RU2850454C9 - PHARMACEUTICAL COMPOSITION CONTAINING HMG-CoA REDUCTASE INHIBITORS AND FENOFIBRATE - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: method is proposed for preparing a multilayer pharmaceutical composition for the treatment of cardiovascular diseases, containing a combination of fixed doses of rosuvastatin or its pharmaceutically acceptable salt and fenofibrate or its pharmaceutically acceptable salt, wherein fenofibrate or its pharmaceutically acceptable salt and rosuvastatin or its pharmaceutically acceptable salt are present in separate layers, namely a fenofibrate layer and a rosuvastatin layer, and wherein the fenofibrate layer contains finely divided fenofibrate, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer.

EFFECT: preparing a mixture for the fenofibrate layer with a lubricant containing certain excipients, preparing a mixture for the rosuvastatin layer with a lubricant containing certain excipients, and pressing the mixture for the fenofibrate layer with a lubricant and the mixture for the rosuvastatin layer with a lubricant using a multilayer pressing machine.

1 cl, 2 dwg, 9 tbl, 5 ex

Description

RELATED APPLICATIONS

This application is related to Indian Provisional Application No. IN 201921030870, filed July 31, 2019, and European Provisional Patent Application No. EP 19201186.4, filed October 2, 2019, which are incorporated herein in their entirety.

FIELD OF TECHNICAL INVENTION

The present invention provides a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, namely a fenofibrate layer and a rosuvastatin layer, wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein the fenofibrate layer comprises finely ground fenofibrate. Furthermore, the present invention provides a method for producing said composition.

PREREQUISITES FOR THE CREATION OF THE INVENTION

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase inhibitor and has a lipid-lowering effect. The chemical name of rosuvastatin is bis[(E)-7-[4(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]. Rosuvastatin corresponds to a compound with the following structure (Formula I):

Rosuvastatin is known, for example, from US RE37314 E and EP 0521471 B1. Both prior art documents disclose that rosuvastatin is particularly effective as an HMG-CoA reductase inhibitor. Furthermore, rosuvastatin calcium is marketed as a single-drug formulation called ^CRESTOR® in tablets of 5 mg, 10 mg, 20 mg, and 40 mg. CRESTOR® has two approved therapeutic indications: the treatment of hypercholesterolemia in adults, adolescents, and children aged 6 years and older, and the prevention of cardiovascular events.

Treatment of hypercholesterolemia is a long-term treatment that may include a first phase of initial oral therapy, followed by a second phase of dose adjustment. Specifically, the recommended starting dose is 5 or 10 mg once daily, with subsequent dose adjustments to 20 or 40 mg, if needed, after 4 weeks of treatment. A dose of 20 mg is used for the prevention of cardiovascular events.

Following oral administration, subsequent metabolism of rosuvastatin is limited. In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450-mediated metabolism.

EP 2306982 B1 aims to improve the dissolution profile ^{of CRESTOR®} . For this purpose, it discloses a pharmaceutical composition in which rosuvastatin calcium is combined with an alkali metal carbonate, bicarbonate, or a mixture thereof. The molar ratio of these components is 1:0.43-1.75 (rosuvastatin calcium: alkali metal carbonate, bicarbonate, or a mixture thereof). This composition is reported to have a favorable dissolution profile of rosuvastatin calcium in a 0.1 N HCl medium, provided that the weight fraction of the anhydrous form of sodium carbonate in the pharmaceutical composition is from 0.5% to 2%. A preferred pharmaceutical composition is an oral dosage form such as a tablet or another oral dosage form such as a capsule, pellet, minitablet, etc.

Fenofibrate is a peroxisome proliferator-activated receptor alpha (PPARα) activator. By activating PPARα, fenofibrate increases lipolysis and the clearance of triglyceride-rich atherogenic particles from plasma by activating lipoprotein lipase and reducing the production of apoprotein CIII. Activation of PPARα also causes increased synthesis of apoproteins AI and AII. Chemically, fenofibrate is 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid 1-methylethyl ester and has the following structure (Formula II):

Fenofibrate is described in GB 1415295 A. In addition, fenofibrate is marketed as a single drug formulation in various pharmaceutical forms and strengths, for example as TRICOR ^® in 54 mg and 160 mg tablets; or as SUPRALIP ^® in the UK or as SECALIP SUPRA® in Spain in 160 mg tablets, and as LIPANTHYL ^® in 200 mg capsules.

SUPRALIP®/SECALIP SUPRA® 160 mg tablets are indicated for the treatment of severe hypertriglyceridemia with or without low HDL cholesterol, mixed hyperlipidemia in patients intolerant to statins, and mixed hyperlipidemia in patients at high cardiovascular risk. The recommended dose for these indications is one tablet containing 160 mg fenofibrate once daily. After oral administration, fenofibrate is rapidly hydrolyzed by esterases to form the active metabolite, fenofibric acid. Fenofibric acid is first conjugated with glucuronic acid and then excreted in the urine.

U.S. Patent No. 6,277,405 B1 relates to a method for preparing a composition with purportedly improved dissolution of fenofibrate compared to certain commercially available products. The method comprises the following steps: (a) preparing a suspension of finely divided fenofibrate with a particle size of less than 20 μm in a solution of a hydrophilic polymer and, optionally, a surfactant (surfactant), (b) applying the suspension obtained in step (a) to an inert water-soluble carrier. The disclosed composition purportedly exhibits dissolution of at least 75% of fenofibrate in 30 minutes as measured by the paddle stirrer method at 75 rpm according to Ph. Eur. in a dissolution medium consisting of water with 2% by weight of polysorbate 80, or in a dissolution medium consisting of water with 0.025 M sodium lauryl sulfate.

US 2011/0311625 A1 states that the solubility of the active pharmaceutical ingredient affects the bioavailability of the drug. Furthermore, it states that fenofibrate is a poorly soluble drug. Due to its poor water solubility, fenofibrate suffers from the problem of low solubility. It is poorly absorbed from the gastrointestinal tract, so its bioavailability is considered incomplete and unpredictable. It is claimed that poor solubility can be compensated for by using a specific fenofibrate dosage form: a tablet containing a core and a layer surrounding the core, where the layer surrounding the core comprises fenofibrate, a hydrophilic polymer, and a hydrophilic carrier.

EP 0330532 B1 proposes a new therapeutic composition containing fenofibrate, finely ground together with a solid surfactant. The new composition is claimed to have improved fenofibrate dissolution and, consequently, increased bioavailability. The daily dose can be reduced from 300 mg to 200 mg and from 100 mg to 67 mg without any compromise in therapeutic efficacy.

Instead of single-drug formulations, some prior art publications suggest using a combination of fenofibrate and an HMG-CoA inhibitor. This is supposed to be the most effective means of controlling cholesterol and lipids. In fact, fenofibrate therapy is often prescribed in conjunction with statins, as clinicians appear to prefer the use of fenofibrate due to its triglyceride-lowering and HDL-cholesterol-elevating effects, while an HMG-CoA inhibitor is used for its beneficial effects in lowering LDL cholesterol and raising HDL cholesterol, and/or its effect on a related disease. Fixed-dose combinations containing a fibrate and a statin as active pharmaceutical ingredients are known from the documents cited below.

