method. Conversely, if e.g. the particle size d_(0.90) is equal to or smaller than 15 μιη, it means that 90 % of the volume of particles of ezetimib or its pharmaceutically acceptable salt are equal to or smaller than 15 μιη, measured with the laser scattering method. In a preferred embodiment of the invention, rosuvastatin should have the particle size d_(0.90) larger than 100 μιη, more preferably larger than 150 μιη and most preferably the particle size d(o.90) should be larger than 175 μιη, measured with the laser scattering method.

Preferably, d_(0.90) of rosuvastatin is in the range of 100-225 μιη, more preferably d_(0.90) is in the range of 130-200 μιη and most preferably d_(0.90) is in the range of 150-175 μιη, measured with the laser scattering method.

Preferably, d_(0.90) of ezetimibe is smaller than or equal to 25 μιη, more preferably d_(0.90) is smaller than or equal to 20 μιη and most preferably d_(0.90) is smaller than or equal to 15 μιη, measured with the laser scattering method. In a more preferred embodiment of the invention, ezetimibe should have the particle size d₍o.90) equal to or smaller than 15 μιη, preferably equal to or smaller than 10 μιη, measured with the laser scattering method. The term "ezetimibe layer" refers to one of the two layers of the two-layer tablet that contains the active substance ezetimibe as the only active substance in this layer, and pharmaceutically acceptable excipients.

Preferably, the ezetimibe layer comprises at least one first pharmaceutically acceptable excipient and at least one second pharmaceutically acceptable excipient. More preferably, the ezetimibe layer comprises a granulate comprising ezetimibe and at least one first pharmaceutically acceptable excipient, and an extragranular phase comprising at least one second pharmaceutically acceptable excipient. Preferably, the second pharmaceutically acceptable excipients include 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, relative to the total weight of the ezetimibe layer.

Furthermore, the first and the second pharmaceutically acceptable excipients in the ezetimibe layer may be selected from:

- a filler or a combination of fillers, preferably 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 from the prior art,

- a disintegrant or a combination of disintegrants selected from the group of the sodium salt of croscarmellose, sodium salt of carboxymethyl starch, crospovidone and alginates,

- a binder or a combination of binders selected from the group of water-soluble polymers as polyvinylpyrrolidone, preferably polyvinylpyrrolidone with the average molecular weight of up to 1,500,000, preferably up to 60,000, water-soluble cellulose derivatives, preferably methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, 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 (referred to as poloxamers, where the term "poloxamer" means a polymer of formula HO(C₂H₄)a(C₃H₆0) (C₂H₄0)<2H, wherein "a" and "b" indicate the number of oxyethylene and oxypropylene units), alkyl sulphates, preferably sodium lauryl sulphate, sodium stearyl sulphate, sodium dioctyl sulfosuccinate, alkyl aryl sulfonates, preferably sodium dodecyl benzene sulfonate, polyethylene glycols and polysorbates.

In a preferred embodiment, the ezetimibe layer comprises a granulate and an extragranular phase, wherein the granulate is substantially free of cellulose and its derivatives. The extragranular phase may be free of cellulose and its derivaties, or may contain cellulose and/or its derivatives in an amount of up to 10.5% by weight, incl. the limit values, relative to the weight of the ezetimibe layer. I.e., the ezetimibe layer either comprises pharmaceutically acceptable excipients different from cellulose and its derivatives, or it comprises cellulose and its derivatives, preferably microcrystalline cellulose, at a concentration of up to 10.5% by weight, incl. the limit values, relative to the weight of the ezetimibe layer, in the extragranular phase only.

The term "rosuvastatin layer" refers to one of the two layers of the two-layer tablet that contains the active substance rosuvastatin as the only active substance in this 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 basic stabilizing excipients.

