Active Coating of Atorvastatin Calcium to Combination Tablet with Once Daily Fenofibrate

Abstract

The present invention relates to a coating technology for active ingredients to develop a combination formulation containing atorvastatin, which must be rapidly absorbed to reach an effective blood concentration, and fenofibrate, which can be taken once a day. In order to resolve the non-uniformity of content, which is one of the problems of the coating process, the present invention increased the amount of coating solvent during the coating process, thereby securing process conditions with improved properties of the coating layer and uniformity of the main component content. The coating process of the main component can be proposed as a good method to replace existing multilayer tablet technology for realizing different release rates required by two main components, and new formulations can be developed using existing manufacturing facilities.

Description

Technology Field

[0001] The present invention relates to a composite formulation comprising a film coating layer containing an active ingredient and a method for manufacturing the same. More specifically, it relates to a composite formulation comprising a film coating layer containing an active ingredient with improved properties of the coating layer and uniformity of the content of the active ingredient in the coating layer, and a method for manufacturing the same. Background Technology

[0002] Globally, cardiovascular disease, particularly coronary heart disease, is one of the leading causes of death, and risk factors for cardiovascular disease include elevated low-density lipoprotein cholesterol (LDL-C), elevated triglycerides, and decreased high-density lipoprotein cholesterol (HDL-C).

[0003] Current lipid therapy guidelines emphasize reducing LDL-C to decrease cardiovascular risk, and statin drugs, which can limit the rate of cholesterol synthesis in the body, are used as a primary method to lower LDL-C levels and reduce cardiovascular mortality.

[0004] Although statin therapy is effective in improving lipid levels in patients with dyslipidemia, clinical trials have confirmed reports that approximately 10 to 22% of patients taking the drug experience side effects of muscle pain.

[0005] In addition, it has been reported that patients at risk of cardiovascular disease who are taking stan-type drugs are having difficulty achieving the target reduction in LDL-C, and that 45% of diabetic patients and 60% of patients at risk of cardiovascular disease are not seeing the level of treatment effect set by treatment guidelines.

[0006] In particular, it was confirmed that 59.1% of patients with diabetes and dyslipidemia had LDL-C levels of 70 mg / dL or higher, making it difficult to manage adequately with statin drugs alone.

[0007] In addition, even if a patient's LDL-C level reaches an appropriate level, the risk of cardiovascular disease is not adequately reduced by a decrease in LDL-C alone, so combination therapy with other drugs is required.

[0008] For example, two meta-analyses of 14 randomized clinical trials involving more than 90,000 patients in the United States showed that more than 16% of patients prescribed statin drugs experienced cardiovascular disease during a 5-year follow-up period, and this figure was slightly higher at 17% in patients with diabetes.

[0009] Mixed dyslipidemia, characterized by low levels of LDL-C and high levels of triglycerides and LDL-C, is on the rise in Korea as well, and in the United States, it was reported that as of 2006, 21% of the total adult population already had mixed dyslipidemia.

[0010] For the reasons mentioned above, while monotherapy is effective for each lipid parameter, combination therapy is necessary for the comprehensive management of dyslipidemia; the combined administration of atorvastatin and fenofibrate is currently used as an effective treatment method by simultaneously reducing triglycerides and LDL-C.

[0011] Atorvastatin, a lipid-lowering agent classified as a statin, is a reversible inhibitor of the synthesis of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is the rate-limiting enzyme in the biosynthesis of cholesterol.

[0012] Atorvastatin is rapidly absorbed after oral administration, reaching maximum plasma concentration within 1 to 2 hours, and is metabolized into active metabolites by CYP450 3A4.

[0013] Fenofibrate is a derivative of febric acid, and its lipid-regulating effect is mediated by the activation of peroxisome proliferator-activated receptor-α.

[0014] Fenofibrate is 30–50% absorbed when taken on an empty stomach and 60–90% after a meal, so it is recommended to take it after a meal, and it has the characteristic of maintaining blood concentration for a long time with a half-life of about 14 hours.

[0015] Systemic metabolism of fenofibrate involves rapid conversion of the drug into major active metabolites, such as febric acid and other derivatives, by the intestines, plasma, and tissues. It has been reported that the recommended dose of atorvastatin for hyperlipidemia is 20–40 mg once daily, and there are no changes in the pharmacokinetic parameters of atorvastatin when administered in combination with fenofibrate 160 mg.

