JP6848469B2 - Method for Producing Ezetimibe-Containing Pharmaceutical Composition - Google Patents

Description

The present invention relates to a method for producing a pharmaceutical composition containing ezetimibe. More specifically, the present invention relates to a method for producing an ezetimibe-containing pharmaceutical composition having good elution properties.

で表され、小腸でのコレステロールの吸収を選択的に阻害し、肝臓のコレステロール含量を低下させ、血中コレステロールを低下させると考えられており、高コレステロール血症、家族性高コレステロール血症、ホモ接合体性シトステロール血症などに効果を有する高脂血症治療剤として、「ゼチーア（登録商標）錠１０ｍｇ」の名称で販売されている。 Ezetimibe (chemical name: (3R, 4S) -1- (4-fluorophenyl) -3-[(3S) -3- (4-fluorophenyl) -3-hydroxypropyl], which is one of the sterol absorption inhibitors] -4- (4-Hydroxyphenyl) azetidine-2-one) is of formula (I) :.

Represented by, it is thought to selectively inhibit the absorption of cholesterol in the small intestine, lower the cholesterol content in the liver, and lower blood cholesterol, hypercholesterolemia, familial hypercholesterolemia, homozygous. It is marketed under the name of "Zetia (registered trademark) tablet 10 mg" as a therapeutic agent for hyperlipidemia having an effect on zytosterolemia and the like.

Patent Document 1 discloses that hydroxy-substituted azetimibe containing ezetimibe lowers serum cholesterol levels and is useful for the treatment of atherosclerosis, and that it is used in combination with a cholesterol biosynthesis inhibitor. Further, Patent Document 2 describes a method for treating cytosterolemia using hydroxy-substituted azetidineone containing ezetimibe as a sterol absorption inhibitor.

Special Table No. 8-509899 Japanese Patent Publication No. 2004-532186

However, Patent Document 1 describes only two formulation examples, and there is room for further improvement in order to obtain good dissolution characteristics. Further, Patent Document 2 does not clearly describe a specific example of a preparation using ezetimibe, and there is room for examination.

Therefore, it is an object of the present invention to provide a production method for obtaining a further ezetimibe-containing pharmaceutical composition having good elution characteristics.

In the ezetimib-containing pharmaceutical composition, the present inventors have a first pulverization step of pulverizing ezetimib as a drug substance by a predetermined pulverizer, and further pulverizing the obtained pulverized product by a predetermined pulverizer. (Ii) Dissolution rate as compared with the ezetimib-containing pharmaceutical composition obtained by a production method having the same particle size (particle size distribution) but having only one pulverization step by providing a pulverization step and pulverizing the mixture. We have found that good dissolution characteristics such as improvement of the above can be obtained, and further studies have been carried out to complete the present invention.

That is, the present invention
[1] (a) First pulverization step of pulverizing ezetimibe with a pin mill or a jet mill,
(B) The second pulverization step of supplying the pulverized product obtained in the step (a) as a raw material and pulverizing it with a pin mill or a jet mill, and (c) producing the pulverized ezetimibe obtained in the step (b). Graining process,
Method for producing ezetimibe-containing pharmaceutical composition containing
[2] The production method according to the above [1], wherein the second pulverization step is performed by a jet mill.
[3] The production method according to the above [1] or [2], in which the first pulverization step is performed by a jet mill, and the granules obtained in the steps [4] and (d) (c) are tableted and tablets. The production method according to any one of the above [1] to [3], further comprising a step of obtaining the above.

According to the present invention, an ezetimibe-containing pharmaceutical composition having good elution characteristics can be obtained by using a pin mill or a jet mill and providing two pulverization steps to pulverize ezetimibe, which is a drug substance.

It is a graph which shows the elution property of ezetimibe in a tablet.

In the present invention, in a method for producing a pharmaceutical composition containing ezetimib as an active drug, the first pulverization step of pulverizing ezetimib with a pin mill or a jet mill, and (b) the pulverized product obtained in step (a) are used as raw materials. It is characterized in that the pulverized ezetimib obtained by the second pulverization step of supplying as is and pulverizing by a pin mill or a jet mill is used. This makes it possible to obtain an ezetimibe-containing pharmaceutical composition having good elution characteristics.

