This pharmaceutical and pharmaceutical preparation method

Abstract

The invention relates to a pharmaceutical composition containing ezetimibe or its pharmaceutical salt and fenofibrate or its pharmaceutical salt as the active ingredient, which contains a specific antioxidant and thereby reduces the degradation of ezetimibe and the formation of related substances, and improves the stability of the pharmaceutical composition, thereby maintaining good efficacy, and a method for preparing such a pharmaceutical composition.

Description

Pharmaceutical composition and method for preparing the same

[0001] Cross-citation with related application(s)

[0002] This application claims the benefit of priority to Korean Patent Application No. 10-2023-0095476, filed July 21, 2023, the entire contents of which are incorporated herein by reference.

[0003] The present invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt thereof and fenofibrate or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition exhibits improved stability and excellent efficacy by reducing the decomposition of ezetimibe and the production of related substances, and a method for producing the same.

[0004] Ezetimibe is a selective cholesterol absorption inhibitor, sold under the brand names EZETROL™ and ZETIA™. Ezetimibe works by inhibiting cholesterol reabsorption in the small intestine and is used as a treatment or dietary supplement to lower cholesterol in patients with hyperlipidemia.

[0005] Meanwhile, fenofibrate exhibits a body mechanism that reduces neutral fat and cholesterol by helping the action of enzymes that break down lipid proteins in the blood, and is used as a treatment for hyperlipidemia.

[0006] It is known that ezetimibe and fenofibrate can be more effective in treating triglycerides when administered together, and thus, attempts are being made to administer them together or develop a combination drug containing them.

[0007] However, ezetimibe is known to be unstable in alkaline environments and generates numerous volatile substances.

[0008] In general, to ensure consistent efficacy, pharmaceuticals must suppress the decline in active ingredient content not only immediately after manufacturing but also during storage. Furthermore, during the same period, the increase in decomposition products of the active ingredient, i.e., impurities or related substances, must be minimized. Therefore, preventing the incorporation of impurities into pharmaceuticals and suppressing the increase in related substances is crucial for pharmaceutical quality control.

[0009] As described above, ezetimibe generates numerous related compounds in alkaline environments. Co-existence of ezetimibe and fenofibrate has been reported to further increase ezetimibe decomposition and the production of related compounds, such as ezetimibe ketone. Consequently, the development of a combination drug that combines ezetimibe and fenofibrate to enhance dosing convenience for hyperlipidemic patients while also anticipating their synergistic effects has encountered limitations.

[0010] Accordingly, there is a continuous demand for the development of a pharmaceutical composition that can improve stability by reducing the production of flexible substances in a combination drug containing the above ezetimibe and fenofibrate.

[0011] Accordingly, the present invention provides a pharmaceutical composition comprising ezetimibe and fenofibrate as active ingredients, which exhibits improved stability and excellent efficacy by reducing the decomposition of ezetimibe and the production of related substances, and a method for producing the same.

[0012] The present invention relates to a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt thereof;

[0013] Fenofibrate or a pharmaceutically acceptable salt thereof;

[0014] An antioxidant of the following chemical formula 1; and

[0015] A pharmaceutical composition comprising pharmaceutically acceptable excipients is provided:

[0016] [Chemical Formula 1]

[0017]

[0018] In the above chemical formula 1, R1 is an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, R2 is a straight or branched alkyl group having 1 to 5 carbon atoms, and n is an integer of 1 or 2.

[0019] The present invention also comprises a step of granulating a mixture comprising an active ingredient including ezetimibe, fenofibrate or a pharmaceutically acceptable salt thereof, an antioxidant of the above chemical formula 1, and pharmaceutically acceptable excipients including a diluent, a disintegrant and a binder; and

[0020] A method for producing the pharmaceutical composition is provided, comprising the step of mixing a lubricant into the granules and compressing the granules.

[0021] The present inventors continued their research to improve the stability of pharmaceutical compositions containing ezetimibe and fenofibrate by using various pharmaceutically acceptable stabilizers.

[0022] As a result of this study, it was confirmed that by including the antioxidant of the above chemical formula 1 as a stabilizer in the pharmaceutical composition, the decomposition of the ezetimibe and the production of volatile substances such as ezetimibe ketone are greatly reduced, and a pharmaceutical composition with improved stability can be provided.

