JP2021116284A - Ezetimibe and atorvastatin-containing pharmaceutical composition - Google Patents

Abstract

To provide a pharmaceutical composition containing ezetimibe and atorvastatin which has excellent elution properties with time.SOLUTION: A pharmaceutical composition contains ezetimibe and atorvastatin or their pharmaceutically acceptable salts or hydrates. The ezetimibe and atorvastatin or their pharmaceutically acceptable salts or hydrates are separately contained in different forms of granulated granules.SELECTED DRAWING: None

Description

The present invention relates to a pharmaceutical composition comprising ezetimibe and atorvastatin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. More specifically, it relates to a pharmaceutical composition containing ezetimibe and atorvastatin calcium hydrate, which have good elution properties over time.

Conventionally, active ingredients having a similar or different mechanism of action, which are considered to be effective for the same disease, are blended into one solid preparation. This is because the combination of a plurality of active ingredients has many merits such as enhancing the effect, suppressing side effects, and reducing the prescription of a doctor as compared with a single agent.

For example, ezetimibe (chemical name: (3R, 4S) -1- (4-fluorophenyl) -3-[(3S) -3- (4-fluoro)) that selectively inhibits the absorption of cholesterol and plant sterol in the small intestine. (Phenyl) -3-hydroxypropyl] -4- (4-hydroxyphenyl) azetimibe-2-one) and atorvastatin calcium hydrate (chemical name: bis {(3R, 5R) -7) that inhibits cholesterol biosynthesis. -[2- (4-Fluorophenyl) -5- (1-methylethyl) -3-phenyl-4- (phenylcarbamoyl) -1H-pyrrole-1-yl] 3,5-dihydrooxyheptanoate} 1 Tablets containing calcium / trihydrate) are used as therapeutic agents for hypercholesterolemia and familial hypercholesterolemia, such as "Atorvastatin® Combination Tablets LD" and "Atorvastatin® Combination Tablets HD". (Non-Patent Document 1).

Further, in Patent Document 1, a tablet containing ezetimibe, which does not contain crospovidone and contains 0.1 to 2.8% by weight of 1-vinyl-2-pyrrolidone such as povidone with respect to the total weight of the uncoated tablet. It is disclosed that tablets containing a polymer have a high chemical stability improving effect of ezetimibe and a high suppressing effect of tablet coloring.

JP-A-2018-172359

"Atozet (registered trademark) combination tablet LD / Atozet (registered trademark) combination tablet HD" package insert

However, in the formulation of Non-Patent Document 1, it is confirmed that the dissolution rate decreases with time. Therefore, it is desired to develop a combination tablet of ezetimibe and atorvastatin having good dissolution characteristics over time.

Further, Patent Document 1 also does not particularly describe the dissolution characteristics when ezetimibe is blended with other active ingredients or when it is blended with other active ingredients.

Therefore, it is an object of the present invention to provide a pharmaceutical composition containing further ezetimibe and atorvastatin, which have good dissolution characteristics over time.

In a pharmaceutical composition containing ezetimibe and atorvastatin, the present inventors combine ezetimibe with atorvastatin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof in the form of separate granulated granules. The present invention has been completed by finding that a pharmaceutical composition having good dissolution characteristics over time can be obtained by containing the mixture.

That is, the present invention
[1] A pharmaceutical composition containing ezetimibe and atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein ezetimibe and atorvastatin or a pharmaceutically acceptable salt thereof. Or a pharmaceutical composition in which those hydrates are contained in the form of different granulated granules,
[2] The pharmaceutical composition according to the above [1], wherein the atorvastatin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof is atorvastatin calcium hydrate.
[3] The pharmaceutical composition according to the above [1] or [2], which is a dosage form of a tablet, and [4] the pharmaceutical composition according to any one of the above [1] to [3], which is a single-layer tablet. Regarding.

According to the present invention, ezetimibe and atorvastatin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof are contained in the form of different granulated granules, whereby ezetimibe and atorvastatin, or atorvastatin, or The dissolution characteristics of the pharmaceutical composition containing the pharmaceutically acceptable salt or a hydrate thereof can be improved over time.