The active drug in the present invention is ezetimibe, which has an action of inhibiting the absorption of cholesterol in the small intestine as a small intestinal cholesterol transporter inhibitor. The content of the active drug in the pharmaceutical composition is, for example, preferably 5 to 20 mg as ezetimibe, and more preferably 10 mg.

(A) First pulverization step According to the method for producing an ezetimibe-containing pharmaceutical composition of the present invention, first, a first pulverization step of pulverizing ezetimibe, which is a drug substance, with a pin mill or a jet mill is carried out. In this first pulverization step, ezetimibe is used as a feedstock, but the ezetimibe that can be used is not particularly limited.

A pin mill or a jet mill can be used for the first pulverization step. A pin mill is, for example, a crushing device capable of finely pulverizing a raw material by an impact force when the raw material passes between a large number of opposing pins rotating at high speed. As the pin mill, those generally used in the pharmaceutical field can be used, and examples thereof include Exceed Mill EM-1A and Exceed Mill EM-2 manufactured by Makino Sangyo Co., Ltd. A jet mill is a jet mill in which compressed air, high-pressure steam, or high-pressure gas of several atmospheres or more is ejected from an injection nozzle, and the raw material particles are accelerated by this jet flow, and the accelerated particles collide with each other or collide with the accelerated particles. It is a device that grinds by impact and grinding. Examples of the jet mill include SK-jet O mill manufactured by Seishin Co., Ltd., single track jet mill, spiral jet mill AS manufactured by Hosokawa Micron Co., Ltd., counter jet mill, micron jet, and the like.

The crushing conditions in the first crushing step depend on the equipment used, the state of the raw material ezetimibe, etc., but for example, the average particle size of the obtained fine powder is in the range of 1 to 30 μm and / or the particle size distribution is in the range of 0.5 to 50 μm. It is preferable to set the condition of the device so as to be inside.

The first pulverization step is preferably performed by a jet mill from the viewpoint that better effects of the present invention can be obtained and good elution characteristics can be exhibited.

(B) Second pulverization step According to the method for producing an ezetimib-containing pharmaceutical composition of the present invention, a second pulverization step of repulverizing the finely pulverized product obtained in the first pulverization step with a pin mill or a jet mill as a feed material. Is carried out. As the pin mill and jet mill used in this second crushing step, the same ones used in the first crushing step can be used. By performing this second pulverization step, even if the final particle size (particle size distribution) is about the same, the elution rate is improved as compared with the case where ezetimibe obtained only in the first pulverization step is used. be able to. By performing the pulverization step twice in this way, it is considered that the solubility is improved regardless of the particle size (particle size distribution).

The crushing conditions of the second pulverization step depend on the equipment used, the state of the pulverized product obtained by the first pulverization step as a feed material, and the like, for example, the average particle size of the obtained fine powder is 1 to 4 μm / Or it is preferable to set the conditions of the device so that the particle size distribution is in the range of 0.5 to 15 μm.

The second pulverization step is preferably performed by a jet mill from the viewpoint that better effects of the present invention can be obtained and good elution characteristics can be exhibited.

_{The particle size distribution of pulverized ezetimibe obtained in the second pulverization step preferably has d 50 of 1} to 4 μm from the viewpoint that the effects of the present invention can be more easily exhibited and better elution characteristics can be obtained. It is more preferably 2 μm, further preferably _{1 to 1.5 μm, preferably d 90} is 1 to 6 μm, more preferably 1 to 4 μm, and further preferably 1 to 2 μm. preferable. The particle size distribution is a value obtained on a volume basis by a laser diffraction / scattering method (dry measurement method), assuming that the particles are spherical.

(C) Granulation Step According to the method for producing an ezetimibe-containing pharmaceutical composition of the present invention, the pulverized ezetimibe obtained as described above is subjected to a granulation step. The granulation method of ezetimibe is not particularly limited, but a spray-dry granulation method, a fluidized bed granulation method, or the like, which are usually used in the present technical field, can be used. When fluidized bed granulation is adopted, for example, pulverized ezetimibe is placed in a fluidized bed granulator together with an excipient and a disintegrant, and fluidized bed granulation is performed using a granulation solution containing a binder and a surfactant. , Drying, sizing.