[0023] Therefore, by using such a pharmaceutical composition, it is possible to secure ease of administration for hyperlipidemia patients while maintaining excellent synergistic effects from combined administration of ezetimibe and fenofibrate, and thus can greatly contribute to the effective treatment of hyperlipidemia, etc.

[0024] Hereinafter, a pharmaceutical composition and a method for manufacturing the same according to a specific embodiment of the invention will be described in more detail.

[0025] Throughout the specification, the term “related substance” may refer to a substance that may be included in the raw material synthesis process of the active ingredient or in the finished pharmaceutical product manufactured from the pharmaceutical composition, and may mean a type of impurity to the active ingredient that can be used for quality assessment of the finished pharmaceutical product, etc. For example, the category of related substances may include all impurities such as ezetimibe or a salt thereof, or ezetimibe ketone derived from fenofibrate or a salt thereof, which are included as active ingredients in the pharmaceutical composition of one embodiment described below.

[0026] According to one embodiment of the invention, a pharmaceutical composition is provided comprising: ezetimibe or a pharmaceutically acceptable salt thereof; fenofibrate or a pharmaceutically acceptable salt thereof; an antioxidant of the following chemical formula 1; and a pharmaceutically acceptable excipient:

[0027] [Chemical Formula 1]

[0028]

[0029] In the above chemical formula 1, R1 is an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, R2 is a straight or branched alkyl group having 1 to 5 carbon atoms, and n is an integer of 1 or 2.

[0030] Early in our research, the inventors of the present invention noted that ezetimibe primarily produces a large amount of related substances in alkaline environments and exhibits poor stability. Therefore, we attempted to add a stabilizer in the form of an organic or inorganic acid, such as citric acid or tartaric acid, to a pharmaceutical composition comprising ezetimibe and fenofibrate. However, as supported by the comparative examples below, it was confirmed that the addition of such acidic stabilizers alone was not sufficient to suppress the production of related substances resulting from the combined use of ezetimibe and fenofibrate.

[0031] Accordingly, the present inventors continued additional research and experiments to identify a suitable stabilizer for the pharmaceutical composition comprising the ezetimibe and fenofibrate. As a result of these additional research and experiments, they discovered that adding the antioxidant of Chemical Formula 1 as a stabilizer very effectively inhibits the decomposition of the ezetimibe and the production of related substances such as ezetimibe ketone, thereby improving the stability of the pharmaceutical composition and maintaining the excellent synergistic effect of these active ingredients, thereby completing the invention.

[0032] For reference, the antioxidant of the above chemical formula 1 is a type of neutral antioxidant component, and is expected to be able to inhibit the decomposition of the ezetimibe itself without causing a change in pH within the pharmaceutical composition.

[0033] In the pharmaceutical composition of the above embodiment, the antioxidant may be a compound in which R1 in the above chemical formula 1 is a methyl group, an ethyl group, or a methoxy group, R2 is a t-butyl group, and n is 1 or 2. In a more specific example, the antioxidant of the above chemical formula 1 may be a compound in which R1 is a methyl group, R2 is a t-butyl group, and n is 2. In the most specific example, the antioxidant of the above chemical formula 1 may have a structure in which the t-butyl group of R2 is bonded to the 2, 6-position adjacent to the hydroxyl group.

[0034] Since the above antioxidant has this structure, it can more effectively inhibit the decomposition of ezetimibe and the production of volatile substances, while reducing side effects such as the antioxidant affecting the efficacy of the pharmaceutical composition or exhibiting toxicity in the human body.

[0035] Additionally, the antioxidant may be included in an amount of about 0.07 to about 0.60 wt%, or about 0.08 to about 0.55 wt%, or about 0.1 to about 0.5 wt%, based on the total weight of the pharmaceutical composition, for example, the total weight of a unit dosage form such as a tablet of the pharmaceutical composition.

[0036] If the content of the antioxidant is excessively low, the production of related substances, including ezetimibe ketone, cannot be sufficiently suppressed, and it has been confirmed that it is difficult to maintain the stability and efficacy of the pharmaceutical composition. Furthermore, during the manufacturing process of the pharmaceutical composition, the antioxidant may not be uniformly mixed, which may locally reduce the stability of the pharmaceutical composition. Conversely, if the content of the antioxidant is excessively high, not only is it difficult to further suppress the production of related substances, but the antioxidant may also exhibit toxicity in the human body.