EP 1185274 B1, for example, discloses a combination of an HMG-CoA reductase inhibitor, rosuvastatin, with an inducer, inhibitor or substrate of the P450-3A4 isoenzyme, for simultaneous, separate or sequential use in therapy.

WO 2005/034908 A2 discloses pharmaceutical compositions comprising a combination of a fibrate and a statin and a common carrier. The carrier is selected from the group consisting of a hydrophobic, a hydrophilic, and a water-miscible carrier. The common carrier contains a dissolved mass fraction of at least 80%, but preferably 99.9%, of the total amount of the fibrate and statin (active ingredients). However, the implementation of such a solution is associated with technical difficulties. Fenofibrate and statin must be dissolved in a mixture of PEG 6000 and poloxamer 188 (70:30) or in glycerol monostearate at 70°C, and then the solution must be sprayed onto lactose in a fluidized bed. In addition, the release of fenofibrate from such a composition does not reach the required level.

EP 1 853 249 A2 discloses a pharmaceutical composition comprising at least two active pharmaceutical ingredients, namely fenofibrate as a first ingredient and an HMG-CoA reductase inhibitor or derivative thereof as a second ingredient. The document provides a single solid dosage form for oral administration comprising a solid fenofibrate composition and a solid HMG-CoA reductase inhibitor composition, preferably a statin composition, wherein the active ingredients are present in different parts of the dosage form. The document discloses that the fibrate contained in the composition is present in the form of a solid solution. According to the disclosed examples, fenofibrate granulate was prepared by a rather labor-intensive method, namely, according to the method of WO 2005/034920 A1. Again, this means that fenofibrate must be dissolved in a solution of polyethyleneglycol 6000 and poloxamer 188 (70:30 weight ratio) at 75°C, and then the homogeneous solution must be sprayed onto the lactose. In addition to this drawback, namely, the separation of the active ingredients into two parts, the dissolution profile of fenofibrate in the described pharmaceutical composition is also unsatisfactory.

WO 2008/075320 A2 discloses a method for preparing an oral pharmaceutical composition containing fenofibrate alone or in combination with at least one other antilipidemic agent in a single dosage form suitable for once- or twice-daily administration. The document discloses that the method for preparing an oral pharmaceutical composition containing fenofibrate includes the steps of preparing a solution containing fenofibrate, a surfactant, and a hydrophilic polymer, and spraying the solution onto one or more inert carriers to produce granules. The preparation of the fenofibrate composition according to this document requires preparing a fenofibrate solution and using the solution to prepare the granules.

Kumar et al., IJPSR, 2016; Vol. 7(1): 413-23, disclose a combination of rosuvastatin calcium and fenofibrate in a bilayer tablet in which the rosuvastatin layer provides sustained release of rosuvastatin and the fenofibrate layer provides immediate release of fenofibrate.

In summary, the majority of the aforementioned prior art discloses formulations containing fenofibrate or rosuvastatin alone. Only a few prior art documents relate to combinations of a fibrate and a statin in a single dosage form. Most notably, however, none of the prior art documents teach how fenofibrate dissolution can be improved if both fenofibrate and rosuvastatin are combined in a single dosage form. Furthermore, known fixed-dose combinations are disadvantageous from a manufacturing standpoint. Preparing a solid solution of the active ingredients significantly complicates the manufacturing process. To prepare such a solid solution, the manufacturer must use heating equipment and add certain excipients (e.g., PEG, poloxamers, waxes).

Furthermore, none of the prior art documents have demonstrated an effective improvement in treatment compliance with the provided fixed-dose combination of fenofibrate and rosuvastatin that is bioequivalent in vivo to the concomitant administration of SECALIP SUPRA® and CRESTOR® monotherapy.

Taking into account the prior art, there is an urgent need to develop a new combination product of fenofibrate and rosuvastatin that would not have the disadvantages inherent in traditional formulations of the prior art.

PURPOSE OF THE INVENTION

Therefore, the aim of the present invention is to provide a combination product of fenofibrate and rosuvastatin that is easier to manufacture and has an improved dissolution profile, at least for fenofibrate.

ESSENCE OF THE INVENTION

The inventors of the present invention have unexpectedly found that a pharmaceutical composition comprising a fixed dose combination of rosuvastatin and fenofibrate or pharmaceutically acceptable salts thereof, wherein the composition has a multilayer structure and rosuvastatin and fenofibrate are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and the fenofibrate layer comprises fenofibrate, which is in the form of micronized fenofibrate, exhibits an excellent dissolution profile of fenofibrate. The preferred dissolution profile of fenofibrate is characterized by greater than 74% of the contained fenofibrate being dissolved within 30 minutes when measured in a USP Type II dissolution apparatus using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirring at 50 rpm.

Advantageously, the compositions of the present invention can be prepared by conventional wet granulation methods, i.e., unlike the fixed-dose combinations of the prior art, they do not require the preparation of a solid solution of fenofibrate. On the other hand, the compositions of the present invention exhibit a more rapid dissolution of fenofibrate than the fixed-dose combinations of the prior art, i.e., they exhibit a dissolution profile in which more than 74% of the fenofibrate by weight is released within 30 minutes when measured in a USP Type II dissolution apparatus using 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirring at 50 rpm.

The pharmaceutical composition of the present invention has the advantage of being able to reproduce in vivo the bioavailability obtained upon co-administration of equivalent doses of the marketed SECALIP SUPRA® and CRESTOR®. In this sense, the inventors have found that the total drug exposure obtained after once-daily administration of the fixed dose combination of the present invention is bioequivalent to the total drug exposure obtained after co-administration of a 160 mg tablet of SECALIP SUPRA® and a 20 mg tablet of CRESTOR® once-daily. This means that the fixed dose combination of the present invention exhibits comparable pharmacokinetic bioavailability parameters (e.g., C _max , T _max , AUC _0-t , AUC _0-∞ ) of fenofibric acid, the active metabolite of fenofibrate, and rosuvastatin.

Surprisingly, due to the faster in vitro dissolution profile of fenofibrate in the multilayer pharmaceutical composition of the present invention compared to the monolayer pharmaceutical compositions of the prior art, the multilayer pharmaceutical composition of the present invention is able to reproduce the in vivo bioavailability of SECALIP SUPRA®.

Furthermore, the inventors have found that a multilayer pharmaceutical composition containing a fixed dose combination of rosuvastatin and fenofibrate or their pharmaceutically acceptable salts exhibits good stability of both active ingredients at a temperature of 40°C and a relative humidity of 75% over periods of 1 month, 2 months and 3 months.