Further, according to the present invention, it is not necessary to use a double-layer tablet as in the preparation of Non-Patent Document 1, but a single-layer tablet can be used, and a simpler method for producing a preparation can be adopted.

It is a graph which shows the elution rate (%) of ezetimibe. It is a graph which shows the elution rate (%) of ezetimibe. It is a graph which shows the elution rate (%) of ezetimibe. It is a graph which shows the elution rate (%) of atorvastatin.

The present invention relates to a pharmaceutical composition containing ezetimibe and atorvastatin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein ezetimibe, atorvastatin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or It is characterized in that these hydrates are contained in the form of different granulated granules. Further, by uniformly containing each pharmaceutical composition in the form of different granulated granules as a single-layer tablet, it is possible to obtain a tablet capable of suppressing the initial good dissolution property and the decrease in dissolution with time.

As described above, ezetimibe used in the present invention is (3R, 4S) -1- (4-fluorophenyl) -3-[(3S) -3- (4-fluorophenyl) -3-hydroxypropyl] -4-. It is (4-hydroxyphenyl) azetimibe-2-one and has an action of inhibiting the absorption of cholesterol in the small intestine as a cholesterol transporter inhibitor of the small intestine.

The amount of ezetimibe in the pharmaceutical composition is, for example, preferably 5 to 20 mg, more preferably 10 mg as ezetimibe.

The atorvastatin used in the present invention, or a pharmaceutically acceptable salt thereof, or a hydrate thereof is the above-mentioned atorvastatin, bis {(3R, 5R) -7- [2- (4-fluorophenyl) -5. -(1-Methylethyl) -3-phenyl-4- (phenylcarbamoyl) -1H-pyrrole-1-yl] 3,5-dihydrooxyheptanoic acid}, or a pharmaceutically acceptable salt thereof, or theirs. It is a hydrate and has the effect of inhibiting the biosynthesis of cholesterol.

Pharmaceutically acceptable salts of atorvastatin include pharmaceutically acceptable non-toxic organic acids such as acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Examples thereof include addition salts of inorganic acids, metal salts such as sodium salt, potassium salt and calcium salt, ammonium salts, amine salts and amino acid salts. Of these, the calcium salt of atorvastatin is particularly preferable.

The hydrate of atorvastatin or a pharmaceutically acceptable salt of atorvastatin is not particularly limited, but a hydrate of atorvastatin calcium salt, particularly atorvastatin monocalcium trihydrate is preferable.

The amount of atorvastatin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof in the pharmaceutical composition is preferably 5 to 20 mg as atorvastatin, more preferably 10 mg or 20 mg.

The compounding ratio of ezetimibe and atorvastatin used in the present invention, or a pharmaceutically acceptable salt thereof, or a hydrate thereof (in terms of atorvastatin) is not particularly limited, but is 1: 1 to 1: 1. 2 is preferable, and 1: 1 or 1: 2 is more preferable.

In addition to the active ingredient ezetimibe and atorvastatin, or a pharmaceutically acceptable salt thereof, or hydrates thereof, pharmaceutical compositions include, for example, excipients, stabilizers, disintegrants, binders. Additives commonly used in the art, such as surfactants, lubricants, fluidizers, acidulants, sweeteners, fragrances, refreshers, colorants, etc., can be included.

In the pharmaceutical composition of the present invention, ezetimibe, which is an active ingredient, and atorvastatin, a pharmaceutically acceptable salt thereof, or a hydrate thereof are contained as separate granules. In addition to the active ingredient, these granulated granules can contain additives such as excipients, disintegrants, binders, stabilizers and surfactants.

Granulated granules containing ezetimibe include, but are not limited to, excipients, disintegrants, binders, surfactants and the like. Specifically, it is preferable that ezetimibe, an excipient and a disintegrant are contained in the granulation nucleus, and the binder and the surfactant are granulated as a granulation solution.