[0037] In contrast, as the content of the antioxidant is optimized, the production of flexible substances can be minimized and the stability of the pharmaceutical composition of one embodiment can be maximized. For example, according to the experimental results of the present inventors, a pharmaceutical composition of one embodiment including the antioxidant in an optimized amount can exhibit excellent stability in that the total generated content of related substances including ezetimibe ketone is less than 0.4 wt%, or from about 0 wt% to less than about 0.4 wt%, or from about 0 wt% to less than about 0.35 wt%, or from about 0 wt% to less than about 0.30 wt%, based on the total weight of the pharmaceutical composition, and the generated content of ezetimibe ketone as the related substance is less than about 0.2 wt%, or from about 0 wt% to less than about 0.2 wt%, or from about 0 wt% to less than about 0.19 wt%, even after being stored open for more than 3 months under accelerated conditions of about 40°C and a relative humidity of about 75%.

[0038] Meanwhile, in the pharmaceutical composition of the above-described embodiment, the ezetimibe may be included in the form of ezetimibe or a salt thereof, and specific examples of the ezetimibe salt include calcium salt, hydrochloride salt, hydrobromide salt, sulfate salt, phosphate salt, acetate salt, malate salt, fumarate salt, lactate salt, tartrate salt, citrate salt, gluconate salt, besylate salt, or camsylate salt.

[0039] The ezetimibe or its salt may be included in an amount of about 1 to about 5 wt%, or about 1.5 to about 4 wt%, based on the total weight of the pharmaceutical composition. In a specific example, the ezetimibe or its salt may be included in an amount of about 5 to about 25 mg, or about 7.5 to about 20 mg, in a unit dosage form (e.g., 1 tablet) of the pharmaceutical composition.

[0040] Additionally, in the pharmaceutical composition of the above embodiment, the fenofibrate may be included in the form of fenofibrate or fenofibrate choline salt, etc.

[0041] The fenofibrate or its salt may be included in an amount of about 15 to about 40 wt%, or about 20 to about 35 wt%, based on the total weight of the pharmaceutical composition. In a specific example, the fenofibrate or its salt may be included in an amount of about 75 to about 200 mg, or about 100 to about 180 mg, in a unit dosage form (e.g., 1 tablet) of the pharmaceutical composition. In this way, by optimizing the amount of each active ingredient, an excellent synergistic effect can be exhibited by the combined use of ezetimibe and fenofibrate.

[0042] Meanwhile, the pharmaceutical composition of one embodiment may further include, in addition to each of the above-described active ingredients and antioxidants, the pharmaceutically acceptable excipients, and examples of such excipients may include at least one selected from the group consisting of diluents, disintegrants, binders, and lubricants.

[0043] Among these, the diluent may include at least one selected from the group consisting of lactose, starch, mannitol, microcrystalline cellulose, carboxymethyl cellulose and hydrates thereof, sodium lauryl sulfate, polysorbate (e.g., polysorbate 80), polyethylene oxide, polypropylene oxide, and combinations thereof. In addition, the binder may include at least one selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, copovidone, and derivatives thereof.

[0044] In addition, the disintegrant may include at least one selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and derivatives thereof.

[0045] Additionally, the lubricant may include at least one selected from the group consisting of magnesium stearate, talc, colloidal silicon dioxide, light anhydrous silicic acid, and sodium stearyl fumarate.

[0046] However, the excipients used in the pharmaceutical composition of this embodiment are not limited to the examples described above, and various other pharmaceutically acceptable excipients may be additionally used. Furthermore, the content of each excipient may be included in the typical amount depending on its function, and therefore, further description thereof will be omitted.

[0047] Meanwhile, the pharmaceutical composition may be manufactured and provided in the form of tablets to be taken orally once or twice daily, for example, and more specifically, may be provided in the form of film-coated tablets to be taken once daily. By providing such a dosage form, the synergistic effect of ezetimibe and fenofibrate can be achieved with a single daily dose, thereby enhancing the convenience of administration for patients with hyperlipidemia, etc.

[0048] When the above pharmaceutical composition is provided in the form of such a film-coated tablet, after the above-described pharmaceutical composition is manufactured into a tablet form, a coating agent for coating the tablet, such as an opadry-based coating agent, may be additionally included.

[0049] The pharmaceutical composition described above can be used as a therapeutic agent or dietary supplement for patients with hyperlipidemia, and can be used as a therapeutic agent or supplement for various diseases requiring reduction of cholesterol and / or neutral fat.