Therefore, the multilayer pharmaceutical composition of the present invention, comprising a fixed-dose combination of rosuvastatin and fenofibrate or their pharmaceutically acceptable salts, represents a significant improvement over the corresponding monotherapeutic agents, as it provides two active ingredients in a single tablet for once-daily administration, thereby reducing the patient's pill burden. Thus, the fixed-dose combination is convenient for patients with mixed dyslipidemia, who currently require separate administration of two monotherapeutic agents, thereby addressing a medical need and improving compliance.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

Fig. 1 shows the mean plasma concentration (MPC) of fenofibrate, expressed as the mean plasma concentration of its metabolite, fenofibric acid, over 96 hours following a single oral administration of: a) the fixed dose combination of the present invention in the form of a bilayer tablet of rosuvastatin and fenofibrate from Example 4c (test case, points are marked with squares); b) SECALIP SUPRA® 160 mg tablet (comparator, points are marked with circles). MPC stands for mean plasma concentration (μg/ml) and T stands for time expressed in hours.

Fig. 2 shows the mean plasma concentration (MPC) of rosuvastatin over 96 hours following a single oral administration of: a) the fixed dose combination of the present invention in the form of a bilayer tablet of rosuvastatin and fenofibrate from Example 4c (test, dots are shown as squares); b) 20 mg CRESTOR® tablets (comparator, dots are shown as circles). MPC is the mean plasma concentration (ng/mL) and T is the time expressed in hours.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified, terms in this description have their ordinary meaning in the relevant technical field.

The present invention relates to compositions for the treatment of cardiovascular diseases, including, but not limited to, ischemic heart disease, heart failure and cardiomyopathy, congenital heart defects, atherosclerosis, ischemia/reperfusion, hypertension, restenosis, acute rheumatic fever, rheumatic heart disease and arterial inflammation.

The present invention relates to pharmaceutical compositions with a synergistic effect obtained through the combined use of fenofibrate with a statin. These compositions are presented as multi-dose dosage forms obtained by separately preparing the two active ingredients. The excipients used in the compositions are selected to minimize interactions between them and the active ingredients, and the compositions are prepared accordingly. The multi-dose dosage forms prepared in this manner can be formulated so that the two active ingredients can have different and/or identical release characteristics.

As mentioned above, fenofibrate and statin active agents are characterized by solubility/dissolution issues. Developing a pharmaceutical formulation with a high dissolution rate for a poorly soluble drug is known to be very challenging. However, the inventors succeeded in producing a multilayer composition containing rosuvastatin and fenofibrate or their pharmaceutically acceptable salts, wherein fenofibrate dissolution after 60 minutes is at least 20% higher than that of a composition containing a monolayer of rosuvastatin or its pharmaceutically acceptable salt and fenofibrate or its pharmaceutically acceptable salt.

As used herein, the term "rosuvastatin" refers to a molecule represented by the structural formula (I), as well as pharmaceutically acceptable salts thereof. The multilayer composition of the present invention comprises an amount of rosuvastatin calcium or, alternatively, an amount of another pharmaceutically acceptable salt equivalent to the amount of rosuvastatin calcium. Examples of such salts include barium salts, strontium salts, zinc salts, cesium salts, cadmium salts, magnesium salts, sodium salts, and ammonium salts.

As used herein, the term "fenofibrate" means the molecule represented by the structural formula (II), as well as pharmaceutically acceptable salts thereof.

The present invention provides a multilayer pharmaceutical composition comprising a combination of fixed doses of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, and a method for producing said multilayer composition.

In a preferred embodiment of the present invention, a multilayer pharmaceutical composition is provided comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the multilayer composition is a bilayer immediate release tablet.

In another embodiment of the present invention, a multilayer pharmaceutical composition is provided, comprising a combination of fixed doses of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and the dissolved amount of fenofibrate after 60 minutes from the multilayer composition, containing the combination of fixed doses, is at least 20% greater than from the composition, containing a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and the amount of fenofibrate dissolved after 60 minutes from the multilayer composition comprising the fixed dose combination is at least 20% greater than from a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof; as measured in a USP Type II dissolution apparatus using 1000 ml of 0.05 M sodium lauryl sulfate in water as a dissolution medium at 37°C and with stirring at 50 rpm.

In another embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and the fenofibrate layer comprises finely ground fenofibrate, and the amount of fenofibrate dissolved after 60 minutes from the multilayer composition comprising the fixed dose combination is at least 20% greater than from a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof; as measured in a USP Type II dissolution apparatus using 1000 ml of 0.05 M sodium lauryl sulfate in water as a dissolution medium at 37°C and with stirring at 50 rpm.

In another embodiment of the present invention, there is provided a bilayer tablet comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the amount of fenofibrate dissolved after 60 minutes from the bilayer tablet comprising the fixed dose combination is at least 20% greater than from a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof; as measured in a USP Type II dissolution apparatus using 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and with stirring at 50 rpm.

In another embodiment of the present invention, a multilayer pharmaceutical composition is provided, comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein rosuvastatin or a pharmaceutically acceptable salt thereof is present in an amount of 5 mg to 50 mg, and fenofibrate or a pharmaceutically acceptable salt is present in an amount of 100 mg to 200 mg.

In a preferred embodiment of the present invention, a bilayer tablet is provided containing a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein rosuvastatin or a pharmaceutically acceptable salt thereof is present in an amount of 5 mg to 20 mg, and fenofibrate or a pharmaceutically acceptable salt is present in an amount of 140 mg to 180 mg.

In another embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein (1) rosuvastatin or a pharmaceutically acceptable salt thereof is present in an amount of 5 mg to 20 mg, and fenofibrate or a pharmaceutically acceptable salt thereof is present in an amount of 140 mg to 180 mg, and (2) rosuvastatin and fenofibrate are not mixed with each other, (3) fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and (4) the amount of fenofibrate dissolved after 60 minutes from the multilayer composition is at least 20% greater than from a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof; as measured in a USP Type II dissolution apparatus using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirring at 50 rpm.

In a preferred embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the multilayer composition comprises from 5 to 20 mg of rosuvastatin or a pharmaceutically acceptable salt and 160 mg of fenofibrate, wherein (1) rosuvastatin and fenofibrate are not mixed with each other, (2) fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and (3) more than 67% of the total weight content of fenofibrate is dissolved after 15 minutes, and (4) the amount of fenofibrate dissolved over a period of 60 minutes from the multilayer composition is at least 20% greater than from a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof salts; as measured in a USP Type II dissolution apparatus using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirring at 50 rpm.

In another embodiment of the present invention, there is provided a bilayer tablet comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein rosuvastatin or a pharmaceutically acceptable salt thereof is present in an amount of from 5 mg to 20 mg, and fenofibrate or a pharmaceutically acceptable salt is present in an amount of from 140 mg to 180 mg, and wherein the amount of fenofibrate dissolved after 60 minutes from the bilayer tablet is at least 20% greater than from a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof; as measured in a USP Type II dissolution apparatus using 1000 ml of 0.05 M sodium lauryl sulfate in water as a dissolution medium at 37°C and with stirring at 50 rpm.

In a preferred embodiment, the present invention relates to a bilayer tablet comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the bilayer tablet comprises 5 to 20 mg of rosuvastatin or a pharmaceutically acceptable salt thereof and 160 mg of fenofibrate and/or wherein the amount of fenofibrate dissolved after 60 minutes from the bilayer tablet is at least 20% greater than from a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof; as measured in a USP Type II dissolution apparatus using 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and with stirring at 50 rpm.