[0016] In general, when different drug release rates are required in the design of combination formulations, such as with atorvastatin and fenofibrate, the most commonly used method is to utilize a technology that implements different drug release rates through multilayer tablet formulations.

[0017] Research utilizing a bilayer tablet composition of an immediate-release layer and a sustained-release layer to secure the desired drug release rate and achieve optimal therapeutic effects has been attempted by various researchers, and results demonstrating the achievement of these objectives have been published. The problem to be solved

[0018] The present invention solves the problem of significant process losses caused by separate manufacturing facilities and the characteristics of the multilayer tablet manufacturing process, and enables the desired drug release to be secured without the introduction of new manufacturing facilities. means of solving the problem

[0019] One aspect of the present invention is

[0020] A core containing a first active ingredient; and

[0021] A composite formulation comprising a film coating layer containing a second active ingredient,

[0022] The above film coating layer provides a composite formulation comprising hydroxypropylmethylcellulose and polyvinyl alcohol.

[0023] A step of manufacturing a core containing a first active ingredient;

[0024] A step of preparing a coating solution containing a second active ingredient by dissolving the second active ingredient, hydroxypropylmethylcellulose, and polyvinyl alcohol in a solvent; and

[0025] The present invention provides a method for manufacturing a composite formulation according to the present invention, comprising the step of coating the coating solution onto the core. Effects of the invention

[0026] A composite formulation according to one aspect of the present invention not only ensures uniformity of the surface properties and content of the film coating layer containing the active ingredient, but also guarantees the release rate of the active ingredient contained in the film coating layer. Therefore, the composite formulation can replace existing multilayer tablet technology for the different release rates required by the two ingredients. Ultimately, the composite formulation is expected to reduce investment costs for new manufacturing facilities, enable the development of new formulations using existing facilities, and serve as an alternative to losses in the multilayer tablet manufacturing process. Brief explanation of the drawing

[0027] Figure 1 is a concept formulation of the present invention. Figure 2 is a schematic diagram of the manufacturing process of a complex formulation. Figure 3 is a graph showing the dissolution rate of fenofibrate from the core tablets of Examples 1 to 4. Figure 4 is a graph showing the dissolution rate of fenofibrate from the core tablets of Examples 4 to 6. Figure 5 is a graph showing the dissolution rate of fenofibrate from the core tablets of Examples 7 to 9. FIG. 6 is a photograph taken of (a) Example 10, (b) Example 11, (c) Example 12, and (d) Example 13 as a test to confirm the characteristics of the coating surface of the present specification. FIG. 7 is a photograph taken of the microscopic characteristics of the coating layer of the present specification using a polarizing microscope: (a) Example 12 (b) Example 13, and a field emission scanning electron microscope: (c) Example 12 (d) Example 13. Figure 8 is a graph comparing the dissolution rate of fenofibrate from the combination formulation of Example 13 with that of a control drug. Figure 9 is a graph comparing the dissolution rate of atorvastatin from the combination preparation of Example 13 with that of a control drug. Specific details for implementing the invention

[0028] All technical terms used in this invention, unless otherwise defined, are used in the sense generally understood by a person skilled in the art related to this invention. Additionally, while preferred methods or samples are described herein, similar or equivalents are also included within the scope of this invention. The contents of all publications cited as references in this specification are incorporated herein by reference in their entirety.

[0029] The present invention has diligently investigated a coating agent capable of ensuring the release rate of the active ingredient contained in the film coating layer while securing the surface properties and content uniformity of the active ingredient-containing film coating layer of a composite formulation comprising an active ingredient-containing film coating layer. As a result, it was found that the surface properties of the coating layer could be improved when the coating solvent was 80% ethanol. Furthermore, it was discovered that by increasing the amount of coating solvent to ensure content uniformity and proceeding with the coating process, both the properties of the coating layer and the content uniformity of the main ingredient in the coating layer could be secured.

[0030] Therefore, one aspect of the present invention is

[0031] A core containing a first active ingredient; and

[0032] A composite formulation comprising a film coating layer containing a second active ingredient,

[0033] The above film coating layer provides a composite formulation comprising hydroxypropylmethylcellulose and polyvinyl alcohol.

[0034] The 'complex preparation' according to the present invention may mean a combination of two or more drugs or active ingredients present in a single administration unit.

[0035] The first active ingredient may comprise, for example, fenofibrate or a pharmaceutically acceptable salt thereof, and the second active ingredient may comprise, for example, atorvastatin or a pharmaceutically acceptable salt thereof.