The pharmaceutically acceptable non-basic excipients in the rosuvastatin layer may include: - a filler or a 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 from the prior art,

- a binder or a combination of binders selected from the group of water-soluble polymers such as polyvinylpyrrolidone, preferably polyvinylpyrrolidone with the average molecular weight of up to 1,500,000, preferably up to 60,000, water-soluble cellulose derivatives, preferably methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sugar alcohols, preferably mannitol, sorbitol,

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

- a disintegrant or a combination of disintegrants selected from the group of the sodium salt of croscarmellose, sodium salt of carboxymethyl starch, crospovidone and alginates. "Basic stabilizing excipients" are such excipients that, after dispersing the pharmaceutical composition in an aqueous environment, increase the pH value above pH 9. Such substances are e.g. carbonates such as calcium carbonate, hydroxides of alkaline metals and alkaline earth metals such as calcium hydroxide, calcium phosphate, or calcium hydrogen phosphate, basic amino acids or meglumine.

The definitions of the ezetimibe layer and the rosuvastatin layer inherently indicate that the claimed "two-layer tablet" consists of an ezetimibe layer and a rosuvastatin layer. This two- layer tablet can be preferably coated. The coating of the tablets then comprises film-forming substances such as hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, and optionally other excipients selected from the group of softeners such as e.g. triethyl citrate, dibutyl sebacate, or polyethylene glycol, surfactants such as e.g. sodium lauryl sulphate, colorants such as e.g. iron oxides and titanium dioxide, and additives preventing sticking of tablets together, e.g. talc. The coating takes up 0.1 to 15 % of the core weight, more preferably 0.5 to 10 % of the core weight and most preferably 1 to 5 % of the core weight. So if the coating takes up e.g. 1 % of the core weight then the coated core takes up 101 % of the core weight.

If the text refers to a "tablet", it is to be understood as referring to the "two-layer tablet" according to the invention, unless indicated otherwise.

The tablet in accordance with the present invention can be prepared by means of a production process comprising the following steps:

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

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

c) rosuvastatin or its pharmaceutically acceptable salt, ester, hydrate or solvate, is mixed together with at least one pharmaceutically acceptable non-basic excipient,

d) the obtained tableting blend of ezetimibe and rosuvastatin is compressed into two- layer tablets having a circular horizontal cross-section,

e) the obtained two-layer tablets are optionally coated. As the pharmaceutically acceptable excipients, the rosuvastatin layer can comprise at least one pharmaceutically acceptable non-basic excipient as defined in the above-described "rosuvastatin layer". The term "at least one pharmaceutically acceptable non-basic excipient" refers to one or more excipients, each of which is a non-basic excipient. The first pharmaceutically acceptable excipient and the second pharmaceutically acceptable excipients are as defined in the above-described "ezetimibe layer".

A preferred embodiment comprises a preparation method wherein a mixture of ezetimibe with at least one first pharmaceutically acceptable excipient according to point a) is wetted with the use of water and the obtained mixture is processed into granulate by means of fluid granulation. Another preferred embodiment comprises a preparation method wherein the at least one first pharmaceutically acceptable excipient in accordance with point a) is selected from a group comprising a filler, a binder, a disintegrant, a surfactant or any combinations thereof. In a preferred embodiment, the at least one first pharmaceutically acceptable excipient is other than cellulose and its derivatives.

Another preferred embodiment comprises a preparation method wherein the at least one second pharmaceutically acceptable excipient in accordance with point b) is a filler, a binder or a disintegrant, or a combination of these substances. Another preferred embodiment comprises a preparation method wherein after the addition of the at least one second pharmaceutically acceptable excipient according to point b) in the extragranular phase and at least one subsequent homogenization, a glidant or a combination of glidants is added and the obtained mixture is homogenized. In still another preferred embodiment, the at least one second pharmaceutically acceptable excipient according to point b) in the extragranular phase is a glidant, which is stearic acid or its acceptable salts, preferably magnesium stearate, calcium stearate or aluminum stearate, at a concentration of 0.15 to 0.5% by weight., incl. the limit values, relative to the weight of the ezetimibe layer, and at least one additional pharmaceutically acceptable excipient selected from a group comprising a filler, a binder and a disintegrant. In another preferred embodiment, the second pharmaceutically acceptable excipients according to point b) in the extragranular phase are other than cellulose and its derivatives. In yet another preferred embodiment, the second pharmaceutically acceptable excipients according to point b) in the extragranular phase are cellulose and/or its derivatives, preferably microcrystalline cellulose, in a total amount of up to 10.5 % by weight, incl. the limit values, relative to the weight of the ezetimibe layer.