In another embodiment of the present invention, there is provided a bilayer tablet comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein (1) rosuvastatin or a pharmaceutically acceptable salt thereof is present in an amount of 5 mg to 20 mg, and fenofibrate or a pharmaceutically acceptable salt thereof is present in an amount of 140 mg to 180 mg, and (2) rosuvastatin and fenofibrate are not mixed with each other, (3) fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and/or (4) the amount of fenofibrate dissolved after 60 minutes from the bilayer tablet is at least 20% greater than from a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof; as measured in a USP Type II dissolution apparatus using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirring at 50 rpm.

In a preferred embodiment of the present invention, there is provided a bilayer tablet comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the bilayer tablet comprises 5 to 20 mg of rosuvastatin or a pharmaceutically acceptable salt and 160 mg of fenofibrate, wherein (1) rosuvastatin and fenofibrate are not mixed with each other (i.e., do not constitute a monolayer), (2) fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and (3) more than 67% of the weight content of fenofibrate is dissolved after 15 minutes, and/or (4) the amount of fenofibrate dissolved over a period of 60 minutes from the bilayer tablet is at least 20% greater than from a composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof; as measured in a USP Type II dissolution apparatus using 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and with stirring at 50 rpm.

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers, and wherein fenofibrate is micronized fenofibrate. In a preferred embodiment, the micronized fenofibrate has a volume mean diameter D(v, 50) greater than 0.02 μm and less than or equal to 20 μm, preferably greater than 0.04 μm and less than or equal to 10 μm, more preferably greater than 0.05 μm and less than or equal to 7 μm, even more preferably greater than 0.05 μm and less than or equal to 5 μm, most preferably greater than 0.05 μm and less than or equal to 4 μm.

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers, and wherein fenofibrate is micronized fenofibrate, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively. In a preferred embodiment, the micronized fenofibrate has a volume mean diameter D(v, 50) greater than 0.02 μm and less than or equal to 20 μm, preferably greater than 0.04 μm and less than or equal to 10 μm, more preferably greater than 0.05 μm and less than or equal to 7 μm, even more preferably greater than 0.05 μm and less than or equal to 5 μm, most preferably greater than 0.05 μm and less than or equal to 4 μm.

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers, and wherein fenofibrate is micronized fenofibrate, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and the amount of fenofibrate dissolved after 60 minutes from the multilayer composition comprising the fixed dose combination is at least 20% greater than from the composition comprising a monolayer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof; as measured in a USP Type II dissolution apparatus using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirring at 50 rpm.

In a preferred embodiment, the micronized fenofibrate has a volume mean diameter D(v, 50) greater than 0.02 μm and less than or equal to 20 μm, preferably greater than 0.04 μm and less than or equal to 10 μm, more preferably greater than 0.05 μm and less than or equal to 7 μm, even more preferably greater than 0.05 μm and less than or equal to 5 μm, most preferably greater than 0.05 μm and less than or equal to 4 μm.

In another embodiment, the finely divided fenofibrate has a particle size distribution (PSD) such that D(v,10) is greater than 0.02 μm and less than or equal to 7 μm, preferably greater than 0.04 μm and less than or equal to 5 μm, more preferably greater than 0.04 μm and less than or equal to 4 μm, even more preferably greater than 0.05 μm and less than or equal to 3 μm, even more preferably greater than 0.05 μm and less than or equal to 2 μm; and/or D(v,50) is greater than 0.04 μm and less than or equal to 20 μm, preferably greater than 0.08 μm and less than or equal to 10 μm, more preferably greater than 0.1 μm and less than or equal to 7 μm, even more preferably greater than 0.1 μm and less than or equal to 5 μm, even more preferably greater than 0.1 μm and less than or equal to 4 μm; and/or D(v,90) is greater than 0.05 μm and less than or equal to 47 μm, preferably greater than 0.1 μm and less than or equal to 25 μm, more preferably greater than 0.2 μm and less than or equal to 18 μm, even more preferably greater than 0.4 μm and less than or equal to 13 μm, even more preferably greater than 0.5 μm and less than or equal to 10 μm.

The particle size distribution width of finely ground fenofibrate, expressed as a range, may be from 1.2 to 3, preferably from 1.3 to 2.5, more preferably from 1.6 to 2.3. According to Chew et al J Pharm Pharmaceut Sci 2002, 5, 162-168, the "range" corresponds to the following ratio: [D(v,0.9) - D(v,0.1)]/D(v,0.5).

The RFD parameters (D(v,0.9), D(v,0.5) and D(v,0.1)) of finely divided fenofibrate are determined by measuring the characteristic equivalent diameter of a sphere, known as the volume diameter, using laser diffraction.

In another embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a combination of fixed doses of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers, and wherein fenofibrate is not in the form of a solid solution or a solid dispersion. In this context, the fact that fenofibrate is not in the form of a solid solution or a solid dispersion means that the fenofibrate layer is absent or contains a weight fraction of less than 20% of a formulator or carrier selected from the group consisting of polyethylene glycols, polypropylene glycols, polyoxyethylenes, polyoxypropylenes, poloxamers, saturated straight-chain hydrocarbons, sorbitan esters, paraffins, fats, oils and mixtures thereof, the melting point of which is below 100°C. Preferably, the fenofibrate layer is free of, or contains less than 20% by weight of, excipients or a carrier with a melting point below 100°C, regardless of the class of compounds from which the excipients or carrier are selected. In a preferred embodiment, the compositions of the present invention comprise a fenofibrate layer that is free of, or contains less than 20% by weight of, an excipient or a carrier with a melting point below 75°C, preferably below 80°C, more preferably below 90°C, even more preferably below 100°C.

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein the composition exhibits a dissolution profile according to which, over a period of 30 minutes, a fenofibrate weight fraction of greater than 74%, preferably greater than 77%, more preferably greater than 80%, even more preferably greater than 83% is dissolved; as measured in a USP Type II dissolution apparatus using 1000 ml of 0.05 M sodium lauryl sulfate in water as a dissolution medium at 37°C and with stirring at a speed of 50 revolutions per minute.