On the other hand, granulated granules containing atorvastatin, a pharmaceutically acceptable salt thereof, or a hydrate thereof are not particularly limited, but are not particularly limited, but are excipients, disintegrants, stabilizers, and binders. Etc. are included. Specifically, atorvastatin, a pharmaceutically acceptable salt thereof, or a mixture of hydrates, excipients, disintegrants, stabilizers and binders thereof is preferably granulated.

The excipient is not particularly limited, and is, for example, celluloses (crystalline cellulose, ethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromerose), etc.) and derivatives thereof, starch (corn starch, potato starch, etc.). Wheat starch, rice starch, partially pregelatinized starch, hydroxypropyl starch, etc.) and their derivatives, sugars (dextrose, lactose, sucrose, refined sucrose, powdered sugar, trehalose, dextran, dextrin, etc.), sugar alcohols (D-mannitol, xylitol, etc.) , Sorbitol, erythritol, etc.), glycerin fatty acid ester, inorganic powder (magnesium aluminometasilicate, synthetic hydrotalcite), anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium hydrogen phosphate hydrate, sodium hydrogen carbonate, etc. Inorganic salt can be mentioned. Of these, celluloses such as crystalline cellulose and sugars such as lactose and lactose hydrate are preferable. As the excipient used for the granulated granules of ezetimib, sugars such as lactose and lactose hydrate are preferable, and atorvastatin, a pharmaceutically acceptable salt thereof, or an excipient used for those hydrates is preferable. , Celluloses such as crystalline cellulose, and / or sugars such as lactose and lactose hydrate are preferred. Excipients may be used alone or in combination of two or more.

The content of the excipient in the pharmaceutical composition varies depending on the type of the excipient used and is not particularly limited, but is usually preferably 55% by mass or more, preferably 65% by mass or more. More preferably, 95% by mass or less is preferable, and 85% by mass or less is more preferable.

The stabilizer is not particularly limited, but for example, metal salts such as calcium carbonate, magnesium carbonate, calcium hydroxide, magnesium hydroxide, magnesium silicate, magnesium aluminate, and magnesium aluminum hydroxide are preferable. Magnesium carbonate is most preferred. The stabilizer is preferably contained in the granulated granules of atorvastatin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. The stabilizer may be used alone or in combination of two or more.

When a stabilizer is used, the content in the pharmaceutical composition varies depending on the type of stabilizer used and is not particularly limited, but is usually preferably 0.3% by mass or more, preferably 0.5. It is more preferably mass% or more, preferably 5.0 mass% or less, and more preferably 3.0 mass% or less. When the content of the stabilizer in the pharmaceutical composition is less than 0.3% by mass, related substances tend to increase.

The disintegrant is not particularly limited, but is, for example, carboxystarch sodium, carboxymethyl starch sodium, starch, partially pregelatinized starch, corn starch, lactose, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate crystalline cellulose. , Low-substituted hydroxypropyl cellulose, croscarmellose, croscarmellose sodium, carboxymethyl cellulose calcium, carmellose, hydroxypropyl starch, crospovidone and the like. Among them, the disintegrant such as croscarmellose sodium is preferable from the viewpoint of rapid disintegration, and may be used alone or in combination of two or more.

When a disintegrant is used, the content in the pharmaceutical composition varies depending on the type of the disintegrant used and is not particularly limited, but is usually preferably 0.5% by mass or more, preferably 1.0% by mass. The above is more preferable, 20.0% by mass or less is preferable, and 10.0% by mass or less is more preferable. By setting the content of the disintegrant to 1.0% by mass or more, the preparation tends to have better disintegration property.

The binder is not particularly limited, and examples thereof include povidone, hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, crystalline cellulose, and crystalline cellulose / carmellose sodium. Of these, povidone and hydroxypropyl cellulose are preferable because of their rapid disintegration. As the binder used for the granulated granules of ezetimib, povidone and / or hydroxypropyl cellulose is preferable, and as a binder used for the granulated granules of atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof. Is preferably hydroxypropyl cellulose. The binder may be used alone or in combination of two or more.

