Pharmaceutical composition containing an HMG-CoA reductase inhibitor and fenofibrate

Abstract

The present invention provides a multi-layer 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 fenofibrate or a pharmaceutically acceptable salt thereof and the rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, i.e., a fenofibrate layer and a rosuvastatin layer, wherein the fenofibrate and the rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and the fenofibrate layer comprises micronized fenofibrate. Further, the present invention provides a process for preparing said composition.

Description

Technical Field

[0001] Related Applications This application is related to Indian Provisional Patent Application No. 201921030870 filed on July 31, 2019 and European Provisional Patent Application No. 19201186.4 filed on October 2, 2019, which are incorporated herein by reference in their entirety.

[0002] Field of the 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, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and the fenofibrate layer contains micronized fenofibrate. Further, the present invention provides a process for preparing said composition.

Background Art

[0003] Background of the Invention Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase and has lipid-lowering activity. 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 having the following structure (Formula I).

Chemical

[0004] Rosuvastatin is known, for example, from U.S. Reissue Patent No. 37314E and European Patent No. 0521471B1. Both prior art documents disclose that rosuvastatin is particularly effective as an HMG-CoA reductase inhibitor. Further, rosuvastatin calcium is available on the market as a single formulation under the name CRESTOR® in the form of 5 mg tablets, 10 mg tablets, 20 mg tablets, and 40 mg tablets. CRESTOR® has two approved therapeutic indications, namely, the treatment of hypercholesterolemia in adults, adolescents, and children 6 years of age and older, and the prevention of cardiovascular events.

[0005] The treatment of hypercholesterolemia is a long-term treatment that may include an initial oral treatment phase followed by a subsequent second dose adjustment phase. In particular, the recommended starting dose is 5 or 10 mg once daily, which may then be switched to 20 or 40 mg with dose adjustment, which can be done after 4 weeks of treatment if necessary. For the prevention of cardiovascular events, the dose used is 20 mg.

[0006] After oral administration, the metabolism of rosuvastatin is limited. In vitro metabolism studies using human hepatocytes have shown that rosuvastatin is an insufficient substrate for cytochrome P450-based metabolism.

[0007] European Patent No. 2306982B1 aims to improve the dissolution profile of CRESTOR®. For this purpose, European Patent No. 2306982B1 discloses a pharmaceutical composition in which rosuvastatin calcium is provided together with an alkali metal carbonate, bicarbonate, or a mixture thereof. The molar ratio of these components is 1:0.43 to 1.75 (rosuvastatin calcium: alkali metal carbonate, bicarbonate, or a mixture thereof). This composition is reported to have a beneficial dissolution profile of rosuvastatin calcium in a 0.1N HCl medium when the anhydrous form of sodium carbonate is present in the range of 0.5 wt% to 2 wt% of the pharmaceutical composition. The pharmaceutical composition is preferably an oral dosage form such as a tablet or another oral dosage form such as a capsule, pellet, or mini-tablet.

[0008] Fenofibrate is an activator of peroxisome proliferator-activated receptor α (PPARα). Through activation of PPARα, fenofibrate increases lipolysis, activates lipoprotein lipase, and decreases the production of apolipoprotein CIII, thereby promoting the removal of atherogenic triglyceride-rich particles from plasma. Activation of PPARα also induces an increase in the synthesis of apolipoproteins AI and AII. Chemically, fenofibrate is 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid 1-methylethyl ester and has the following structure (Formula II).

Chemical formula

[0009] Fenofibrate is disclosed in British Patent No. 1415295A. In addition, fenofibrate is available commercially in various pharmaceutical forms and dosage forms as a single formulation, such as TRICOR® in the form of tablets of 54 mg and 160 mg, in the form of 160 mg tablets as SUPRALIP® in the UK, or as SECALIP SUPRA® in Spain, and as LIPANTHYL® in the form of 200 mg capsules, and is on the market.

[0010] In the case of SUPRALIP® / SECALIP SUPRA® 160 mg tablets, these tablets are indicated for the treatment of severe hypertriglyceridemia regardless of the presence or absence of low HDL cholesterol, for the treatment of mixed hyperlipidemia when statins are not tolerated, and for the treatment of mixed hyperlipidemia in patients at high cardiovascular risk. The recommended dose for the above indications is one tablet containing 160 mg of fenofibrate taken once daily. After oral administration, fenofibrate is rapidly hydrolyzed to the esterase and then to the active metabolite, fenofibric acid. Fenofibric acid is mainly conjugated with glucuronic acid and then excreted in the urine.

[0011] U.S. Patent No. 6277405B1 relates to a method for preparing a composition in which the dissolution of fenofibrate is improved when compared to several commercially available products. This method includes: (a) preparing a suspension of micronized fenofibrate having a particle size of less than 20 μm in a solution of a hydrophilic polymer and optionally a surfactant; and (b) adding the suspension of step (a) to an inert water-soluble carrier. The disclosed composition is said to exhibit at least 75% dissolution of fenofibrate in 30 minutes when measured using the rotating blade method at 75 rpm in a dissolution medium composed of water containing 2% by weight of polysorbate 80 or in a dissolution medium composed of water containing 0.025 M of sodium lauryl sulfate according to the European Pharmacopoeia.

[0012] U.S. Patent Application Publication No. 2011 / 0311625A1 teaches that the solubility of a drug substance affects the bioavailability of the drug. Further, U.S. Patent Application Publication No. 2011 / 0311625A1 teaches that fenofibrate is a poorly soluble drug. Due to its low water solubility, fenofibrate has the problem of low solubility. Fenofibrate is thought to have insufficient absorption in the digestive tract, and as a result, its bioavailability is considered to be incomplete and irregular. It is claimed that the insufficient dissolution characteristics are alleviated by providing fenofibrate in a specific form, namely a tablet comprising a core and a layer surrounding the core, and the layer surrounding the core contains fenofibrate, a hydrophilic polymer, and a hydrophilic carrier.

[0013] European Patent No. 0330532B1 proposes a new therapeutic composition containing fenofibrate co-micronized with a solid surfactant. The new composition is claimed to have improved dissolution of fenofibrate and thus increased bioavailability. The daily dose of the drug can be reduced from 300 mg to 200 mg and from 100 mg to 67 mg without any compromise regarding the efficiency of the treatment.

[0014] Instead of a single drug formulation, several prior art references have proposed using a combination of fenofibrate and an HMG-CoA inhibitor. This should be the most effective means of cholesterol and lipid management. In fact, treatment with fenofibrate is often prescribed together with a statin because clinicians seem to prefer the use of fenofibrate, for example, for its triglyceride-lowering and HDL-C increasing effects, while HMG-CoA inhibitors are used for their LDL-C lowering and HDL-C raising effects and / or their positive effects on related diseases. Fixed-dose combinations containing fibrate and statin as the active ingredients are known from the following documents.