[0036] The above atorvastatin can be selected from lipid-lowering agents classified as statin drugs, which are reversible inhibitors of the synthesis of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme in the biosynthesis of cholesterol.

[0037] The first active ingredient may contain 160 mg of fenofibrate or a pharmaceutically acceptable salt thereof based on fenofibrate, and the second active ingredient may contain 40 mg of atorvastatin or a pharmaceutically acceptable salt thereof based on atorvastatin.

[0038] The above pharmaceutically acceptable salts may be prepared from inorganic or organic bases. Salts derived from inorganic bases may include, for example, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines may include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, N-alkylglucarmine, theobromine, purine, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0039] The above pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids may include, but are not limited to, acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0040] The core containing the first active ingredient may be any pharmaceutical formulation commonly used in the pharmaceutical field. For example, the core may be in the form of a tablet, a hard capsule, or a soft capsule, but is not limited thereto. The filling portion filled into the hard capsule or soft capsule may be any pharmaceutical formulation commonly used in the pharmaceutical field, such as granules, pellets, powders, tablets, liquids, or a combination thereof.

[0041] A film coating layer containing the second active ingredient can be formed on the surface of the core. The film coating layer contains a combination of hydroxypropylmethylcellulose and polyvinyl alcohol as a coating base.

[0042] When the above combination preparation is subjected to a dissolution test according to the comparative dissolution test guidelines, the similarity factor value with the reference drugs, Pravafenix capsules and Lipitor tablets, may be 50 or higher.

[0043] A composite formulation was prepared by forming a film coating layer containing a second active ingredient and various coating agents on a tablet or capsule core containing a first active ingredient, and then tests were conducted to confirm the characteristics of the coating surface according to the coating agent and coating solvent, as well as to evaluate the drug release and equivalence of the composite formulation. As a result, it was confirmed that the characteristics of the film coating layer of the composite formulation improved when the coating agent and coating solvent were increased (see Test Examples 5 and 6). In addition, when the coating solvent was 80% ethanol, it was confirmed that the fine characteristics of the cross-section of the film coating layer were more appropriate than when purified water was used, and it was found to have dissolution equivalence with the reference drug (see Test Example 6), showing results that could secure excellent film coating characteristics and a dissolution rate equivalent to that of the reference drug.

[0044] A schematic diagram of a composite formulation according to one embodiment of the present invention is shown in FIG. 1.

[0045] Figure 1 is a schematic diagram showing a composite formulation in which a film coating layer containing a second active ingredient is coated on the surface of a tablet core containing a first active ingredient.

[0046] In addition to the above components, the composite formulation of the present invention may further include pharmaceutically acceptable additives in the core and the active ingredient-containing film coating layer. The additives may be selected from the group consisting of diluents, disintegrants, binders, stabilizers, lubricants, and any combination thereof.

[0047] The above diluent may be selected from the group consisting of microcrystalline cellulose, lactose, rudipress, mannitol, calcium dihydrogen phosphate, starch, low-substituted hydroxypropyl cellulose, and any combination thereof, but is not limited thereto. The above alkalizing agent may be, for example, microcrystalline cellulose.

[0048] The above binder may be selected from the group consisting of polyvinylpyrrolidone vinyl acetate, hydroxypropylmethylcellulose, polyacrylic acid, and mixtures thereof. The above binder may be, for example, hydroxypropylmethylcellulose.

[0049] The above binder may be included in an amount of 15 to 25 weight percent relative to the total weight of the tablet containing the first active ingredient.

[0050] The above disintegrant may be selected from the group consisting of crospovidone, sodium starch glycolate, sodium croscarmellose, low-substituted hydroxypropylcellulose, starch, alginate, sodium alginate, and any combination thereof, for example, sodium starch glycolate may be used.

[0051] The above alkalizing agent may be selected from the group consisting of ammonium carbonate, sodium carbonate, borax, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and mixtures thereof, but is not limited thereto. The above alkalizing agent may be, for example, sodium bicarbonate.

[0052] The above alkalizing agent may be included in an amount of 2.5% by weight or more relative to the total weight of the tablet containing the first active ingredient. Specifically, the above alkalizing agent may be included in an amount of 2.5% by weight or more and 5% by weight or less relative to the total weight of the tablet containing the first active ingredient.