When a binder is used, the content in the pharmaceutical composition varies depending on the type of the binder used and is not particularly limited, but is usually preferably 1.0% by mass or more, preferably 2.0% by mass. The above is more preferable. When the content of the binder exceeds 10.0% by mass, the content of other additives such as disintegration tends to decrease relatively, the elution property tends to decrease, and the stability (increase of related substances of the active ingredient). ) Tends to affect. Similarly, the content of the binder in the pharmaceutical composition is preferably 10.0% by mass or less, more preferably 5.0% by mass or less. If the content of the binder is less than 1.0% by mass, it tends to be difficult to obtain sufficient tablet strength and sufficient solubility.

The surfactant is not particularly limited, and is, for example, benzalkonium chloride, benzethonium chloride, polyoxyethylene (40) monostearate (polyoxyl 40 stearate), sorbitan sesquioleate (sorbitan sesquioleate). , Glyceryl monostearate (glycerin monostearate), sodium lauryl sulfate, polyoxyethylene lauryl ether (lauromacrogol) and the like. Of these, sodium lauryl sulfate, which is an anionic surfactant, is particularly preferable because better elution characteristics can be obtained. In particular, it is preferable to use a surfactant for the granulated granules of ezetimibe. These may be used alone or in combination of two or more.

When a surfactant is used, the content in the pharmaceutical composition varies depending on the type of the surfactant used and is not particularly limited, but is usually preferably 0.1% by mass or more, and is usually 0.5. It is more preferably mass% or more, preferably 7.0 mass% or less, and more preferably 5.0 mass% or less.

Examples of the lubricant include, but are not limited to, stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, hydrogenated oil, glycerin fatty acid ester, and talc. Be done. Of these, magnesium stearate is preferable because of its high smoothness. These may be used alone or in combination of two or more.

When a lubricant is used, the content in the pharmaceutical composition varies depending on the type of the lubricant used and is not particularly limited, but is usually preferably 0.1% by mass or more, and is 0.3. More preferably by mass% or more. If the content of the lubricant exceeds 5.0% by mass, the content uniformity tends to be adversely affected, and it tends to be difficult to obtain more sufficient dissolution property. Similarly, the content of the lubricant in the pharmaceutical composition is preferably 5.0% by mass or less, more preferably 3.0% by mass or less. If the content of the lubricant is less than 0.1% by mass, it tends to cause a tableting disorder.

The fluidizing agent is not particularly limited, and examples thereof include silicates such as calcium silicate, hydrous silicon dioxide, talc, titanium oxide, stearic acid, calcium stearate, and magnesium aluminometasilicate. These may be used alone or in combination of two or more.

When a fluidizing agent is used, the content in the pharmaceutical composition may be such that the above-mentioned powder additive can flow smoothly in the production of the pharmaceutical composition, and this is the fluidization to be used. It is not particularly limited because it differs depending on the type of the agent.

The pharmaceutical composition of the present invention is useful for the treatment of hypercholesterolemia and familial hypercholesterolemia.

The dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as each active ingredient can be contained as granulated granules, and examples thereof include tablets and granules. The pharmaceutical composition of the present invention may be a coated tablet such as a sugar-coated tablet or a film-coated tablet made of a functional polymer.

The dose of the pharmaceutical composition of the present invention varies depending on age, body weight, route of administration, etc., and is, for example, 10 mg of ezetimibe and 10 mg or 20 mg of atorvastatin per day for an adult.

(Manufacturing method of granulated granules)
As a method for producing granulated granules, a method general in the present technical field can be used, and the method is not particularly limited. Granulation granules of ezetimib are prepared by, for example, putting ezetimib in a fluidized bed granulator together with an excipient and a disintegrant, performing fluidized bed granulation using a granulation solution containing a binder and a surfactant, and drying. It can be obtained by sizing. Granulation granules of atorvastatin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, excipients, for example, atorvastatin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. It can be obtained by putting it in a stirring granulator together with a stabilizer, a disintegrant, a binder and the like, performing stirring granulation using purified water, drying and sizing.