[0015] For example, European Patent No. 1185274B1 discloses a combination of rosuvastatin, an HMG-CoA reductase inhibitor, with an inducer, inhibitor, or substrate of P450 isozyme 3A4 for use simultaneously, separately, or sequentially in therapy.

[0016] International Publication No. 2005 / 034908A2 discloses a pharmaceutical composition comprising a combination of a fibrate, a statin, and a common vehicle. The vehicle is selected from the group consisting of a hydrophobic vehicle, a hydrophilic vehicle, and a water-miscible vehicle. At least 80% w / w, but preferably 99.9% w / w, of the total amount of the fibrate and statin (active substances) is dissolved in the common vehicle. However, achieving such a solution requires advanced technology. Fenofibrate and statin need to be dissolved in a mixture of PEG 6000 and poloxamer 188 (70:30) or glyceryl monostearate at 70°C, and then the solution needs to be sprayed onto fluidized lactose. Furthermore, the release characteristics of fenofibrate from such a composition are insufficient.

[0017] EP 1853249 A2 discloses a pharmaceutical composition comprising at least two active ingredients, namely fenofibrate as a first component and an HMG-CoA reductase inhibitor or its derivative as a second component. EP 1853249 A2 provides a single solid dosage form for oral administration, which comprises a solid fenofibrate composition and a solid HMG-CoA reductase inhibitor composition, preferably a statin composition, and the active substances are present in separate entities. This document discloses that the fibrate contained in the composition exists in the form of a solid solution. According to the disclosed examples, the fenofibrate granules were prepared in a very brittle manner, i.e., according to the method of WO 2005 / 034920 A1. This also requires that the fenofibrate be dissolved in a solution of polyethylene glycol 6000 and poloxamer 188 (70:30 w / w ratio) at 75 °C, and then the homogeneous solution needs to be sprayed onto lactose. In addition to this drawback, the separation of the active substances in the two entities and the dissolution profile of the fenofibrate in the disclosed pharmaceutical composition are also insufficient.

[0018] WO 2008 / 075320 A2 discloses a process for preparing an oral pharmaceutical composition comprising fenofibrate alone or in combination with at least one other antihyperlipidemic agent in a single dosage form that can be conveniently administered once or twice a day. This document discloses a process for preparing an oral pharmaceutical composition comprising fenofibrate, which process comprises preparing a solution comprising fenofibrate, a surfactant, and a hydrophilic polymer, and spraying this solution onto one or more inert carriers to prepare granules. This document also requires the preparation of a fenofibrate composition by preparing a solution of fenofibrate and using this solution to prepare granules.

[0019] Kumar et al., IJPSR, 2016; Vol. 7(1): 413-23 discloses a combination of rosuvastatin calcium and fenofibrate as a bilayer tablet in which the rosuvastatin layer provides a sustained release of rosuvastatin and the fenofibrate layer provides an immediate release of fenofibrate.

[0020] In summary, most of the above prior art discloses single drug formulations of fenofibrate and rosuvastatin. There are very few prior art documents regarding the combination of fibrate and statin drugs in a single dosage form. However, most notably, none of the prior art documents teach how the dissolution of fenofibrate can be improved when both fenofibrate and rosuvastatin are combined in a single dosage form. Furthermore, known fixed-dose combinations are disadvantageous with respect to their manufacture. The preparation of solid solutions of the active substances introduces a high degree of complexity into the manufacturing process. To prepare such solid solutions, manufacturers have to use heating equipment and add specific excipients (e.g., PEG, poloxamer, wax).

[0021] In addition, none of the prior art documents show that a fixed-dose combination of fenofibrate and rosuvastatin that is biologically equivalent in vivo to the co-administration of the single-agent therapies SECALIP SUPRA® and CRESTOR® is effective in improving treatment compliance.

[0022] In view of the prior art, there is a strong need to develop a new combination product of fenofibrate and rosuvastatin that overcomes the known drawbacks of the prior art compositions. SUMMARY OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION

[0023] Object of the Invention Accordingly, an object of the present invention is to provide a combination product of fenofibrate and rosuvastatin that can be easily manufactured and has an improved dissolution profile, at least for fenofibrate.

Means for Solving the Problems

[0024] Summary of the Invention The inventors of the present invention have surprisingly found that a pharmaceutical composition comprising a fixed-dose combination of rosuvastatin and fenofibrate or a pharmaceutically acceptable salt thereof exhibits an excellent dissolution profile of fenofibrate. This composition has a multi-layer structure, where rosuvastatin and fenofibrate are found in separate layers, and fenofibrate and rosuvastatin are immediately released from the fenofibrate layer and the rosuvastatin layer, respectively. The fenofibrate layer contains fenofibrate in the form of micronized fenofibrate. Preferably, the dissolution profile of fenofibrate is characterized by the fact that when measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, more than 74% of the fenofibrate content dissolves within 30 minutes.

[0025] Advantageously, the composition of the present invention can be obtained by a conventional wet granulation process. That is, in contrast to the fixed-dose combinations of the prior art, the composition of the present invention does not require the preparation of a solid solution of fenofibrate. On the other hand, the composition of the present invention exhibits faster dissolution of fenofibrate than the fixed-dose combinations of the prior art. That is, when measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, the composition of the present invention exhibits a dissolution profile such that more than 74% by weight of fenofibrate is released within 30 minutes.

[0026] The pharmaceutical composition of the present invention advantageously enables the in vivo bioavailability of the co - ingestion of commercially available SECALIP SUPRA® and CRESTOR® at equivalent doses to be reproduced. In this sense, the inventors have found that the total drug exposure shown after once - daily administration of the fixed - dose combination of the present invention is biologically equivalent to the total drug exposure obtained after once - daily co - administration of SECALIP SUPRA® 160 mg tablets and CRESTOR® 20 mg tablets. This means that the fixed - dose combination of the present invention shows equivalent pharmacokinetic parameters (e.g., C max , T max , AUC 0~t , AUC 0~∞ ) for the bioavailability of fenofibric acid, the active metabolite of fenofibrate, and rosuvastatin.

[0027] Surprisingly, due to the faster in vitro dissolution profile of fenofibrate in the multilayer pharmaceutical composition of the present invention compared to the prior - art single - layer pharmaceutical composition, the multilayer pharmaceutical composition of the present invention can reproduce the in vivo bioavailability of SECALIP SUPRA®.