[0053] The above lubricant may be selected from the group consisting of, but is not limited to, metal stearate salts such as stearic acid, calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils, high melting point waxes, glyceryl fatty acid esters, glycerol dibehenate, and mixtures thereof. The above lubricant may be, for example, magnesium stearate.

[0054] A composite formulation according to the present invention can be prepared according to a method comprising the step of coating a core containing a first active ingredient with a coating solution comprising fenofibrate or a pharmaceutically acceptable salt thereof, hydroxypropylmethylcellulose, and polyvinyl alcohol.

[0055] Specifically, a method for manufacturing a composite formulation according to the present invention may include the step of manufacturing a core containing a first active ingredient; the step of manufacturing a coating solution containing a second active ingredient by dissolving a second active ingredient, hydroxypropylmethylcellulose, and polyvinyl alcohol in a solvent; and the step of coating the core with the coating solution.

[0056] The above core may be manufactured by adding one or more pharmaceutically acceptable additives selected from the group consisting of diluents, disintegrants, binders, stabilizers, lubricants, and any combination thereof. The description of the above composition may be applied in the same manner as previously described.

[0057] In addition, the coating in the above manufacturing method can be performed using conventional methods used for coating pharmaceuticals in the field, for example, a coating method using a fan coating machine can be used.

[0058] The coating solvent mentioned above may be, for example, 80% ethanol.

[0059] The composite formulation of the present invention exhibits excellent uniformity of properties and content in the film coating layer containing atorvastatin or a pharmaceutically acceptable salt thereof. Accordingly, it can improve patient compliance with a composite agent containing atorvastatin or a pharmaceutically acceptable salt thereof, which is effective in alleviating and treating symptoms of hyperlipidemia, and is useful for the treatment of hyperlipidemia.

[0060] The present invention will be explained in more detail below according to examples and test examples. However, this does not limit the present invention.

[0061] [Example]

[0062] The present invention will be explained in more detail below through the following examples. However, the following examples are merely illustrative of the present invention and do not limit the scope of the present invention.

[0063] Examples 1-9: Preparation of a core of a complex formulation containing the first active ingredient, fenofibrate

[0064] The granules for tableting of Examples 1-9 listed in Table 1 below were prepared by mixing the main components and excipients, excluding the lubricant and alkalizing agent, in a V-type mixer at a rotational speed of 50 rpm for 10 minutes, followed by a bonding process using a high-shear mixer with an agitator of 100 rpm and a chopper of 1,500 rpm, using purified water as the binding solvent for 5 minutes. The mixture was then dried in a cabinet-type dryer at 50°C until the drying loss was less than 2%, and finally sieved using a 16-mesh sieve to produce the granules. Tablets were prepared by compressing the granules using a rotary tablet press to achieve a hardness of at least 10 kp (Fig. 2).

[0065]

[0066] Examples 1-4

[0067] Examples 1 to 4 are examples for comparing the dissolution improvement effect according to the type of added disintegrant and alkalizing agent, and the compositions of Examples 1-4 listed in Table 1 are prepared in the same way as the method of Examples 1 to 9.

[0068] Examples 4-6

[0069] Examples 4 to 6 are examples for comparing changes in the elution pattern according to the amount of alkalizing agent, and the compositions of Examples 4-6 listed in Table 1 are prepared in the same way as the methods of Examples 1 to 9.

[0070] Examples 7-9

[0071] Examples 7 to 9 are examples for comparing changes in the elution pattern according to the increase or decrease of the binder, and the compositions of Examples 7-9 listed in Table 1 are prepared using the same method as in Examples 1 to 9.

[0072] Examples 10-13: Preparation of a combination formulation containing a second active ingredient, atorvastatin

[0073] Examples 10 to 13 are examples designed to ensure uniformity of the content of the main component present in the coating layer due to the characteristics of the coating surface and the coating process. The formulation of Example 8 was prepared by mixing the active ingredient with a coating base containing various components and contents of Examples 10-14 listed in Table 2 in a 3:2 ratio and dispersing the mixture in purified water and 80% ethanol to achieve a solid content ratio of 10% in the coating solution. Coating was performed using a fan coating machine. When purified water was used as the coating solvent, the intake temperature was controlled to maintain the tablet surface temperature at 45°C or higher, and when 80% ethanol was used as the coating solvent, the intake temperature was controlled to maintain the tablet surface temperature at 32°C or higher. To prevent damage to the tablet during the initial coating process, the rotation speed of the coating machine was started at 12 rpm and increased to 20 rpm while proceeding with the coating.