[0050] Meanwhile, according to another embodiment of the invention, a method for preparing the above-described pharmaceutical composition is provided. This method may include, for example, a step of granulating a mixture comprising an active ingredient including ezetimibe, fenofibrate, or a pharmaceutically acceptable salt thereof, an antioxidant of the above-described chemical formula 1, and pharmaceutically acceptable excipients including a diluent, a disintegrant, and a binder; and a step of mixing a lubricant into the granules and compressing the granules.

[0051] In a more specific example, the diluent, disintegrant, and antioxidant may be first mixed with the fenofibrate or a salt thereof, ezetimibe or a salt thereof, and then the binder may be further mixed with a solvent such as purified water and granulated by a wet granulation process or the like.

[0052] Thereafter, an oral tablet including the pharmaceutical composition of one embodiment can be manufactured by drying and sizing the wet granules using a method such as fluidized bed drying, mixing a lubricant into the granules, and compressing the granules.

[0053] Additionally, if necessary, a pharmaceutical composition in the form of a film-coated tablet can be prepared by coating the oral tablet with a coating agent.

[0054] By controlling the mixing order of the above active ingredients and antioxidants, etc., and manufacturing a pharmaceutical composition in tablet form by granulation, etc., a pharmaceutical composition of one embodiment with improved stability can be manufactured.

[0055]

[0056] Hereinafter, preferred examples are presented to aid understanding of the invention. However, the following examples are provided solely to facilitate understanding of the invention and are not intended to limit the scope of the invention.

[0057]

[0058] Comparative Examples 1 to 5 and Examples 1 to 6

[0059] Pharmaceutical compositions (tablets) of examples and comparative examples containing the compositions of Table 1 or 2 below were prepared by the following method.

[0060] First, using a high-speed mixer, ezetimibe and diluent passed through a 20-mesh standard sieve, and disintegrant and antioxidant (or stabilizer) passed through a 50-mesh standard sieve were sequentially added to fenofibrate and mixed under high-speed stirring. Separately, a binder was additionally mixed with purified water to create a binder solution, which was then added to granulate the mixture using a wet granulation process. Thereafter, the wet granules were dried in a fluidized bed dryer and sieved using a 1.2 mm oscillator.

[0061] A lubricant passed through a 30 mesh standard sieve was added to the granules manufactured above, and tablets of the examples and comparative examples were manufactured by pressing under the conditions of 500±3% and 7±3 kp.

[0062] Active ingredient name Comparative example 1 (weight %) Example 1 (weight %) Example 2 (weight %) Example 3 (weight %) Example 4 (weight %) Example 5 (weight %) Example 6 (weight %) Active ingredient 1 Ezetimibe 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Active ingredient 2 Fenofibrate 32.00 32.00 32.00 32.00 32.00 32.00 32.00 Diluent 43.60 43.58 75 43.50 43.40 43.10 42.60 40.60 Disintegrant 15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00 Binder 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Antioxidant (or Stabilizer) Butylhydroxytoluene 00.01 25 0.100 200.50 1.00 3.00 Lubricant 2.40 2.40 2.40 2.40 2.40 2.40 2.40 2.40 2.40 Total (per tablet; Weight%)100.0100.0100.0100.0100.0100.0100.0100.0

[0063] Classification Ingredient name Comparative example 2 (weight%) Comparative example 3 (weight%) Comparative example 4 (weight%) Comparative example 5 (weight%) Active ingredient 1 Ezetimibe 2.00 2.00 2.00 2.00 2.00 Active ingredient 2 Fenofibrate 32.00 32.00 32.00 32.00 Diluent 42.60 41.60 42.60 41.60 Disintegrant 15.00 15.00 15.00 15.00 Binder 5.00 5.00 5.00 5.00 Antioxidant (or stabilizer) Citric acid 1.00 2.00 00 Tartaric acid 001.00 2.00 Lubricant 2.40 2.40 2.40 2.40 Total (per 1 tablet; weight%) 100.0 100.0 100.0 100.0

[0064] Test Example 1: Stability Evaluation of Pharmaceutical Compositions by Type of Antioxidant (Stabilizer)