[0028] Furthermore, the inventors have found that a multilayer pharmaceutical composition comprising a fixed - dose combination of rosuvastatin and fenofibrate, or pharmaceutically acceptable salts thereof, exhibits good stability of both active ingredients over periods of 1 month, 2 months, and 3 months at a temperature of 40 °C and a relative humidity of 75%.

[0029] Accordingly, the multilayer pharmaceutical composition of the present invention comprising a fixed-dose combination of rosuvastatin and fenofibrate, or a pharmaceutically acceptable salt thereof, provides two active ingredients in a single tablet for once-daily treatment, thus showing appropriate improvement over the corresponding monotherapies in order to reduce the burden of the number of tablets for the patient. Accordingly, the fixed-dose combination is convenient for patients with mixed dyslipidemia who currently need to receive two monotherapies separately, thus addressing unmet medical needs and providing improvement to ensure treatment compliance and adherence.

Brief Description of the Drawings

[0030] Brief Description of the Drawings

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0031] Detailed Description of the Invention Unless otherwise specified, the terms in this specification are intended to have their ordinary meanings in the relevant art.

[0032] The present invention relates to a composition for the treatment of cardiovascular diseases including, but not limited to, coronary heart disease, heart failure and cardiomyopathy, congenital heart disease, atherosclerosis, ischemia / reperfusion, hypertension, restenosis, acute rheumatic fever, rheumatic heart disease, and arteritis.

[0033] The present invention relates to a pharmaceutical preparation having a synergistic effect of the combined use of fenofibrate and statin. The preparation is presented in a plurality of dosage forms produced by formulating the two active agents separately. The excipients used in the preparation are selected such that the interaction between those excipients and the active agents is minimized, and the preparation is prepared accordingly. The plurality of dosage forms thus prepared can be manufactured such that the two active agents can have different release characteristics and / or the same release characteristics.

[0034] As described above, both fenofibrate and statin-based active agents have solubility / dissolution problems. It is known that it is very difficult to develop a pharmaceutical form with a high dissolution rate for drugs that are difficult to dissolve. However, the inventors have succeeded in producing a multilayer composition containing rosuvastatin and fenofibrate or pharmaceutically acceptable salts thereof, and the dissolution of fenofibrate after 60 minutes is at least 20% more than that of a composition containing a single layer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof.

[0035] As used herein, the term "rosuvastatin" defines a molecule represented by structural formula (I), but also defines its pharmaceutically acceptable salts. The multilayer composition of the present invention contains a certain amount of calcium rosuvastatin, or an equal amount of another pharmaceutically acceptable salt of this calcium rosuvastatin. Examples of such salts include barium salts, strontium salts, zinc salts, cesium salts, cadmium salts, magnesium salts, sodium salts, and ammonium salts.

[0036] As used herein, the term "fenofibrate" is defined as the molecule represented by structural formula (II), but also as its pharmaceutically acceptable salts.

[0037] 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, and a process for the preparation of said multilayer composition.

[0038] In a preferred embodiment, 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, said multilayer composition being an immediate-release two-layer tablet.

[0039] In another embodiment, 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 and rosuvastatin are each immediately released from a fenofibrate layer and a rosuvastatin layer, and the dissolution of fenofibrate after 60 minutes from the multilayer composition comprising the fixed-dose combination is at least 20% higher compared to a composition comprising a single layer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof.

[0040] In another embodiment, 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 and rosuvastatin are each immediately released from a fenofibrate layer and a rosuvastatin layer, and the dissolution of fenofibrate after 60 minutes from the multilayer composition comprising the fixed-dose combination, when measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, is at least 20% higher compared to a composition comprising a single layer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof.

[0041] In another embodiment, 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 and rosuvastatin are each immediately released from a fenofibrate layer and a rosuvastatin layer, the fenofibrate layer comprises micronized fenofibrate, and the dissolution of fenofibrate after 60 minutes from the multilayer composition comprising the fixed-dose combination, when measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, is at least 20% higher compared to a composition comprising a single layer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof.

[0042] In another embodiment, the present invention provides 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 dissolution of fenofibrate 60 minutes after from the bilayer tablet containing the fixed-dose combination, when measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, is at least 20% higher compared to a composition containing a single layer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof.

[0043] In another embodiment, 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 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 thereof is present in an amount of 100 mg to 200 mg.

[0044] In a preferred embodiment, the present invention provides 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 5 mg to 20 mg, and fenofibrate or a pharmaceutically acceptable salt thereof is present in an amount of 140 mg to 180 mg.

[0045] In another embodiment, 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 (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, (2) rosuvastatin and fenofibrate are not mixed with each other, (3) fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, and (4) the dissolution of fenofibrate after 60 minutes from the multilayer composition, measured using a USP Type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, is at least 20% higher compared to a composition comprising a single layer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof.

[0046] In a preferred embodiment, 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, the multilayer composition comprising 5 to 20 mg of rosuvastatin or a pharmaceutically acceptable salt thereof and 160 mg of fenofibrate, wherein (1) rosuvastatin and fenofibrate are not mixed with each other, (2) fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, respectively, (3) the dissolution of fenofibrate after 15 minutes is more than 67% w / w of the total fenofibrate content, and (4) the dissolution of fenofibrate after 60 minutes from the multilayer composition, measured using a USP Type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, is at least 20% higher compared to a composition comprising a single layer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof.

[0047] In another embodiment, the present invention provides 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 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 the dissolution of fenofibrate after 60 minutes from the bilayer tablet, measured using a USP Type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, is at least 20% higher compared to a composition comprising a single layer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof.

[0048] In a preferred embodiment, the present invention provides a bilayer tablet comprising a fixed-dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, the bilayer tablet comprising 5 - 20 mg of rosuvastatin or a pharmaceutically acceptable salt thereof and 160 mg of fenofibrate, and / or the dissolution of fenofibrate after 60 minutes from the bilayer tablet, measured using a USP Type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, is at least 20% higher compared to a composition comprising a single layer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof.

[0049] In another embodiment, the present invention provides 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, (2) rosuvastatin and fenofibrate are not mixed with each other, (3) fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and / or (4) the dissolution of fenofibrate after 60 minutes from the bilayer tablet, when measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, is at least 20% higher compared to a composition containing a single layer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof.

[0050] In a preferred embodiment, the present invention provides a bilayer tablet comprising a fixed-dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, the bilayer tablet comprising 5 to 20 mg of rosuvastatin or a pharmaceutically acceptable salt thereof and 160 mg of fenofibrate, wherein (1) rosuvastatin and fenofibrate are not mixed with each other (i.e., not a single layer), (2) fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, (3) the dissolution of fenofibrate after 15 minutes is more than 67% w / w of the fenofibrate content, and / or (4) the dissolution of fenofibrate after 60 minutes from the bilayer tablet, when measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, is at least 20% higher compared to a composition containing a single layer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, 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 and rosuvastatin are present in separate layers, and fenofibrate is micronized fenofibrate. In a preferred embodiment, the micronized fenofibrate has a volume median 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, and most preferably greater than 0.05 μm and less than or equal to 4 μm.