[0074]

[0075] Test Example 1: Measurement of dissolution rate according to the type of disintegrant and alkalizing agent

[0076] To evaluate the dissolution rate of fenofibrate for the core tablets of Examples 1 to 4 above, a dissolution test was conducted as follows.

[0077] After confirming that fenofibrate was classified as a poorly soluble drug under pH 1.2, 4.0, and 6.8 conditions, which are the evaluation conditions for pharmaceutical equivalence testing, the dissolution test was conducted in a pH 4.0 + 0.5% sodium lauryl sulfate solution according to Method 2 (Paddle Method) of the General Test Methods of the Korean Pharmacopoeia. The dissolution test solution was operated at a temperature of 37.0℃ and a rotation speed of 50 rpm. The standard solution and the test solution were analyzed at a wavelength of 288 nm using a UV-visible spectrophotometer.

[0078] The results are shown in Figure 3 below.

[0079] As a result, as shown in Figure 3, the best improvement in dissolution was confirmed in Example 4, in which an alkalizing agent was added. Among the three types of disintegrants, sodium starch glycolate was found to be the most effective, while sodium croscarmellose and crospovidone were found to have relatively less effect. Through the above results, it was confirmed that the alkalizing agent had the greatest effect on improving dissolution. This was because the solubility of the main component, fenofibrate, tended to increase as the pH increased, and thus the dissolution rate improved as the pH in the microenvironment increased with the addition of the alkalizing agent. In the case of adding a disintegrant, the disintegration of the tablet proceeded rapidly, but the effect on improving the dissolution rate of fenofibrate was not significantly improved due to the pH-dependent solubility of the main component.

[0080] Test Example 2: Measurement of dissolution rate according to the dosage of alkalizing agent

[0081] The method for evaluating the dissolution rate of fenofibrate for the core tablets of Examples 4 to 6 above is carried out in the same manner as Test Example 1.

[0082] The results are shown in Figure 4 below.

[0083] As a result, as shown in Figure 4, it was confirmed that the elution pattern changed significantly even with a relatively small change in the ratio of the alkalizing agent, and in the case of Example 6 with 2.5% added, no significant improvement effect was observed. This appears to be because the addition of 2.5% did not cause a change in the pH of the microenvironment, so it did not result in an improvement in elution.

[0084] Test Example 3: Measurement of dissolution rate according to increase or decrease in binder

[0085] The method for evaluating the dissolution rate of fenofibrate for the core tablets of Examples 7 to 9 above is carried out in the same manner as Test Example 1.

[0086] The results are shown in Figure 5 below.

[0087] As a result, as shown in Figure 5, it was confirmed that the overall dissolution rate was partially improved by adding 6 mg of sodium starch glycolate to the tablet. It was also confirmed that as the amount of the binder, hydroxypropylmethylcellulose, increased, the dissolution time increased due to the increase in the hardness and binding strength of the tablet, and thus the dissolution rate slowed down. It was confirmed that Example 8, with 80 mg added, showed the dissolution pattern most similar to the control drug, Pravafenix Capsule.

[0088] Test Example 4: Test for Confirmation of Coating Surface Characteristics According to Coating Base and Coating Solvent

[0089] To confirm the film properties of the composite formulation coated according to the formulations of Examples 10 to 13 above, a verification test was performed as follows.

[0090] For the film appearance verification test, the coating surface of the composite formulation was photographed using an optical camera.

[0091] The results are shown in Figure 6 below.

[0092] As a result, as shown in 6, in (a) and (b), the proportion of atorvastatin, the main component among the solid components in the coating solution, is about 57%, so it can be confirmed that the film layer is not formed normally.

[0093] Test Example 5: Test for Confirmation of Micro-characteristics of Coated Surface According to Coating Base and Coating Solvent

[0094] To confirm the film micro-morphology of the composite formulation coated according to the formulations of Examples 12-13 above, a verification test was performed as follows.

[0095] For the micro-specification verification test, the cross-section of the coating layer of the composite formulation was observed using a polarized light microscope and a field emission scanning electron microscope (FE-SEM).