In another embodiment, the compositions of the present invention exhibit a dissolution profile such that: at least 48% by weight of fenofibrate is dissolved in 5 minutes, 49 to 79% by weight of fenofibrate is dissolved in 10 minutes, 65 to 95% by weight of fenofibrate is dissolved in 15 minutes, 68 to 98% by weight of fenofibrate is dissolved in 20 minutes, 74 to 100% by weight of fenofibrate is dissolved in 30 minutes, 79 to 100% by weight of fenofibrate is dissolved in 45 minutes, and 80 to 100% by weight of fenofibrate is dissolved in 60 minutes; as measured in a USP Type II dissolution apparatus using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirring at 50 rpm. In a preferred embodiment, the compositions of the present invention exhibit a dissolution profile such that: at least 43% by weight of fenofibrate is dissolved in 5 minutes, 54 to 74% by weight of fenofibrate is dissolved in 10 minutes, 70 to 90% by weight of fenofibrate is dissolved in 15 minutes, 73 to 93% by weight of fenofibrate is dissolved in 20 minutes, 78 to 98% by weight of fenofibrate is dissolved in 30 minutes, 84 to 100% by weight of fenofibrate is dissolved in 45 minutes, and 85 to 100% by weight of fenofibrate is dissolved in 60 minutes; as measured in a USP Type II dissolution apparatus using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirring at 50 rpm. In a more preferred embodiment, the compositions of the present invention exhibit a dissolution profile such that: at least 38% by weight of fenofibrate is dissolved in 5 minutes, 59 to 69% by weight of fenofibrate is dissolved in 10 minutes, 75 to 85% by weight of fenofibrate is dissolved in 15 minutes, 78 to 88% by weight of fenofibrate is dissolved in 20 minutes, 83 to 93% by weight of fenofibrate is dissolved in 30 minutes, 89 to 99% by weight of fenofibrate is dissolved in 45 minutes, and 90 to 100% by weight of fenofibrate is dissolved in 60 minutes; as measured in a USP Type II dissolution apparatus using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirring at 50 rpm.

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein fenofibrate is micronized fenofibrate, and wherein fenofibrate is not in the form of a solid dispersion.

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein fenofibrate is micronized fenofibrate, wherein fenofibrate is not in the form of a solid dispersion, and wherein the composition exhibits a dissolution profile according to which more than 74% of the fenofibrate is dissolved by weight in 30 minutes; as measured in a USP Type II dissolution apparatus using 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and with stirring at 50 rpm.

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate and rosuvastatin are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein fenofibrate is finely divided fenofibrate, wherein fenofibrate is not in the form of a solid dispersion, and wherein the composition exhibits a dissolution profile according to which: in 5 minutes at least 48% of fenofibrate is dissolved by weight, in 10 minutes a fenofibrate mass fraction of 49 to 79% is dissolved by weight, in 15 minutes a fenofibrate mass fraction of 65 to 95% is dissolved by weight, in 20 minutes a fenofibrate mass fraction of 68 to 98%, 73 to 100% fenofibrate is dissolved by weight in 30 minutes, 79 to 100% fenofibrate is dissolved by weight in 45 minutes, and 80 to 100% fenofibrate is dissolved by weight in 60 minutes; as measured in a USP Type II dissolution apparatus using 1000 mL of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirring at 50 rpm.

In one embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 160 mg of fenofibrate, fenofibrate or a pharmaceutically acceptable salt thereof exhibits a maximum plasma concentration (C _max ) of from 6,500 μg/mL to 12,500 μg/mL, based on the plasma concentration of its metabolite fenofibric acid. In a preferred embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 160 mg of fenofibrate, fenofibrate or a pharmaceutically acceptable salt thereof exhibits a maximum plasma concentration (C _max ) of from 8,000 μg/mL to 11,000 μg/mL, based on the plasma concentration of its metabolite fenofibric acid. In a more preferred embodiment, following post-meal oral administration of a single dose of the fixed dose combination of the present invention equivalent to 160 mg fenofibrate, fenofibrate or a pharmaceutically acceptable salt thereof exhibits a maximum plasma concentration ( _Cmax ) of 9,000 μg/ml to 10,000 μg/ml, based on the plasma concentration of its metabolite, fenofibric acid. The term _Cmax refers to the maximum concentration of the metabolite, fenofibric acid, in the blood following post-meal oral administration of a single dose of the fixed dose combination of the present invention.

In one embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 20 mg rosuvastatin, rosuvastatin or a pharmaceutically acceptable salt thereof exhibits a maximum plasma concentration (C _max ) of from 9,000 ng/mL to 29,000 ng/mL. In a preferred embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 20 mg rosuvastatin, rosuvastatin or a pharmaceutically acceptable salt thereof exhibits a maximum plasma concentration (C _max ) of from 13,000 ng/mL to 23,000 ng/mL. In a more preferred embodiment, following post-fed oral administration of a single dose of the fixed dose combination of the present invention equivalent to 20 mg of rosuvastatin, rosuvastatin or a pharmaceutically acceptable salt thereof exhibits a maximum plasma concentration (C _max ) of 17,000 ng/mL to 19,000 ng/mL. The term "C _max " refers to the maximum concentration of rosuvastatin in the blood following post-fed oral administration of a single dose of the fixed dose combination of the present invention.

In one embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 160 mg fenofibrate, fenofibrate or a pharmaceutically acceptable salt thereof exhibits a time to reach the maximum plasma concentration (T _max ) of from 1.5 hours to 7 hours, based on the concentration of its metabolite, fenofibric acid, in plasma. In a preferred embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 160 mg fenofibrate, fenofibrate or a pharmaceutically acceptable salt thereof exhibits a time to reach the maximum plasma concentration (T _max ) of from 5 hours to 6 hours, based on the concentration of its metabolite, fenofibric acid, in plasma. In a more preferred embodiment, following post-meal oral administration of a single dose of the fixed dose combination of the present invention equivalent to 160 mg of fenofibrate, fenofibrate or a pharmaceutically acceptable salt thereof exhibits a time to reach maximum plasma concentration ( _Tmax ) of 5.25 hours to 5.75 hours, based on the plasma concentration of its metabolite, fenofibric acid. The term " _Tmax " denotes the time in hours to reach _Cmax following post-meal oral administration of a single dose of the fixed dose combination of the present invention.

In one embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 20 mg of rosuvastatin, rosuvastatin or a pharmaceutically acceptable salt thereof exhibits a time to reach the maximum plasma concentration (T _max ) of from 1 hour to 7 hours. In a preferred embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 20 mg of rosuvastatin, rosuvastatin or a pharmaceutically acceptable salt thereof exhibits a time to reach the maximum plasma concentration (T _max ) of from 4 hours to 7 hours. In a more preferred embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 20 mg of rosuvastatin, rosuvastatin or a pharmaceutically acceptable salt thereof exhibits a time to reach the maximum plasma concentration (T _max ) of from 5.25 hours to 5.75 hours. The term "T _max " means the time in hours until C _max is reached after oral administration after a meal of a single dose of the fixed dose combination of the present invention.

In one embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 160 mg fenofibrate, fenofibrate or a pharmaceutically acceptable salt thereof exhibits an area under the plasma concentration curve from 0 to 96 hours (AUC (0-t)) of 80,500 μg⋅h/mL to 310,500 μg⋅h/mL, based on the plasma concentration of its metabolite, fenofibric acid. In a preferred embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 160 mg fenofibrate, fenofibrate or a pharmaceutically acceptable salt thereof exhibits an area under the plasma concentration curve from 0 to 96 hours (AUC (0-t)) of 122,500 μg⋅h/mL to 222,500 μg⋅h/mL, based on the plasma concentration of its metabolite, fenofibric acid. In a more preferred embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 160 mg of fenofibrate, fenofibrate or a pharmaceutically acceptable salt thereof exhibits an area under the plasma concentration curve from 0 to 96 hours (AUC (0-t)) of from 147,500 μg⋅h/mL to 197,500 μg⋅h/mL, based on the concentration of its metabolite, fenofibric acid, in plasma. The term "AUC" refers to the area under the plasma concentration-time curve following oral administration of a single dose of the composition of the present invention. AUC _0-∞ refers to the area under the plasma concentration-time curve from time 0 to infinity, and AUC _0-t refers to the area under the plasma concentration-time curve from time 0 to time t.