[0052] In one embodiment, 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 and rosuvastatin are present in separate layers, and fenofibrate is micronized fenofibrate, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, respectively. In a preferred embodiment, the micronized fenofibrate has a volume median 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, and most preferably greater than 0.05 μm and less than or equal to 4 μm.

[0053] In one embodiment, 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 and rosuvastatin are present in separate layers, fenofibrate is micronized fenofibrate, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and the dissolution of fenofibrate 60 minutes after from the multilayer composition containing the fixed-dose combination is at least 20% higher compared to a composition containing a single layer of rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, as measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirring at 50 revolutions per minute. In a preferred embodiment, the micronized fenofibrate has a volume median 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, and most preferably greater than 0.05 μm and less than or equal to 4 μm.

[0054] In another embodiment, the micronized 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.

[0055] The width of the particle size distribution of the micronized fenofibrate, expressed as span, can be 1.2 to 3, preferably 1.3 to 2.5, more preferably 1.6 to 2.3. According to Chew et al J Pharm Pharmaceut Sci 2002, 5, 162-168, "span" corresponds to the following relationship: [D(v, 0.9) - D(v, 0.1)] / D(v, 0.5).

[0056] The PSD parameters (D(v, 0.9), D(v, 0.5), and D(v, 0.1)) of the micronized fenofibrate are determined by measuring the characteristic equivalent spherical diameter, known as the volume diameter, by laser diffraction.

[0057] In another embodiment, 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 and rosuvastatin are present in separate layers, and fenofibrate is neither in the form of a solid solution nor in the form of a solid dispersion. In this context, the fact that fenofibrate is neither in the form of a solid solution nor in the form of a solid dispersion means that the fenofibrate layer contains less than 20% w / w or does not contain an excipient or carrier selected from the group consisting of polyethylene glycol, polypropylene glycol, polyoxyethylene, polyoxypropylene, poloxamer, linear saturated hydrocarbons, sorbitan esters, paraffin, fats, oils, and mixtures thereof, and has a melting point of less than 100°C. Preferably, the fenofibrate layer contains less than 20% w / w or does not contain an excipient or carrier and has a melting point of less than 100°C regardless of the class of compound from which the excipient or carrier is selected. In a preferred embodiment, the composition of the present invention contains less than 20% w / w or does not contain an excipient or carrier and comprises a fenofibrate layer having a melting point of less than 75°C, preferably less than 80°C, more preferably less than 90°C, and even more preferably less than 100°C.

[0058] In another embodiment, 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 and rosuvastatin are present in separate layers, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and the composition, when measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, exhibits a dissolution profile in which more than 74% w / w, preferably more than 77% w / w, more preferably more than 80% w / w, and even more preferably more than 83% w / w of fenofibrate dissolves within 30 minutes.

[0059] In another embodiment, when the composition of the present invention is measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, up to 48% w / w of fenofibrate dissolves in 5 minutes, 49 - 79% w / w of fenofibrate dissolves in 10 minutes, 65 - 95% w / w of fenofibrate dissolves in 15 minutes, 68 - 98% w / w of fenofibrate dissolves in 20 minutes, 74 - 100% w / w of fenofibrate dissolves in 30 minutes, 79 - 100% w / w of fenofibrate dissolves in 45 minutes, and 80 - 100% w / w of fenofibrate dissolves in 60 minutes, showing a dissolution profile. In another preferred embodiment, when the composition of the present invention is measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, up to 43% w / w of fenofibrate dissolves in 5 minutes, 54 - 74% w / w of fenofibrate dissolves in 10 minutes, 70 - 90% w / w of fenofibrate dissolves in 15 minutes, 73 - 93% w / w of fenofibrate dissolves in 20 minutes, 78 - 98% w / w of fenofibrate dissolves in 30 minutes, 84 - 100% w / w of fenofibrate dissolves in 45 minutes, and 85 - 100% w / w of fenofibrate dissolves in 60 minutes, showing a dissolution profile. In another more preferred embodiment, when the composition of the present invention is measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, up to 38% w / w of fenofibrate dissolves in 5 minutes, 59 - 69% w / w of fenofibrate dissolves in 10 minutes, 75 - 85% w / w of fenofibrate dissolves in 15 minutes, 78 - 88% w / w of fenofibrate dissolves in 20 minutes, 83 - 93% w / w of fenofibrate dissolves in 30 minutes, 89 - 99% w / w of fenofibrate dissolves in 45 minutes, and 90 - 100% w / w of fenofibrate dissolves in 60 minutes, showing a dissolution profile.

[0060] In another embodiment, 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 and rosuvastatin are present in separate layers, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and the fenofibrate is micronized fenofibrate and the fenofibrate is not in the form of a solid dispersion.

[0061] In another embodiment, 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 and rosuvastatin are present in separate layers, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and the fenofibrate is micronized fenofibrate and the fenofibrate is not in the form of a solid dispersion, and when this composition is measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, it exhibits a dissolution profile in which more than 74% w / w of the fenofibrate dissolves within 30 minutes.

[0062] In another embodiment, 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 and rosuvastatin are present in separate layers, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, respectively. Fenofibrate is micronized fenofibrate, and fenofibrate is not in the form of a solid dispersion. When measured using a USP type II dissolution apparatus with 1000 ml of 0.05 M sodium lauryl sulfate in water as the dissolution medium at 37°C and stirred at 50 revolutions per minute, the dissolution profile of fenofibrate shows that up to 48% w / w of fenofibrate dissolves in 5 minutes, 49 - 79% w / w of fenofibrate dissolves in 10 minutes, 65 - 95% w / w of fenofibrate dissolves in 15 minutes, 68 - 98% w / w of fenofibrate dissolves in 20 minutes, 73 - 100% w / w of fenofibrate dissolves in 30 minutes, 79 - 100% w / w of fenofibrate dissolves in 45 minutes, and 80 - 100% w / w of fenofibrate dissolves in 60 minutes.