More than 80% by weight of the declared contents of ezetimibe are released from the two- layer tablets according to the invention during 30 min in dissolution tests. In a preferred embodiment, more than 90% by weight of the declared contents of ezetimibe and in an especially preferred embodiment, more than 95% of the declared contents of ezetimibe is released during 30 min in dissolution tests. More than 75% by weight of the declared contents of ezetimibe are released from the two- layer tablets according to the invention during 20 min in dissolution tests. In a preferred embodiment, more than 80% by weight of the declared contents of ezetimibe and in an especially preferred embodiment, more than 86% of the declared contents of ezetimibe is released during 20 min in dissolution tests.

The disintegration time of the two-layer tablets according to the invention is less than 15 min, preferably less than 8 min, most preferably less than 5 min, measured with the method according to the European Pharmacopoeia. The hardness of the two-layer tablets according to the invention is at least 60 N, preferably more than 110 N and most preferably more than 140 N, measured with the method according to the European Pharmacopoeia.

Preferred aspects of the invention are the following embodiments:

I. An embodiment of the invention is represented by a two-layer tablet comprising 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,45)-l-(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 pharmaceutically acceptable excipients, that has a circular horizontal cross-section with the diameter D and height h and where 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 represented by a two-layer tablet comprising as the active substances rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, with a circular horizontal cross-section with the diameter D and height h and wherein the D : h ratio is in the range from 1.70 : 1.00 to 2.10 : 1.00 for tablets with the strength of rosuvastatin and ezetimibe of 40 and 10 mg, respectively; from 1.85 : 1.00 to 2.36 : 1.00 for tablets with the strength of rosuvastatin and ezetimibe of 20 and 10 mg, respectively; and from 1.90 : 1.00 to 2.46 : 1.00 for tablets with the strength of rosuvastatin and ezetimibe of 10 and 10 mg, respectively.

3. Another embodiment of the invention is a two-layer oral tablet comprising rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, and pharmaceutically acceptable excipients, with a circular horizontal cross-section with the diameter D and height h, wherein the height h has a value from 3.5 to 6.5 mm, more preferably from 3.7 mm to 6.3 mm. A preferred embodiment is a two-layer tablet comprising as the active substances rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, having a circular horizontal cross- section with the diameter D and height h, wherein the height h has a value of 5.8 + 0.5 mm for tablets with the strength of rosuvastatin and ezetimibe of 40 and 10 mg; 4.7 + 0.5 mm for tablets with the strength of rosuvastatin and ezetimibe of 20 and 10 mg, respectively; and 4.2 + 0.5 mm for tablets with the strength of rosuvastatin and ezetimibe of 10 and 10 mg, respectively. 4. Another embodiment of the invention is a two-layer oral tablet comprising rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, and pharmaceutically acceptable excipients, with a circular horizontal cross-section with the diameter D and height h, wherein the diameter D has a value in the range from 8.0 to 12.0 mm, preferably from 8.5 mm to 11.5 mm, most preferably from 8.9 to 11.1 mm. A preferred embodiment is a two- layer tablet comprising as the active substances rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, having a circular horizontal cross-section with the diameter D and height h, wherein the diameter d has a value of 11 + 0.1 mm for tablets with the strength of rosuvastatin and ezetimibe of 40 and 10 mg, ; 9.8 + 0.1 mm for tablets with the strength of rosuvastatin and ezetimibe of 20 and 10 mg, respectively; and 9.0 + 0.1 mm for tablets with the strength of rosuvastatin and ezetimibe of 10 and 10 mg, respectively.