[0096] As shown in Fig. 7, a finely raised portion was observed in the cross-section of Example 12, confirming that the surface characteristics of Example 13 were relatively more suitable. Looking at Fig. 7 (c) and (d), crystal portions determined to be due to the recrystallization of hydroxypropylmethylcellulose were identified in the FE-SEM image of Example 12, confirming that using 80% ethanol as a coating solvent is appropriate. This indicates that when purified water, a solvent with relatively high solubility, was used, hydropoxymethylcellulose, the main polymer material of the coating substrate, was dispersed as fine particles in the coating solution. However, instead of adhering to the surface of the purified water, it dissolved in the solvent and then redeposited during the drying process in the coating process. Consequently, the surface of the coating layer appeared relatively rough, and the flexibility of the coating layer was also reduced due to the recrystallized hydropropylmethylcellulose.

[0097] Test Example 6: Evaluation of drug release and equivalence of a fenofibrate combination formulation containing a film coating layer with an active ingredient, atorvastatin

[0098] To evaluate the dissolution rate equivalence of Example 13 and the control drugs, Pravafenix capsules and Lipitor tablets, the method for evaluating the dissolution rate was carried out in the same manner as in Test Example 1, and the equivalence was evaluated based on the similarity factor (f2 value).

[0099] In the following formula, n is the number of comparison points, Rt is the average dissolution rate of the reference drug, and Tt is the average dissolution rate of the test drug.

[0100]

[0101] The results are shown in Figures 8 and 9 below.

[0102] As a result, as shown in Fig. 9, in the case of atorvastatin, the active ingredient present in the coating layer, although it was slightly faster than the reference drug in the evaluation of dissolution pattern equivalence, the equivalence criterion f2 value was 57.6, which is higher than the Ministry of Food and Drug Safety's drug equivalence standard of 50, thus proving equivalence. In addition, in the case of fenofibrate, the result evaluated according to similarity factors was 79.9, confirming that it exhibited a very similar dissolution pattern as shown in Fig. 8. This indicates that although the initial dissolution rate in the prescription of Example 8 before coating was slightly higher than that of the reference drug, the drug release time of the core tablet was delayed by the dissolution time of the coating layer after the active ingredient coating process, resulting in a dissolution pattern that was more equivalent to that of the reference drug. Thus, it was possible to prove the drug equivalence of both active ingredients contained in the final prescription with the reference drug.

Claims

Claim 1 A composite formulation comprising a core containing a first active ingredient; and a film coating layer containing a second active ingredient, wherein the first active ingredient comprises fenofibrate or a pharmaceutically acceptable salt thereof, and the second active ingredient comprises atorvastatin or a pharmaceutically acceptable salt thereof, wherein the core comprises microcrystalline cellulose, sodium starch glycolate, hydroxymethylcellulose, sodium bicarbonate, and magnesium stearate, and the film coating layer comprises hydroxypropylmethylcellulose and polyvinyl alcohol. Claim 2 delete Claim 3 A combination preparation according to claim 1, wherein the atorvastatin is selected from lipid-lowering agents classified as statin drugs, which are reversible inhibitors of the synthesis of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme in the biosynthesis of cholesterol. Claim 4 A combination preparation according to claim 1, wherein the first active ingredient comprises 160 mg of fenofibrate or a pharmaceutically acceptable salt thereof based on fenofibrate, and the second active ingredient comprises 40 mg of atorvastatin or a pharmaceutically acceptable salt thereof based on atorvastatin. Claim 5 A combination preparation according to claim 1 that, when the combination preparation is subjected to a dissolution test in accordance with the comparative dissolution test guidelines, shows a similarity factor value of 50 or more with the reference drugs, Pravafenix Capsules and Lipitor Tablets. Claim 6 A method for preparing a composite formulation according to any one of claims 1, 3 to 5, comprising: a step of preparing a core containing a first active ingredient; a step of preparing a coating solution containing a second active ingredient by dissolving a second active ingredient, hydroxypropylmethylcellulose, and polyvinyl alcohol in a solvent; and a step of coating the core with the coating solution, wherein the first active ingredient comprises fenofibrate or a pharmaceutically acceptable salt thereof, the second active ingredient comprises atorvastatin or a pharmaceutically acceptable salt thereof, the core comprises microcrystalline cellulose, sodium starch glycolate, hydroxymethylcellulose, sodium bicarbonate, and magnesium stearate. Claim 7 delete Claim 8 delete Claim 9 delete Claim 10 delete Claim 11 A method of preparation according to claim 6, wherein the solvent of the coating solution is 80% ethanol.

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