[0063] In one embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, fenofibrate or a pharmaceutically acceptable salt thereof (equivalent to 160 mg of fenofibrate) exhibits a maximum plasma concentration (C max ) of 6.500 μg / mL to 12.500 μg / mL, expressed as the plasma concentration of its fenofibric acid metabolite. In a preferred embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, fenofibrate or a pharmaceutically acceptable salt thereof (equivalent to 160 mg of fenofibrate) exhibits a maximum plasma concentration (C max) is shown. In a more preferred embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, fenofibrate or a pharmaceutically acceptable salt thereof (equivalent to 160 mg of fenofibrate) has a maximum plasma concentration (C max ) shown. C max The term refers to the maximum concentration of fenofibric acid metabolite in the blood after a single oral administration of the fixed-dose combination of the present invention after a meal.

[0064] In one embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, rosuvastatin or a pharmaceutically acceptable salt thereof (equivalent to 20 mg of rosuvastatin) has a maximum plasma concentration (C max ) shown. In a preferred embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, rosuvastatin or a pharmaceutically acceptable salt thereof (equivalent to 20 mg of rosuvastatin) has a maximum plasma concentration (C max ) shown. In a more preferred embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, rosuvastatin or a pharmaceutically acceptable salt thereof (equivalent to 20 mg of rosuvastatin) has a maximum plasma concentration (C max ) shown. The term "C max " refers to the maximum concentration of rosuvastatin in the blood after a single oral administration of the fixed-dose combination of the present invention after a meal.

[0065] In one embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, fenofibrate or a pharmaceutically acceptable salt thereof (equivalent to 160 mg of fenofibrate) has a maximum plasma concentration (T of 1.5 to 7 hours, expressed as the plasma concentration of its fenofibric acid metabolite max) indicates time. In a preferred embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, fenofibrate or a pharmaceutically acceptable salt thereof (equivalent to 160 mg of fenofibrate) has a maximum plasma concentration (T max ) indicating time. In a more preferred embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, fenofibrate or a pharmaceutically acceptable salt thereof (equivalent to 160 mg of fenofibrate) has a maximum plasma concentration (T max ) indicating time. The term "T max " refers to the time (in hours) at which C max is achieved after a single oral administration of the fixed-dose combination of the present invention after a meal.

[0066] In one embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, rosuvastatin or a pharmaceutically acceptable salt thereof (equivalent to 20 mg of rosuvastatin) has a maximum plasma concentration (T max ) indicating time. In a preferred embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, rosuvastatin or a pharmaceutically acceptable salt thereof (equivalent to 20 mg of rosuvastatin) has a maximum plasma concentration (T max ) indicating time. In a more preferred embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, rosuvastatin or a pharmaceutically acceptable salt thereof (equivalent to 20 mg of rosuvastatin) has a maximum plasma concentration (T max ) indicating time. The term "T max " refers to the time (in hours) at which C max is achieved after a single oral administration of the fixed-dose combination of the present invention after a meal.

[0067] In one embodiment, after an oral single administration of a fixed-dose combination of the present invention after a meal, fenofibrate or a pharmaceutically acceptable salt thereof (corresponding to 160 mg of fenofibrate) exhibits an area under the time / plasma concentration curve (AUC(0 - t)) of 80,500 μg·h / mL to 310,500 μg·h / mL from time 0 to 96 hours, expressed as the plasma concentration of its fenofibric acid metabolite. In a preferred embodiment, after an oral single administration of a fixed-dose combination of the present invention after a meal, fenofibrate or a pharmaceutically acceptable salt thereof (corresponding to 160 mg of fenofibrate) exhibits an area under the time / plasma concentration curve (AUC(0 - t)) of 122,500 μg·h / mL to 222,500 μg·h / mL from time 0 to 96 hours, expressed as the plasma concentration of its fenofibric acid metabolite. In a more preferred embodiment, after an oral single administration of a fixed-dose combination of the present invention after a meal, fenofibrate or a pharmaceutically acceptable salt thereof (corresponding to 160 mg of fenofibrate) exhibits an area under the time / plasma concentration curve (AUC(0 - t)) of 147,500 μg·h / mL to 197,500 μg·h / mL from time 0 to 96 hours, expressed as the plasma concentration of its fenofibric acid metabolite. The term "AUC" refers to the area under the time / plasma concentration curve after an oral single administration of the composition of the present invention. AUC 0 to infinity indicates the area under the plasma concentration vs. time curve from time 0 to infinity, and AUC 0~t indicates the area under the plasma concentration vs. time curve from time 0 to time t.

[0068] In one embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, rosuvastatin or a pharmaceutically acceptable salt thereof (equivalent to 20 mg of rosuvastatin) exhibits an area under the time / plasma concentration curve (AUC(0-t)) of 76,000 ng·h / mL to 210,000 ng·h / mL from time 0 to 96 hours. In a preferred embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, rosuvastatin or a pharmaceutically acceptable salt thereof (equivalent to 20 mg of rosuvastatin) exhibits an area under the time / plasma concentration curve (AUC(0-t)) of 101,000 ng·h / mL to 171,000 ng·h / mL from time 0 to 96 hours. In a more preferred embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, rosuvastatin or a pharmaceutically acceptable salt thereof (equivalent to 20 mg of rosuvastatin) exhibits an area under the time / plasma concentration curve (AUC(0-t)) of 126,000 ng·h / mL to 146,000 ng·h / mL from time 0 to 96 hours. The term "AUC" refers to the area under the time / plasma concentration curve after a single oral administration of the composition of the present invention. AUC0-infinity represents the area under the plasma concentration vs. time curve from time 0 to infinity, and AUC 0~t represents the area under the plasma concentration vs. time curve from time 0 to time t.

[0069] In one embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, fenofibrate or a pharmaceutically acceptable salt thereof (equivalent to 160 mg of fenofibrate) exhibits a half-life (T1 / 2) of 12 to 40 hours, expressed as the plasma concentration of its fenofibric acid metabolite. In a preferred embodiment, after a single oral administration of the fixed-dose combination of the present invention after a meal, fenofibrate or a pharmaceutically acceptable salt thereof (equivalent to 160 mg of fenofibrate) exhibits a half-life (T1 / 2) of 19 to 25 hours, expressed as the plasma concentration of its fenofibric acid metabolite. The term "half-life (T1 / 2)" refers to the time it takes for fenofibrate to lose half of its pharmacological activity.

[0070] In one embodiment, after oral single administration of the fixed-dose combination of the present invention after a meal, rosuvastatin or a pharmaceutically acceptable salt thereof (corresponding to 20 mg of rosuvastatin) exhibits a half-life (T1 / 2) of 6 to 44 hours. In a preferred embodiment, after oral single administration of the fixed-dose combination of the present invention after a meal, rosuvastatin or a pharmaceutically acceptable salt thereof (corresponding to 20 mg of rosuvastatin) exhibits a half-life (T1 / 2) of 10 to 16 hours. The term "half-life (T1 / 2)" refers to the time it takes for rosuvastatin to lose half of its pharmacological activity.