5. In preferred embodiments, the two-layer tablet comprising as the active substances rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, is provided with a coating that takes up 0.1 to 15 % of the core weight, more preferably 0.5 to 10 % of the core weight and most preferably 1 to 5 % of the core weight.

These embodiments bring an unexpectedly improved effect on stability of the composition and on releasing of the active substances from the composition, solving the problems concerning uneven contents of individual active substances in the tablet layers and abrasion of tablets during the production. Those skilled in the art will appreciate that the features of embodiments 1.-5. as described herein above can be combined.

Examples The examples described herein below are only provided to illustrate and to explain the invention and are not in any case intended to restrict the scope of protection, which is only delimited by the wording of the patent claims. Any other modifications of the composition or production methods are possible if they are implemented in line with maintaining the stability of the composition and the dissolution profile of both the active substances.

Examples of a stable formulation of the ezetimibe layer

In the Examples 1 to 6, the tableting blend for the ezetimibe layer was prepared by wet granulation.

Examples of a stable formulation of the rosuvastatin layer In the Examples 7 to 12, the tableting blend for the rosuvastatin layer was prepared by direct mixing.

Stable formulation of a two-layer tablet comprising an ezetimibe layer and a rosuvastatin layer according to the Examples above

Comparative Examples

Comparative Example A - C

Composition prepared in the form of a two-layer tablet having an oblong shape (see Fig. 3).

The tablets prepared according to comparative examples A-C were associated with the following problems with certain parameters which did not comply with the specifications of the Pharmacopoeia (Ph. Eur.):

- substandard uniformity of the contents of the active substances (see Comparative

Example D below)

substandard disintegrability, brittleness and friability (the abrasion was higher than 1%)

substandard homogeneity

Comparative Example D

Contents of rosuvastatin and ezetimibe in tablets with different shapes, determined in the stability test after 6-month storage:

Methods used

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

Variability of the contents of the active ingredients, uniformity of the contents, abrasion, disintegration time, strength

- according to Ph. Eur (European Pharmacopoeia) Dissolution measurements

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

- 900 ml, phosphate buffer, having pH 7.0 + 0.05 with 0.5% of sodium lauryl sulphate, 75 rpm

- HPLC chromatography with a column detector with a UV or PDA detector, column Kinetex 2,6 μ, C18, 30 x 4.60 mm or its equivalent, mobile phase 0.1% of phosphoric acid : methanol (42:58 v/v), solvent acetonitrile : water (60:40, v/v), detection 242 nm

Stability test

- load test, storage at the conditions of 40°C and 75% relative humidity for 6 months

- gradient elution method on HPLC chromatography with a UV (PDA) detector, column Gemini C6-Phenyl, 3 μιη, 150 x 4.6 mm or its equivalent, mobile phase 1.0 ml of phosphoric acid per 1000 ml of water (constituent A) and methanol (constituent B) in the gradient program as specified in the table below, detection 245 nm

Uniformity, variability of the contents

- HPLC chromatography with a column thermostat and UV detector, column Gemini C6- Phenyl, 3 μιη, 150 x 4.6 mm (Phenomenex) or its equivalent, mobile phase 0.085% of phosphoric acid : methanol (35: 65, v/v), detection 245 nm.

Claims

1. A two-layer oral tablet comprising rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, and pharmaceutically acceptable excipients, characterized in that it consists of one ezetimibe layer and one rosuvastatin layer.

2. The two-layer oral tablet in accordance with claim 1, characterized in that the tablet has a circular horizontal cross-section.