In one embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 20 mg rosuvastatin, rosuvastatin or a pharmaceutically acceptable salt thereof exhibits an area under the plasma concentration curve from 0 to 96 hours (AUC (0-t)) of from 76,000 ng⋅h/mL to 210,000 ng⋅h/mL. In a preferred embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 20 mg rosuvastatin, rosuvastatin or a pharmaceutically acceptable salt thereof exhibits an area under the plasma concentration curve from 0 to 96 hours (AUC (0-t)) of from 101,000 ng⋅h/mL to 171,000 ng⋅h/mL. In a more preferred embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 20 mg of rosuvastatin, rosuvastatin or a pharmaceutically acceptable salt thereof exhibits an area under the plasma concentration curve from 0 to 96 hours (AUC (0-t)) of from 126,000 ng⋅h/mL to 146,000 ng⋅h/mL. The term "AUC" refers to the area under the plasma concentration-time curve following oral administration of a single dose of the composition of the present invention. AUC _0-∞ refers to the area under the plasma concentration-time curve from time 0 to infinity, and AUC _0-t refers to the area under the plasma concentration-time curve from time 0 to time t.

In one embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 160 mg fenofibrate, fenofibrate or a pharmaceutically acceptable salt thereof exhibits a half-life (T1/2) of 12 hours to 40 hours in terms of the plasma concentration of its metabolite fenofibric acid. In a preferred embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 160 mg fenofibrate, fenofibrate or a pharmaceutically acceptable salt thereof exhibits a half-life (T1/2) of 19 hours to 25 hours in terms of the plasma concentration of its metabolite fenofibric acid. The term "half-life (T1/2)" means the period of time during which fenofibrate loses half of its pharmacological activity.

In one embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 20 mg of rosuvastatin, rosuvastatin or a pharmaceutically acceptable salt thereof exhibits a half-life (T1/2) of 6 to 44 hours. In a preferred embodiment, following oral administration after a meal of a single dose of the fixed dose combination of the present invention equivalent to 20 mg of rosuvastatin, rosuvastatin or a pharmaceutically acceptable salt thereof exhibits a half-life (T1/2) of 10 to 16 hours. The term "half-life (T1/2)" means the period of time during which rosuvastatin loses half of its pharmacological activity.

The pharmacokinetic parameter values after a single standard dose of the fixed dose combination of the present invention taken after food as mentioned above (i.e. C _max , T _max , AUC _0-t , AUC _0-∞ ) indicate that once daily administration of the fixed dose combination of the present invention is bioequivalent to the total drug exposure obtained after concomitant once daily administration of SECALIP SUPRA® 160 mg tablet and CRESTOR® 20 mg tablet. The 90% confidence interval for the ratio of the pharmacokinetic parameters of the fixed dose combination of the present invention and a comparative composition outside the scope of the present invention is within the acceptable range of 80.00-125.00% according to the bioequivalence study according to the EMA Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr, 2010).

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein the impurity-B content of fenofibrate is below the limit of quantification after 3 months of storage at a temperature of 40°C and a relative humidity of 75%.

In one embodiment of the present invention, a multilayer pharmaceutical composition is provided, comprising a combination of fixed doses of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein the quantitative content of fenofibrate is not lower than 99.00% after 3 months of storage at a temperature of 40°C and a relative humidity of 75%.

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein the total content of impurities related to fenofibrate is below 0.100% after 3 months of storage at a temperature of 40°C and a relative humidity of 75%.

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein the impurity content of the rosuvastatin antiisomer is below 0.250% after 3 months of storage at a temperature of 40°C and a relative humidity of 75%.

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein the 5-oxo impurity content of rosuvastatin is below 0.300% after 3 months of storage at a temperature of 40°C and a relative humidity of 75%.

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein the lactone impurity content of rosuvastatin is below 0.150% after 3 months of storage at a temperature of 40°C and a relative humidity of 75%.

In one embodiment of the present invention, a multilayer pharmaceutical composition is provided, comprising a combination of fixed doses of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein the quantitative content of rosuvastatin is not lower than 99.00% after 3 months of storage at a temperature of 40°C and a relative humidity of 75%.

In one embodiment of the present invention, there is provided a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and wherein the total content of impurities related to rosuvastatin is below 0.700% after 3 months of storage at a temperature of 40°C and a relative humidity of 75%.

In more detailed aspects, the present invention provides a multilayer pharmaceutical composition comprising a combination of fixed doses of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof and suitable pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are selected from one or more fillers or diluents, one or more binders, one or more disintegrants, one or more lubricants, one or more film coating agents, one or more pigments or plasticizers, and the like.

For the purposes of this description, the term "immediate release" means a composition or component, or layer, or unit containing rosuvastatin and fenofibrate that immediately releases rosuvastatin and fenofibrate from the composition, component, layer, or unit, i.e., not according to a delayed or extended release mechanism. The multilayer pharmaceutical composition of the present invention provides immediate release of fenofibrate and rosuvastatin from the fenofibrate layer and the rosuvastatin layer, respectively.

The pharmaceutical excipients for the present invention are selected from one or more fillers, one or more diluents, one or more binders, one or more disintegrants, one or more lubricants, one or more glidants, one or more surfactants/wetting agents, one or more film coating agents, one or more pigments or plasticizers, and the like.

In accordance with the present invention, fillers or diluents may include, but are not limited to, ammonium alginate, calcium carbonate, calcium lactate, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium silicate, calcium sulfate, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, cellulose acetate, corn starch and pregelatinized starch, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lactitol, anhydrous lactose, lactose monohydrate, lactose monohydrate and corn starch, lactose monohydrate and povidone, lactose monohydrate and spray-dried lactose, lactose monohydrate and microcrystalline Cellulose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sterilizable corn starch, sucrose, compressed sugar, confectioners' sugar, sugar pellets, sulfobutyl ether-β-cyclodextrin, sunflower oil, talc, tragacanth, trehalose, xylitol and mixtures thereof.

In accordance with the present invention, binders may include, but are not limited to, gum arabic, agar, alginic acid, calcium carbonate, tribasic calcium phosphate, calcium lactate, carbomer, sodium carboxymethylcellulose, carrageenan, cellulose acetate phthalate, ceratonia, microcrystalline cellulose, chitosan, copovidone, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, glyceryl behenate, guar gum, hydroxyethylcellulose, hydroxyethyl methylcellulose, hydroxypropylcellulose, hydroxypropyl starch, anhydrous lactose, spray-dried lactose, low-substituted hydroxypropylcellulose, hypromellose, inulin, lactose monohydrate, magnesium aluminum silicate, Maltodextrin, maltose, methylcellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, povidone, sodium alginate, pregelatinized starch, starch, sucrose, sunflower oil, hydrogenated vegetable oil, vitamin E, polyethylene glycol succinate, zein, tragacanth, polyethylene glycol, polyvinylpyrrolidone, stearic acid, tricaprylin and mixtures thereof.