[0065] For the pharmaceutical compositions of Examples 2 and 3 and Comparative Examples 1 to 5, the amount of reactive substances produced and the stability of the pharmaceutical compositions were evaluated according to the type of antioxidant (stabilizer) by the following method. Specifically, each pharmaceutical composition was stored in a high-density plastic bottle (HDPE) and stored under accelerated storage conditions of 40±2℃, 75±5%RH, and the lid was opened for about 1 month, and the amount of reactive substances produced was analyzed and evaluated every 1 to 2 weeks using an HPLC device. The amount of reactive substances produced was analyzed and evaluated by dividing it into the content of reactive substances of ezetimibe ketone, the content of other reactive substances, and the total content of reactive substances, and the results of the evaluation are summarized and shown in Table 3 below:

[0066]

[0067] Category Antioxidant (weight%) Evaluation target Initial (weight%) After 7 days (weight%) After 14 days (weight%) After 28 days (weight%) Comparative example 1 None Ezetimibe ketone 0.020.08 0.17 0.21 Other flexible substances 0.000.000.000.00 Total flexible substances 0.020.08 0.17 0.21 Comparative example 2 Citric acid (1 weight%) Ezetimibe ketone 0.020.07 0.16 0.18 Other flexible substances 0.000.000.000.00 Total flexible substances 0.020.07 0.16 0.18 Comparative example 3 Citric acid (2 weight%) Ezetimibe ketone 0.020.07 0.14 0.17 Other flexible substances 0.000.000.000.00 Total flexible substances Material 0.020.07 0.14 0.17 Comparative Example 4 Tartaric acid (1 wt%) Ezetimibe ketone 0.020.08 0.16 0.17 Other flexible substances 0.000.000.000.00 Total flexible substances 0.020.08 0.16 0.17 Comparative Example 5 Tartaric acid (2 wt%) Ezetimibe ketone 0.020.08 0.13 0.18 Other flexible substances 0.000.000.000.00 Total flexible substances 0.020.08 0.13 0.18 Example 2 Butylhydroxytoluene (0.1 wt%) Ezetimibe ketone 0.020.020.020.02 Other flexible substances 0.000.000.000.00 Total flexible substances 0.020.020.020.02 Example 3-Butylhydroxytoluene (0.2 wt%) Ezetimibe Ketone 0.020.020.020.02 Other flexible substances 0.000.000.000.00 Total flexible substances 0.020.020.020.02

[0068] Referring to Table 3 above, it was confirmed that the pharmaceutical compositions of Examples 2 and 3 exhibited excellent stability with a significantly reduced amount of flexible substances produced compared to Comparative Example 1, which did not include a separate antioxidant and stabilizer, and Comparative Examples 2 to 5, which included an organic acid-based stabilizer.

[0069]

[0070] Test Example 2: Stability Evaluation of Pharmaceutical Compositions under Open Accelerated Conditions (40°C and 75% Relative Humidity)

[0071] For the pharmaceutical compositions of Comparative Example 1 and Examples 1 to 4, they were stored in high-density plastic bottles (HDPE) with the lids open under accelerated storage conditions of 40±2℃, 75±5%RH, and the amount of generated reactive substances was analyzed and evaluated using an HPLC device for about 3 months. The amount of generated reactive substances was analyzed and evaluated by dividing it into the content of reactive substances of ezetimibe ketone and the content of other reactive substances, and the results of the evaluation are summarized and presented in Table 4 below:

[0072] Classification Antioxidant (weight%) Evaluation target Initial (weight%) After 3 months (weight%) Comparative example 1 None Ezetimibe ketone N / D 0.21 Other flexible substances N / D 0.47 Example 1 Butylhydroxytoluene (0.0125 weight%) Ezetimibe ketone N / D 0.21 Other flexible substances N / D 0.03 Example 2 Butylhydroxytoluene (0.1 weight%) Ezetimibe ketone N / D 0.19 Other flexible substances N / D 0.03 Example 3 Butylhydroxytoluene (0.2 weight%) Ezetimibe ketone N / D 0.12 Other flexible substances N / D 0.03 Example 4 Butylhydroxytoluene (0.5 weight%) Ezetimibe ketone N / D 0.11 Other flexible substances N / D 0.03

[0073] Referring to Table 4 above, it was confirmed that the pharmaceutical compositions of Examples 1 to 4 exhibited excellent stability with lower amounts of related substances produced compared to Comparative Example 1 even under accelerated conditions. However, it was confirmed that the stability of the pharmaceutical composition of Example 1 was not sufficient compared to Examples 2 to 4 because the amount of related substances produced in Example 1 was close to the standard value.