[0071] The values of the pharmacokinetic parameters after a single unique administration of the fixed-dose combination of the present invention after a meal as described 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 biologically equivalent to the total drug exposure obtained after once-daily co-administration of SECALIP SUPRA (registered trademark) 160 mg tablets and CRESTOR (registered trademark) 20 mg tablets. The 90% confidence interval of the ratio of the pharmacokinetic parameters of the fixed-dose combination of the present invention to those of a comparative composition outside the scope of the present invention is within the acceptance interval of 80.00 to 125.00% according to the EMA guidelines (CPMP / EWP / QWP / 1401 / 98 Rev. 1 / Corr, 2010) for the investigation of bioequivalence.

[0072] In one embodiment, 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, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and impurity B of fenofibrate is below the limit of quantification after a period of 3 months under storage conditions of 40°C and 75% relative humidity.

[0073] In one embodiment, 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, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and the fenofibrate assay is 99.00% or more after a period of 3 months under storage conditions of 40°C and 75% relative humidity.

[0074] In one embodiment, 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, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and the total amount of impurities related to fenofibrate is less than 0.100% after a period of 3 months under storage conditions of 40°C and 75% relative humidity.

[0075] In one embodiment, 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, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and the anti-isomer impurity of rosuvastatin is less than 0.250% after a period of 3 months under storage conditions of 40°C and 75% relative humidity.

[0076] In one embodiment, 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 the fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and the 5-oxo impurity of rosuvastatin is less than 0.300% after a period of 3 months under storage conditions of a temperature of 40 °C and a relative humidity of 75%.

[0077] In one embodiment, 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 the fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and the lactone impurity of rosuvastatin is less than 0.150% after a period of 3 months under storage conditions of a temperature of 40 °C and a relative humidity of 75%.

[0078] In one embodiment, 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 the fenofibrate or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and the rosuvastatin assay is 99.00% or more after a period of 3 months under storage conditions of a temperature of 40 °C and a relative humidity of 75%.

[0079] In one embodiment, 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, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, and the total amount of impurities associated with rosuvastatin is less than 0.700% after a period of 3 months under storage conditions of 40°C and 75% relative humidity.

[0080] In a more detailed aspect, the present invention provides a multilayer pharmaceutical composition comprising a fixed-dose combination of rosuvastatin or a pharmaceutically acceptable salt thereof, fenofibrate or a pharmaceutically acceptable salt thereof, and a suitable pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is 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, and one or more pigments or plasticizers, etc.

[0081] For the purposes of this specification, the term "immediate release" means a composition or component or layer or unit that releases rosuvastatin and fenofibrate immediately, i.e., without following a delayed or sustained release mechanism, from the composition or component or layer or unit containing rosuvastatin and fenofibrate. The multilayer pharmaceutical composition according to the present invention provides immediate release of fenofibrate and rosuvastatin from the fenofibrate layer and the rosuvastatin layer, respectively.

[0082] The pharmaceutical excipients of 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, and one or more pigments or plasticizers, etc.

[0083] According to the present invention, the filler or diluent may include, but is not limited to, ammonium alginate, calcium carbonate, calcium lactose, anhydrous calcium hydrogen phosphate, calcium phosphate dihydrate, tricalcium phosphate, calcium silicate, calcium sulfate, microcrystalline cellulose, cellulose powder, microcrystalline cellulose silicate, cellulose acetate, corn starch and pregelatinized starch, dextrate, dextrin, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lactitol, lactose anhydrous, 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, polymethacrylate, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sterilizable corn starch, sucrose, compressed sugar, sugar confectioner’s, sugar spheres, sulfobutyl ether b-cyclodextrin, sunflower oil, talc, tragacanth, trehalose, xylitol, and mixtures thereof.

[0084] According to the present invention, the binder may include, but is not limited to, acacia, agar, alginic acid, calcium carbonate, tricalcium phosphate, calcium lactate, carbomer, sodium carboxymethyl cellulose, carrageenan, cellulose acetate phthalate, kidney bean, microcrystalline cellulose, chitosan, copovidone, cottonseed oil, dextrolate, dextrin, dextrose, ethyl cellulose, gelatin, liquid glucose, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, anhydrous lactose, spray-dried lactose, low-substituted hydroxypropyl cellulose, hypromellose, inulin, lactose monohydrate, magnesium aluminum silicate, maltodextrin, maltose, methyl cellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylate, povidone, sodium alginate, pregelatinized starch, starch, sucrose, sunflower oil, hydrogenated vegetable oil, vitamin E, polyethylene glycol succinate, zein, tragacanth, polyethylene glycol, polyvinyl pyrrolidone, stearic acid, tricaprylin, and mixtures thereof.

[0085] According to the present invention, the disintegrant may include, but is not limited to, alginic acid, calcium alginate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose, microcrystalline cellulose, cellulose powder, chitosan, colloidal silicon dioxide, corn starch and pregelatinized starch, croscarmellose sodium, crospovidone, sodium docusate, glycine, guar gum, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, lactose, monohydrate and corn starch, magnesium aluminum silicate, methyl cellulose, polyacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, pregelatinized starch, and mixtures thereof.

[0086] According to the present invention, the lubricant may include, but is not limited to, calcium stearate, canola oil, castor oil, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, lauric acid, leucine, magnesium stearate, light 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.

[0087] According to the present invention, the flow promoter may include, but is not limited to, tricalcium phosphate, powdered cellulose, colloidal silicon dioxide, hydrophobic colloidal silica, magnesium oxide, magnesium trisilicate, magnesium silicate, silicon dioxide, talc, and mixtures thereof.

[0088] According to the present invention, the surfactant / wetting agent may include, but is not limited to, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, sodium docusate, glycine, glycolfurole, hypromellose, poloxamer, phospholipid, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, sodium lauryl sulfate, sorbitan ester (sorbitan fatty acid ester), tricaprylin, and mixtures thereof.

[0089] The dosages and administration ratios of rosuvastatin calcium and fenofibrate can be adjusted based on various factors such as the patient's symptoms, age, and weight. According to the present invention, the dosage of rosuvastatin calcium is typically 0.1 to 100 mg, particularly 1 to 50 mg. More specifically, the unit dosage strength of rosuvastatin calcium for inclusion in the multilayer pharmaceutical composition of the present invention is 5 mg, 10 mg, or 20 mg.