In accordance with the present invention, disintegrants may include, but are not limited to, alginic acid, calcium alginate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, cellulose, microcrystalline cellulose, powdered cellulose, chitosan, colloidal silicon dioxide, corn starch and pregelatinized starch, croscarmellose sodium, crospovidone, docusate sodium, glycine, guar gum, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, lactose monohydrate and corn starch, magnesium aluminum silicate, methylcellulose, potassium polacrilin, povidone, sodium alginate, sodium starch glycolate, starch, pregelatinized starch mixtures thereof.

In accordance with the present invention, lubricants may include, but are not limited to, calcium stearate, canola oil, hydrogenated castor oil, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, lauric acid, leucine, magnesium stearate, light mineral oil, mineral oil, magnesium lauryl sulfate, myristic acid, octyldodecanol, palmitic acid, poloxamer, polyethylene glycol, polyvinyl alcohol, potassium benzoate, sodium benzoate, sodium hyaluronate, sodium lauryl sulfate, sodium stearyl fumarate, spray-dried lactose, sterilizable corn starch, stearic acid, talc, tricaprylin, hydrogenated vegetable oil, zinc stearate, sodium chloride, and mixtures thereof.

According to the present invention, glidants may include, but are not limited to, tribasic calcium phosphate, powdered cellulose, colloidal silicon dioxide, hydrophobic colloidal silicon dioxide, magnesium oxide, magnesium trisilicate, magnesium silicate, silicon dioxide, talc, and mixtures thereof.

According to the present invention, surfactants/wetting agents may include, but are not limited to, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, sodium docusate, glycine, glycofurol, hypromellose, poloxamer, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, sodium lauryl sulfate, sorbitan esters (sorbitan fatty acid esters), tricaprylin, and mixtures thereof.

The dose and dosage ratio of rosuvastatin calcium and fenofibrate can be adjusted based on various factors, such as the patient's symptoms, age, and body weight. According to the present invention, the rosuvastatin calcium dosage is typically between 0.1 and 100 mg, in particular between 1 and 50 mg. More specifically, standard doses of rosuvastatin calcium for inclusion in the multilayer pharmaceutical composition of the present invention are 5, 10, or 20 mg.

According to the present invention, standard doses of fenofibrate for use in the present invention may range from 10 to 500 mg, preferably from 50 to 350 mg. In particular, the standard dose of fenofibrate for inclusion in the multilayer pharmaceutical composition of the present invention is 160 mg.

According to the present invention, a multilayer pharmaceutical composition containing a fixed dose combination can be administered to a patient once or twice a day.

In a more preferred aspect of the invention, the present invention provides a method for preparing a multilayer pharmaceutical composition comprising a fixed dose combination of rosuvastatin calcium, fenofibrate and one or more pharmaceutically acceptable excipients as described/illustrated herein.

In a particularly preferred embodiment, the dosage form of the present invention is a solid dosage form such as a tablet, capsule, powder and sachet, but a tablet is preferred.

The pharmaceutical composition described herein can be prepared using conventional technology well known to those skilled in the art.

A typical bilayer tablet (rosuvastatin calcium and fenofibrate) of the present invention comprises one or more fillers or diluents (such as, for example, lactose, microcrystalline cellulose), one or more binders (such as, for example, povidone, microcrystalline cellulose, lactose, etc.), one or more disintegrants (such as, for example, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, crospovidone), one or more lubricants (for example, magnesium stearate), one or more glidants (for example, tribasic calcium phosphate, colloidal silicon dioxide and magnesium oxide) and/or one or more surfactants (such as, for example, sodium lauryl sulfate).

According to the present invention, a "multilayer pharmaceutical composition" is a multilayer tablet. A multilayer tablet may be, for example, a bilayer tablet.

According to the present invention, a "bilayer tablet" means a tablet containing rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate, wherein rosuvastatin and fenofibrate are present in separate layers (i.e., rosuvastatin and fenofibrate are not mixed together during the preparation of the composition).

According to the present invention, "wet granulation" involves adding a granulating liquid, typically water, acting as a granulating liquid, to a stirred powder containing the materials to be granulated.

According to the present invention, "direct compression" includes a method of producing tablets in which dry ingredients are thoroughly mixed and then compressed into tablets.

According to the present invention, "dissolution" refers to the rate of release of a drug from a dosage form, which can be measured by standard methods.

According to the present invention, the term "multilayer pharmaceutical composition" means a pharmaceutical composition having at least two layers. Examples of multilayer pharmaceutical compositions include, but are not limited to: multilayer tablets, such as bilayer tablets, trilayer tablets, multilayer-coated tablets, compressed granules, coated compressed granules, multilayer granule system (MUPS), tablet in tablet, tablet(s) in capsule, compressed-coated tablets, etc.

The method for producing the pharmaceutical composition of the present invention will now be explained in detail:

EXAMPLES

To further illustrate the present invention, the following examples are provided for clarity of understanding. However, they are in no way intended to limit the scope of the present invention, and those skilled in the art, in light of the teachings of this invention, will recognize that certain changes and modifications can be made thereto without departing from the scope of the invention.

Preparation of fenofibrate (finely ground):

For Comparative Example 1 and Example 2-4, fenofibrate was finely ground to obtain a particle size distribution with the RPD parameters listed in Table 1 below.

Comparative Example 1: Single-layer tablets of rosuvastatin and fenofibrate (not according to the invention)

Mode of production:

Fenofibrate granules were prepared by wet granulation using the ingredients listed above under Serial Nos. 1-9. Rosuvastatin mixture was prepared by mixing rosuvastatin calcium with microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, and light magnesium oxide. The fenofibrate granules and rosuvastatin mixture were then mixed until homogeneous. Sodium stearyl fumarate was added to the fenofibrate granule/rosuvastatin mixture, and the lubricated mixture was compressed on a monolayer compression machine using suitable compression molds. The resulting single-layer tablet was film-coated using Opadry.

Example 2: Bilayer tablets of rosuvastatin and fenofibrate (according to the present invention)

Mode of production:

The production method is the same as described below in Example 3:

Example 3: Bilayer tablets of rosuvastatin and fenofibrate (according to the present invention)

Mode of production:

Layer 1 (Fenofibrate Layer):

The fenofibrate mixture was prepared by sifting the intragranular ingredients listed under Serial Nos. 1-7 above through a suitable sieve and loading them into a suitable granulator. A binder solution was prepared by dissolving povidone (Serial No. 8) in purified water with the addition of isopropyl alcohol to obtain a suitable mixture. Fenofibrate granules were obtained by granulating the fenofibrate mixture (Serial Nos. 1-7) with a granulation solvent in a suitable granulator. Subsequently, the resulting granules and the extragranular ingredients listed under Serial Nos. 11-14 above were mixed until homogeneous. Finally, sodium stearyl fumarate (Serial No. 15) was added to the mixture to obtain the fenofibrate layer mixture with a lubricant.