[0074]

[0075] Test Example 3: Stability Evaluation of Pharmaceutical Compositions under Open Harsh Conditions (75°C)

[0076] For the pharmaceutical compositions of Comparative Example 1 and Examples 4 to 6, they were stored in high-density plastic bottles (HDPE) and stored in an oven with the lid open at a harsh temperature of 75°C for about 4 days, and the amount of generated flexible substances was analyzed and evaluated using an HPLC device. The amount of generated flexible substances was analyzed and evaluated by dividing it into the content of ezetimibe ketone flexible substances, the content of other flexible substances, and the content of total flexible substances, and the results of the evaluation are summarized and presented in Table 5 below:

[0077] Classification Antioxidant (weight%) Evaluation target Initial (weight%) After 1 day (weight%) After 3 days (weight%) After 4 days (weight%) Comparative example 1 None Ezetimibe ketone N / DN / DN / DN / DN / D Other flexible substances 0.02 0.18 0.44 0.61 Total flexible substances 0.02 0.43 1.18 1.45 Example 4 Butylhydroxytoluene (0.5 weight%) Ezetimibe ketone N / DN / DN / DN / DN / D Other flexible substances 0.02 0.18 0.23 0.16 Total flexible substances 0.02 0.21 0.5 2 0.62 Example 5 Butylhydroxytoluene (1.0 weight%) Ezetimibe ketone N / DN / DN / DN / DN / D Other flexible substances 0.02 0.18 0.22 0.24 Total Flexible substances 0.02 0.3 1 0.6 4 0.8 5 Example 6 Butylhydroxytoluene (3.0 wt%) Ezetimibe ketone N / DN / DN / DN / DN / D Other flexible substances 0.02 0.1 6 0.2 5 0.3 8 Total flexible substances 0.02 0.3 0 0.6 3 1.0 4

[0078] Referring to Table 5 above, the pharmaceutical composition of Example 4 has a lower amount of flexible substances produced than Comparative Example 1 even under harsh conditions. The total amount of flexible substances produced in Examples 5 to 6, which increased the amount of pharmaceutical composition in Example 4, actually increased, and thus it was confirmed that the stability of the pharmaceutical composition was not sufficient compared to Example 4.

Claims

1. Ezetimibe or a pharmaceutically acceptable salt thereof; Fenofibrate or a pharmaceutically acceptable salt thereof; An antioxidant of the following chemical formula 1; and Pharmaceutical composition comprising pharmaceutically acceptable excipients: [Chemical Formula 1] In the above chemical formula 1, R1 is an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, R2 is a straight or branched alkyl group having 1 to 5 carbon atoms, and n is an integer of 1 or 2.

2. In the first paragraph, the antioxidant is a pharmaceutical composition comprising a compound in which R1 in the chemical formula 1 is a methyl group, an ethyl group, or a methoxy group, and R2 is a t-butyl group.

3. A pharmaceutical composition according to claim 1, wherein the antioxidant is included in an amount of 0.07 to 0.60 wt% based on the total weight of the pharmaceutical composition.

4. A pharmaceutical composition according to claim 1, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is contained in an amount of 1 to 5 wt% based on the total weight of the pharmaceutical composition.

5. A pharmaceutical composition according to claim 1, wherein the fenofibrate or a pharmaceutically acceptable salt thereof is contained in an amount of 15 to 40 wt% based on the total weight of the pharmaceutical composition.

6. A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient comprises at least one selected from the group consisting of a diluent, a disintegrant, a binder, and a lubricant.

7. A pharmaceutical composition in the form of an oral tablet according to claim 1.

8. A pharmaceutical composition in which the total content of flexible substances including ezetimibe ketone is less than 0.4 wt% after being stored open for 3 months or longer under conditions of 40°C and 75% relative humidity in paragraph 1.

9. A step of granulating a mixture comprising an active ingredient including ezetimibe, fenofibrate or a pharmaceutically acceptable salt thereof, an antioxidant of the above chemical formula 1, and pharmaceutically acceptable excipients including a diluent, a disintegrant and a binder; and A method for producing a pharmaceutical composition of claim 1, comprising the step of mixing a lubricant into the granules and compressing the granules.

10. In the 9th paragraph, the granulating step is a step of wet granulating the mixture; and A method for producing a pharmaceutical composition comprising the step of fluidizing the wet granulation material.