(Manufacturing method of pharmaceutical composition)
As the pharmaceutical composition containing the active ingredient as granulated granules, tablets, granules and the like can be produced, and general methods in the present technical field can be used for each, and the present invention is not particularly limited. For example, each of the above granulated granules is mixed with other additives such as excipients, disintegrants, lubricants, sweeteners and flavors, respectively, as necessary to obtain mixed granules, which are mixed. It can be a granule. Further, in the case of producing tablets, each of the obtained mixed granules may be sequentially put into a tableting machine and tableted to produce a two-layer tablet, or each mixed granule may be mixed. It may be put into a tableting machine as it is to produce a single-layer tablet. Further, other additives such as excipients, disintegrants, lubricants, sweeteners, and fragrances are mixed with each of the above granulated granules, and the granules are put into a tableting machine to be tableted to form a single layer. Tablets can also be produced.

In any of the embodiments, the locking method is not particularly limited, and for example, a hydraulic hand press machine, a single-shot locking machine, using a locking mortar, a locking upper punch and a lower punch, and the like. A method using a rotary lock machine or the like can be used. Tableting may be performed so that the obtained tablet has an appropriate hardness. The tableting pressure is appropriately adjusted according to the tableting method, the equipment used for tableting, the size of the tablet, the type of pharmaceutical ingredient, and the like.

Hereinafter, the present invention will be specifically described based on examples, but the present invention is not intended to be limited to these examples.

Details of the reagents used in the examples are described below.
Crystalline Cellulose: Japan Bureau XVII
Lactose Hydrate: Japan Bureau XVII
Magnesium Carbonate: Japan Bureau XVII
Croscarmellose Sodium: Japan Bureau XVII
Hydroxypropyl Cellulose: Japan Bureau XVII
Povidone: Japanese Bureau XVII
Sodium Lauryl Sulfate: Japan Bureau XVII
Magnesium stearate: Japan Bureau XVII

In the above, the Japanese Pharmacopoeia XVII represents the 17th revised Japanese Pharmacopoeia.

Example 1
According to the formulation shown in Table 1, atrubastatin calcium trihydrate, crystalline cellulose, magnesium carbonate, sodium croscarmellose, and hydroxypropyl cellulose were added to a stirring granulator (FM-VG-05, manufactured by Paulek Co., Ltd.), and further. Purified water was added for granulation. The obtained granulated granules were dried in a fluidized bed granulation dryer (MP01, manufactured by Paulek Co., Ltd.) and then sieved through a 850 μm sieve to obtain granulated granules A. Magnesium stearate was added to the obtained sized granules A and mixed in a plastic bag to obtain mixed granules A. On the other hand, according to the formulation shown in Table 1, popidone was added to an aqueous solution of sodium lauryl sulfate to obtain a granulated solution. Ezetimibe, lactose hydrate, and 3.0 mg of croscarmellose sodium were mixed according to the formulation shown in Table 1 to obtain granulated nuclei. The fluidized bed granulation machine was started to flow, and the obtained granulation nuclei were fluidized while the above granulation liquid was sprayed to obtain fluidized bed granules. The obtained granulated granules were dried in a fluidized bed granulation dryer (MP01, manufactured by Paulek Co., Ltd.) and then sieved through a 850 μm sieve to obtain granulated granules B. Crystalline cellulose, the remaining sodium croscarmellose and magnesium stearate were added to the obtained sized granules B according to the formulation shown in Table 1 and mixed in a plastic bag to obtain mixed granules B. The mixed granules A and the mixed granules B are further mixed with a mixer (V-type mixer (V-20), manufactured by Tokuju Kosakusho Co., Ltd.) and used as a rotary tableting machine (VIRG0512SS2AZ, manufactured by Kikusui Seisakusho Co., Ltd.). Then, the tablet was tableted to a major axis of 7.5 mm to obtain a single-layer tablet.

Comparative Example 1
Atozet (registered trademark) combination tablet LD (manufacturer and distributor: MSD Co., Ltd.) was used.

Comparative Example 2
According to the formulation shown in Table 2, the sized granules A obtained in the same manner as in Example 1 were added with ezetimib, lactose hydrate, crystalline cellulose, croscarmellose sodium, sodium lauryl sulfate and magnesium stearate, which are external addition portions. Was added, mixed, and tableted to a major axis of 7.5 mm with a rotary tableting machine (VIRG0512SS2AZ, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a single-layer tablet.