Layer-2 (Rosuvastatin Layer):

The rosuvastatin mixture was prepared by mixing rosuvastatin calcium, anhydrous lactose, microcrystalline cellulose, crospovidone, and light magnesium oxide in a blender. Screened magnesium stearate was mixed with the previously prepared rosuvastatin mixture to form a lubricated mixture.

Bilayer tablet:

Lubricated fenofibrate and rosuvastatin mixtures were compressed using suitable molds on a bilayer compression machine. The resulting bilayer tablet was film-coated using Opadry.

Dissolution study:

Dissolution studies were performed for:

- A pioneering example of fenofibrate (Supralip ^® ) - 160 mg film-coated tablets

- Comparative example 1 - a single-layer tablet not in accordance with the invention

- Example 3a - a two-layer tablet - according to the invention

Dissolution studies were performed using the following parameters:

Medium: 0.05 M sodium lauryl sulfate in water, Apparatus: Paddle type, Volume: 1000 ml,

Speed: 50 rpm (revolutions per minute)

The obtained dissolution profile results for fenofibrate are shown in Table 5 below.

The above dissolution data indicate that the dissolution of fenofibrate after 60 minutes is at least 20% higher for the bilayer tablet with finely ground fenofibrate than for the single-layer tablet of Comparative Example 1. Thus, the present invention makes it possible to provide a multilayer pharmaceutical composition containing a fixed dose combination of rosuvastatin calcium and fenofibrate, which is characterized by a higher dissolution of fenofibrate after 60 minutes than conventional single-layer compositions.

Example 4: Bilayer tablets of rosuvastatin and fenofibrate (according to the present invention)

Mode of production:

The production method is similar to that described in Example 3:

Dissolution studies: Dissolution studies were performed using the same parameters as described above in Example 3.

Stability study:

A stability study was conducted on the bilayer tablets obtained in Example 4a, Example 4b, and Example 4c at a temperature of 40°C and a relative humidity of 75% for periods of 1 month, 2 months, and 3 months. The stability study results are presented in Table 7a and Table 7b below.

From the stability data presented in Tables 7a and 7b, it can be concluded that the multilayer pharmaceutical composition containing the fixed dose combination of the present invention is stable.

Example 5: Bioavailability study (according to the present invention)

The bioavailability of a fixed-dose combination of the present invention in the form of bilayer tablets of rosuvastatin and fenofibrate was studied.

Research plan

The bioequivalence study was conducted in accordance with the current European Medicines Agency bioequivalence guideline.

Samples

The following samples were used in the bioavailability test:

a) Test sample: Fixed dose combination of the present invention in the form of a bilayer tablet of rosuvastatin and fenofibrate from 4c

b) Comparative sample: SECALIP SUPRA® 160 mg tablet and CRESTOR® 20 mg tablet.

Definitions

The method involved measuring plasma concentrations of fenofibric acid, the active metabolite of fenofibrate, and rosuvastatin, over 96 hours at predetermined time points.

The mean plasma concentration of the metabolite fenofibric acid and rosuvastatin were determined. The fenofibric acid concentration and rosuvastatin concentration values after once-daily administration of the test sample of the present invention are summarized in Table 8. In addition, the fenofibric acid concentration and rosuvastatin concentration values after once-daily administration of the comparative sample are also shown in Table 8. In addition, the plasma concentration-time plot after once-daily administration of the test sample of the present invention is shown for fenofibric acid and rosuvastatin, respectively, in Fig. 1 and Fig. 2.

In addition, the main pharmacokinetic parameters after once-daily administration of the fixed dose combination of the present invention in the form of a bilayer tablet of rosuvastatin and fenofibrate from Example 4c and once-daily administration of the comparative sample products (SECALIP SUPRA® 160 mg tablet and CRESTOR® 20 mg tablet) were measured using the LC-MS/MS method. In particular, the C _max , T _max , AUC, t½ (half-life) and λz (elimination rate constant) values, as well as the standard deviation (SD) of the test sample and the comparative sample are summarized in Table 9.

The above pharmacokinetic parameters and the mean plasma concentration values of the metabolite fenofibric acid and rosuvastatin presented in the tables above unexpectedly demonstrate that once-daily administration of the fixed-dose combination of the present invention in the form of a bilayer tablet of rosuvastatin and fenofibrate from Example 4c is bioequivalent to the total drug exposure resulting from the simultaneous once-daily administration of SECALIP SUPRA® 160 mg tablet and CRESTOR® 20 mg tablet. This means that the fixed-dose combination of the present invention has comparable bioavailability, since the rate and extent to which the metabolite fenofibric acid and rosuvastatin are absorbed from the fixed-dose combination of the present invention and become available at the site of drug action are the same as with the simultaneous administration of the reference samples. Therefore, once-daily administration of the fixed-dose combination according to the present invention can be considered equivalent to once-daily administration of the immediate-release reference sample, i.e., concomitant administration of SECALIP SUPRA® 160 mg tablet and CRESTOR® 20 mg tablet.

In conclusion, the multilayer pharmaceutical composition of the present invention, containing a fixed-dose combination of rosuvastatin and fenofibrate according to Example 4c, represents a suitable improvement over the corresponding SECALIP SUPRA® and CRESTOR® monotherapy, as it provides two active ingredients in a single tablet for once-daily administration, thereby reducing the patient's burden associated with taking tablets. Thus, the fixed-dose combination is convenient for patients suffering from mixed dyslipidemia, who currently need to take two monotherapeutic drugs separately, thereby satisfying a medical need and improving compliance with the treatment regimen.

Claims (11)

A method for preparing a multilayer pharmaceutical composition for treating cardiovascular diseases, comprising a combination of fixed doses of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, namely a fenofibrate layer and a rosuvastatin layer, and wherein the fenofibrate layer contains finely ground fenofibrate, and wherein fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, wherein said method comprises the following steps: a) preparation of a mixture for the fenofibrate layer with a lubricant by i. preparing a fenofibrate mixture by granulating finely ground fenofibrate, lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, crospovidone, iron(III) oxide and sodium lauryl sulfate; ii. preparing a binder solution by dissolving povidone in purified water and adding isopropyl alcohol iii. granulating the mixture of fenofibrate obtained in step i) and the binder solution obtained in step ii) and drying the granules in a suitable dryer; iv. adding microcrystalline cellulose, crospovidone, croscarmellose sodium and colloidal anhydrous silicon dioxide extragranularly to the granules obtained in step iii) v. lubrication of dried granules with sodium stearifumarate; b) preparation of a mixture for the rosuvastatin layer with a lubricant by i. preparing a rosuvastatin mixture by mixing rosuvastatin calcium, anhydrous lactose, microcrystalline cellulose, crospovidone and light magnesium oxide in a mixer; ii. mixing sifted magnesium stearate with the rosuvastatin mixture; and c) pressing the fenofibrate layer mixture with lubricant and the rosuvastatin layer mixture with lubricant using a multi-layer pressing machine.