3. The two-layer oral tablet in accordance with claim 1, characterized in that the tablet has a circular horizontal cross-section with the diameter D and height h 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

4. The two-layer oral tablet in accordance with claim 2, characterized in that the tablet has a circular horizontal cross-section with the diameter D and height h and where the D : h ratio is in the range:

from 1.70 : 1.00 to 2.10 : 1.00 for tablets with the strength of rosuvastatin and ezetimibe of 40 and 10 mg, respectively,

from 1.85 : 1.00 to 2.36 : 1.00 for tablets with the strength of rosuvastatin and ezetimibe of 20 and 10 mg, respectively, or

from 1.90 : 1.00 to 2.46 : 1.00 for tablets with the strength of rosuvastatin and ezetimibe of 10 and 10 mg, respectively.

5. The two-layer oral tablet in accordance with any one of claims 3 or 4, characterized in that the height h has a value from 3.5 to 6.5 mm, preferably from 3.7 mm to 6.3 mm.

6. The two-layer oral tablet in accordance with claim 5, characterized in that the height h has a value:

5.8 + 0.5 mm for tablets with the strength of rosuvastatin and ezetimibe of 40 and 10 mg, respectively,

4.7 + 0.5 mm for tablets with the strength of rosuvastatin and ezetimibe of 20 and 10 mg, respectively, or

4.2 + 0.5 mm for tablets with the strength of rosuvastatin and ezetimibe of 10 and 10 mg, respectively.

7. The two-layer oral tablet in accordance with any one of claims 3 to 6, characterized in that the diameter D has a value in the range from 8.0 to 12.0 mm, preferably from 8.5 mm to 11.5 mm. 8. The two-layer oral tablet in accordance with claim 7, characterized in that the diameter D has a value in the range from 8.9 to 11.1 mm.

The two-layer oral tablet in accordance with claim 8, characterized in that the diameter D has a value:

11 + 0.1 mm for tablets with the strength of rosuvastatin and ezetimibe of 40 and 10 mg, respectively,

9.

8 + 0.1 mm for tablets with the strength of rosuvastatin and ezetimibe of 20 and 10 mg, respectively, or

9.0 + 0.1 mm for tablets with the strength of rosuvastatin and ezetimibe of 10 and 10 mg, respectively.

10. The two-layer oral tablet in accordance with any one of the preceding claims, characterized in that the weight ratio between the ezetimibe layer and the rosuvastatin layer has a value in the range of 1:2 to 2: 1, including the limit values.

11. The two-layer oral tablet in accordance with any one of the preceding claims, characterized in that it is provided with coating.

12. The two-layer oral tablet in accordance with claim 11, characterized in that the tablet coating takes up 0.1 to 15% of the core weight, more preferably 0.5 to 10% of the core weight, most preferably 1 to 5% of the core weight.

13. The two-layer oral tablet in accordance with claims 11 or 12, characterized in that the coating contains a film-forming substance or a combination of film-forming substances selected from the group comprising hydroxypropyl methylcellulose, methylcellulose and polyvinyl alcohol.

14. The two-layer oral tablet in accordance with any one of claims 11 to 13, characterized in that the coating further comprises a softener or a combination of softeners selected from the group comprising triethyl citrate, dibutyl sebacate and polyethylene glycols.

15. The two-layer oral tablet in accordance with any one of the preceding claims, characterized in that

- the ezetimibe layer is free of cellulose and its derivatives or contains cellulose and/or its derivatives in an amount of up to 10.5 % by weight, relative to the total weight of the ezetimibe layer, as an extragranular phase excipient only, and/or

- the rosuvastatin layer is free of basic excipients.

16. A process for production of the tablet according to any one of the preceding claims, comprising the following steps:

b) the obtained granules of ezetimibe are mixed with at least one second pharmaceutically acceptable excipient, to form a tableting blend of ezetimibe layer, c) rosuvastatin or its pharmaceutically acceptable salt, ester, hydrate or solvate, is mixed together with at least one pharmaceutically acceptable excipient, wherein each excipient is non-basic, to form a tableting blend of rosuvastatin layer,

d) the obtained tableting blend of ezetimibe layer and rosuvastatin layer are compressed into two-layer tablets having a circular horizontal cross-section,

e) the obtained two-layer tablets are optionally coated.