Test Example 1: Dissolution Characteristic Test The tablets produced in Example 1 and Comparative Example 2 and the tablets described in Comparative Example 1 are each of an aluminum pillow (exterior pillow film for PTP, gassho bag gasset specification, manufactured by Shohoku Laminate Industry Co., Ltd.). ), Sealed and packaged, and stored for 2 weeks in an environment of a temperature of 60 ° C. and a humidity of 75%. Dissolution tests were performed on each tablet at the start of storage and after 2 weeks (n = 2 each). In the dissolution test, according to the Japanese Pharmacopoeia dissolution test method, in an dissolution tester (trade name: NTR-6000 series, manufactured by Toyama Sangyo Co., Ltd.), as an dissolution test solution, McIlvaine Buffer pH 4.0 + 0.1% polysorbate 80, And McIlvaine Buffer were used and performed by the paddle method. The test conditions were an elution solvent volume of 900 mL, a temperature of 37 ± 0.5 ° C., and a paddle speed of 50 rpm. The results of the tablets of Example 1, Comparative Example 2 and Comparative Example 1 for ezetimibe are shown in FIGS. 1 to 3 and Table 3 as average values, respectively.

From FIGS. 1 to 3 and Table 3, in Comparative Example 1 which is a two-layer tablet, a sufficient dissolution rate was not obtained for the tablet after the storage period had elapsed even after the dissolution time of 60 minutes, and good dissolution characteristics could be obtained. I know I can't. Further, in Comparative Example 2 in which ezetimibe was not used as granulated granules, a sufficient dissolution rate was not obtained in the dissolution time of 60 minutes not only for the tablets after the storage period had elapsed but also for the tablets at the start of storage, and good dissolution was achieved. It turns out that the characteristics cannot be obtained.

Reference example 1
According to the formulation shown in Table 1, the mixed granules A obtained in the same manner as in Example 1 were tableted with a rotary tableting machine (VIRG00512SS2AZ, manufactured by Kikusui Seisakusho Co., Ltd.) to a diameter of 7.5 mm to obtain tablets. rice field.

Reference example 2
The components listed in the mixed granule A column of Table 1 were mixed in a plastic bag and tableted to a diameter of 7.5 mm with a rotary tableting machine (VIRG00512SS2AZ, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets.

Test Example 2
The tablets obtained in Reference Examples 1 and 2 were subjected to the dissolution test without storage in the same manner as in Test Example 1 except that the first solution of the Japanese Pharmacopoeia dissolution test (pH 1.2) was used as the elution solution. (Each n = 3). The results are shown in FIG. 4 and Table 4.

From FIG. 4 and Table 4, when the tablets of atorubastatin calcium trihydrate were prepared by the components listed in the mixed granule A column of Table 1, in Reference Example 1 in which atorvastatin calcium trihydrate was contained as granulated granules. The elution rate was better than that of Reference Example 2 in which the granules were contained without being granulated.

Example 3
The tablet obtained in Example 1 was used as an uncoated tablet and put into a film coating machine (PRC-GTXmini, manufactured by Paulec Co., Ltd.). On the other hand, hypromellose (4.8 mg / tablet), macrogol (0.3 mg / tablet), titanium oxide (0.6 mg / tablet) and talc (0.3 mg / tablet) were dissolved and dispersed in purified water. , A coating liquid (solid content concentration 10% w / w) was prepared. Then, this coating liquid was sprayed in a film coating machine to coat and dry to obtain 191 mg tablets per tablet.

Claims (4)

A pharmaceutical composition comprising ezetimibe and atorvastatin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein ezetimibe, atorvastatin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. A pharmaceutical composition containing hydrates in the form of separate granules. The pharmaceutical composition according to claim 1, wherein the atorvastatin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof is atorvastatin calcium hydrate. The pharmaceutical composition according to claim 1 or 2, which is a dosage form of a tablet. The pharmaceutical composition according to any one of claims 1 to 3, which is a single-layer tablet.

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