[0090] According to the present invention, the unit dosage strength of fenofibrate for use in the present invention can be 10 mg to 500 mg, preferably 50 mg to 350 mg. More specifically, the unit dosage strength of fenofibrate for inclusion in the multilayer pharmaceutical composition of the present invention is 160 mg.

[0091] According to the present invention, the multilayer pharmaceutical composition containing a fixed-dose combination can be administered to a patient once or twice a day.

[0092] In a more preferred embodiment of the present invention, the present invention provides a process for the preparation of a multilayer pharmaceutical composition comprising a fixed-dose combination of rosuvastatin calcium, fenofibrate, and one or more pharmaceutically acceptable excipients described / illustrated herein.

[0093] In a particularly preferred embodiment, the dosage form of the present invention is a solid dosage form such as tablets, capsules, powders, and sachets, but preferably tablets.

[0094] The pharmaceutical composition described herein can be prepared by conventional techniques well known to those skilled in the art.

[0095] A typical two-layer tablet (rosuvastatin calcium and fenofibrate) of the present invention comprises one or more fillers or diluents (e.g., lactose, microcrystalline cellulose, etc.), one or more binders (e.g., povidone, microcrystalline cellulose, lactose, etc.), one or more disintegrants (e.g., microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, crospovidone, etc.), one or more lubricants (e.g., magnesium stearate, etc.), one or more glidants (e.g., tricalcium phosphate, colloidal silicon dioxide, and magnesium oxide, etc.), and / or one or more surfactants (e.g., sodium lauryl sulfate, etc.).

[0096] According to the present invention, the "multilayer pharmaceutical composition" is a multilayer tablet. The multilayer tablet can be, for example, a two-layer tablet.

[0097] According to the present invention, the "two-layer tablet" means a tablet containing rosuvastatin or a pharmaceutically acceptable salt thereof and fenofibrate, and rosuvastatin and fenofibrate are present in separate layers (i.e., rosuvastatin and fenofibrate are not mixed together during the preparation of the composition).

[0098] According to the present invention, "wet granulation" involves adding a granulation fluid that functions as a granulation liquid, generally water, to a stirred powder containing the material to be granulated.

[0099] According to the present invention, "direct compression" includes a method for manufacturing tablets in which the dry ingredients are completely mixed and then compressed into tablets.

[0100] According to the present invention, "dissolution" refers to the rate of drug release from a dosage form that can be measured by a standardized method.

[0101] 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 two-layer tablets, three-layer tablets, multi-coated tablets, compressed pellets, compressed coated pellets, multiple unit pellet systems (MUPS), tablets within tablets, tablets within capsules, and compressed coated tablets.

[0102] Hereinafter, the process for manufacturing the pharmaceutical composition of the present invention will be described in detail.

Example

[0103] Example To further illustrate the present invention, the following examples are provided for the purpose of clarity of understanding. However, it is in no way intended to limit the scope of the present invention, and it will be apparent to those skilled in the art in light of the teachings of the present invention that specific changes and modifications can be made without departing from the scope of the present invention.

[0104] Preparation (micronization) of fenofibrate: In Comparative Example 1 and Examples 2 to 4, fenofibrate was micronized and had a particle distribution characterized by the PSD parameters listed in Table 1 below.

[0105]

Table 1

[0106] Comparative Example 1: Rosuvastatin and fenofibrate single-layer tablets (not according to the present invention)

[0107]

Table 2

[0108] Manufacturing process: Fenofibrate granules were prepared by a wet granulation process using the above components with sieve numbers 1 to 9. The rosuvastatin blend was prepared by mixing rosuvastatin calcium with microcrystalline cellulose, crospovidone, colloidal anhydrous silica, and light magnesium oxide. Subsequently, the fenofibrate granules and the rosuvastatin blend were uniformly mixed. Sodium stearyl fumarate was added to the mixture of fenofibrate granules and rosuvastatin blend, and the lubricating blend was compressed using a suitable apparatus equipped with a single-layer compressor. The obtained single-layer tablets were film-coated using Opadry.

[0109] Example 2: Two-layer tablets of rosuvastatin and fenofibrate (according to the present invention)

[0110]

Table 3

[0111] Manufacturing process: The manufacturing process is the same as that described in Example 3 below.

[0112] Example 3: Two-layer tablet of rosuvastatin and fenofibrate (according to the present invention)

[0113]

Table 4

[0114] Manufacturing process: Layer 1 (fenofibrate layer): The fenofibrate blend was prepared by screening the above intragranular components with sieve numbers 1 to 7 through an appropriate sieve and filling them into an appropriate granulator. The binder solution was prepared by dissolving povidone (sieve number 8) in purified water and adding isopropyl alcohol to obtain an appropriate mixture. The fenofibrate granules were obtained by granulating the fenofibrate blend (sieve numbers 1 to 7) using a granulating solvent in an appropriate granulator. Subsequently, the above-obtained granules and extragranular components with sieve numbers 11 to 14 were uniformly mixed. Finally, sodium stearyl fumarate (sieve number 15) was added to the mixture to obtain a lubricated fenofibrate layer blend.

[0115] Layer 2 (rosuvastatin layer): The rosuvastatin blend was prepared by mixing calcium rosuvastatin, anhydrous lactose, microcrystalline cellulose, crospovidone, and magnesium oxide light in a blender. The selected magnesium stearate was mixed with the previously prepared rosuvastatin blend to obtain a lubricated blend.

[0116] Two-layer tablet: A lubricating blend of fenofibrate and rosuvastatin was compressed using a suitable apparatus equipped with a two-layer compressor. The resulting two-layer tablets were film-coated using Opadry.

[0117] Dissolution test: The dissolution test was carried out for the following: - Innovator sample of fenofibrate (Supralip®), a 160 mg film-coated tablet - Comparative Example 1, single-layer tablet - not according to the present invention - Example 3a, two-layer tablet - according to the present invention.

[0118] The dissolution test was carried out using the following parameters: Medium: 0.05 M SLS in water, Apparatus: paddle type, Volume: 1000 ml, Speed: 50 RPM (revolutions per minute).

[0119] The results of the dissolution profiles of the obtained fenofibrate are shown in Table 5 below.

[0120] [Table 5]

[0121] The above dissolution data provides evidence that the dissolution of fenofibrate after 60 minutes is at least 20% higher for the two-layer tablets containing micronized fenofibrate than for the single-layer tablets of Comparative Example 1. Thus, the present invention can provide a multilayer pharmaceutical composition comprising a fixed-dose combination of rosuvastatin calcium and fenofibrate, which has a higher solubility of fenofibrate after 60 minutes than conventional single-layer compositions.

[0122] Example 4: Two-layer tablets of rosuvastatin and fenofibrate (according to the present invention)

[0123] [Table 6]

[0124] Manufacturing process: The manufacturing process is the same as that described in Example 3.

[0125] Dissolution test: The dissolution test was carried out using the same parameters as in Example 3 above.

[0126] [Table 7]

[0127] The stability test was carried out 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 results of the obtained stability test are shown in Table 7a and Table 7b below.

[0128] [Table 8]

[0129] [Table 9]

[0130] From the stability data shown in Table 7a and Table 7b, it can be concluded that the multilayer pharmaceutical composition containing the fixed-dose combination of the present invention is stable.

[0131] Example 5: Bioavailability test (according to the present invention) The bioavailability of the fixed-dose combination according to the present invention in the form of bilayer tablets of rosuvastatin and fenofibrate was tested.

[0132] Test design The bioequivalence test was carried out in accordance with the existing European Medicines Agency's bioequivalence guidelines.

[0133] Sample The samples used in the bioavailability test are as follows: a) Test sample: A fixed-dose combination according to the invention in the form of a bilayer tablet of 4c of rosuvastatin and fenofibrate b) Reference sample: SECALIP SUPRA® 160 mg tablets and CRESTOR® 20 mg tablets.

[0134] Determination This method involved measuring the plasma concentrations of fenofibric acid, the active metabolite of fenofibrate, and rosuvastatin over 96 hours at a given time point.

[0135] The average plasma concentrations of fenofibric acid metabolite and rosuvastatin were determined. The values of fenofibric acid concentration and rosuvastatin concentration after once-daily administration of the test sample of the present invention are summarized in Table 8. In addition, the values of fenofibric acid concentration and rosuvastatin concentration after once-daily administration of the reference sample are also shown in Table 8. Furthermore, the plasma concentration-time profiles after once-daily administration of the test sample of the present invention are shown in FIGS. 1 and 2 for fenofibric acid and rosuvastatin, respectively.

[0136] [Table 10]

[0137] Furthermore, the main pharmacokinetic parameters shown after once-daily administration of the fixed-dose combination according to the invention in the form of a bilayer tablet of rosuvastatin and fenofibrate of Example 4c, and after once-daily administration of the reference sample products (SECALIP SUPRA® 160 mg tablets and CRESTOR® 20 mg tablets) were measured by the LC-MS / MS method. In particular, the values of Cmax, Tmax, AUC, t1 / 2 (half-life), λz (elimination rate constant), and the standard deviation (SD) of the test sample and the reference sample are summarized in Table 9.

[0138] [Table 11]

[0139] The values of the pharmacokinetic parameters, the fenofibric acid metabolites, and the mean plasma concentrations of rosuvastatin shown in the above table are surprisingly such that once-daily administration of the fixed-dose combination according to the invention in the form of the bilayer tablet of rosuvastatin and fenofibrate of Example 4c is biologically equivalent to the total drug exposure obtained after once-daily co-administration of SECALIP SUPRA® 160 mg tablets and CRESTOR® 20 mg tablets. This means that the fixed-dose combination according to the invention has equivalent bioavailability. This is because the fenofibric acid metabolites and rosuvastatin from the fixed-dose combination according to the invention are absorbed and the rate and extent to which they become available at the site of drug action are the same as those of the co-administration of the reference samples. Thus, once-daily administration of the fixed-dose combination according to the invention can be considered equivalent to once-daily administration of the immediate-release reference samples, i.e., co-administration of SECALIP SUPRA® 160 mg tablets and CRESTOR® 20 mg tablets.

[0140] In conclusion, the multilayer pharmaceutical composition of the invention comprising the fixed-dose combination of rosuvastatin and fenofibrate according to Example 4c provides two active ingredients in one single tablet for once-daily treatment and represents an improvement over the corresponding monotherapies SECALIP SUPRA® and CRESTOR® in order to reduce the tablet burden on the patient. Thus, the fixed-dose combination is convenient for patients with mixed dyslipidemia who currently need to receive two monotherapies separately and thus addresses an unmet medical need and provides an improvement to ensure treatment compliance and adherence.

Claims

1. 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 fenofibrate or a pharmaceutically acceptable salt thereof and the rosuvastatin or a pharmaceutically acceptable salt thereof are present in separate layers, namely, a fenofibrate layer and a rosuvastatin layer, the fenofibrate layer contains micronized fenofibrate, and fenofibrate and rosuvastatin are each immediately released from the fenofibrate layer and the rosuvastatin layer, The micronized fenofibrate has a particle size distribution (PSD) in which D(v,10) is greater than 0.02 μm and not more than 7 μm, and / or D(v,50) is greater than 0.04 μm and not more than 20 μm, and / or D(v,90) is greater than 0.05 μm and not more than 47 μm, and the width of the particle size distribution (PSD) represented as span is composed of 1.2 to 3, 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, The multilayer pharmaceutical composition wherein the fenofibrate is neither in the form of a solid solution nor in the form of a solid dispersion.

2. The multilayer pharmaceutical composition according to claim 1, wherein the fenofibrate layer contains less than 20% w / w of one or more excipients or carriers or does not contain them and has a melting point of less than 75°C.

3. The multilayer pharmaceutical composition according to claim 1, wherein the fenofibrate layer contains less than 20% w / w of one or more excipients or carriers, and the one or more excipients or carriers are selected from the group consisting of polyethylene glycol, polypropylene glycol, polyoxyethylene, polyoxypropylene, poloxamer, linear saturated hydrocarbons, sorbitan esters, paraffin, fats, oils, and mixtures thereof.

4. The pharmaceutical composition according to claim 1, which is a bilayer tablet containing 5 to 20 mg of rosuvastatin or a pharmaceutically acceptable salt and 160 mg of fenofibrate.

5. (a) A lubricated fenofibrate layer blend is i. Preparing a fenofibrate blend by subjecting micronized fenofibrate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, crospovidone, red iron oxide, and sodium lauryl sulfate to a granulation process; ii. Preparing a binder solution by dissolving povidone in purified water and adding isopropyl alcohol; iii. Granulating the fenofibrate blend 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 silica to the granules obtained in step (iii) outside the granules; v. Preparing by lubricating the dried granules with sodium stearyl fumarate. (b) A lubricated rosuvastatin layer blend is i. Preparing a rosuvastatin blend by mixing calcium rosuvastatin, anhydrous lactose, microcrystalline cellulose, crospovidone, and light magnesium oxide in a blender; ii. Preparing by mixing the selected magnesium stearate with the rosuvastatin blend, and (c) A process for preparing the pharmaceutical composition according to any one of claims 1 to 4, comprising compressing the lubricated fenofibrate layer blend and the lubricated rosuvastatin layer blend by a multi-layer compressor.

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