The excipient is not particularly limited, and is, for example, celluloses (crystalline cellulose, ethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl 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 of. Of these, celluloses such as crystalline cellulose and sugars such as lactose and lactose hydrate are preferable. Excipients may be used alone or in admixture of two or more.

When an excipient is used, the amount used in the pharmaceutical composition varies depending on the type of the excipient used and is not particularly limited, but is usually preferably 60% by mass or more, preferably 70% by mass or more. More preferred.

The disintegrant is not particularly limited, but is, for example, crospovidone, carboxymethyl sodium, carboxymethyl starch sodium, starch, partially pregelatinized starch, corn starch, lactose, calcium citrate, light anhydrous silicic acid, synthetic silicic acid. Examples thereof include aluminum crystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose, croscarmellose sodium, carboxymethyl cellulose calcium, carmellose, and hydroxypropyl starch. Of these, croscarmellose sodium and the like are preferable because they are rapidly disintegrating. The disintegrant may be used alone or in combination of two or more.

When a disintegrant is used, the amount used in the pharmaceutical composition varies depending on the type of the disintegrant used and is not particularly limited, but is usually preferably 5% by mass or more, more preferably 7% by mass or more. .. The content of the disintegrant in the pharmaceutical composition is preferably 10% by mass or less, more preferably 8% by mass or less.

Examples of the binder include povidone, hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, crystalline cellulose, crystalline cellulose and carmellose sodium. Of these, povidone is preferable from the viewpoint of good elution characteristics. The binder may be used alone or in combination of two or more.

When a binder is used, the amount used in the pharmaceutical composition varies depending on the type of the binder used and is not particularly limited, but is usually preferably 1% by mass or more, more preferably 2% by mass or more. .. If the content of the binder is less than 1% by mass, it tends to be difficult to obtain sufficient tablet strength, and it tends to be difficult to obtain sufficient elution property. The content of the binder in the pharmaceutical composition of the present invention is preferably 10% by mass or less, more preferably less than 4% by mass. When the content of the binder exceeds 10% by mass, the content of other additives such as disintegrants decreases relatively, and the elution property tends to decrease, resulting in stability (increase in related substances of the active drug). Tends to influence.

The surfactant is not particularly limited, and is, for example, benzalkonium chloride, benzethonium chloride, polyoxyethylene (40) monostearate (polyoxyl 40 stearate), sorbitan sesquioleate (sorbitan sesquioleate). , Polyoxyethylene (20) sorbitan monooleate (polysorbate 80), 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. These may be used alone or in combination of two or more.

When a surfactant is used, the amount used in the pharmaceutical composition varies depending on the type of the surfactant used and is not particularly limited, but is usually preferably 1% by mass or more, preferably 3% by mass or less. preferable.

The pharmaceutical composition according to the present invention includes at least one binder selected from the group consisting of the active drug ezetimib or a pharmaceutically acceptable salt thereof, povidone, hydroxypropyl cellulose and polyvinyl alcohol. Additives commonly used in the art such as excipients, disintegrants, lubricants, surfactants, sweeteners, flavors, stabilizers, fluidizers can be included.

The lubricant is not particularly limited, but for example, stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, light anhydrous silicic acid, hydrogenated oil, glycerin fatty acid ester. , Tarku, etc. 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 amount used in the pharmaceutical composition varies depending on the type of the lubricant used and is not particularly limited, but is usually preferably 1% by mass or more, preferably 3% by mass or less. preferable.

Additives such as sweeteners, flavors, stabilizers, and fluidizing agents are not particularly limited, and those usually used in the art are used, and the content in the pharmaceutical composition is also used. Those skilled in the art can appropriately set it according to the type of the agent.

(D) Tableting Step According to the method for producing a pharmaceutical composition of the present invention, preferably, an excipient, a disintegrant and a lubricant are optionally added to the granulated product obtained in the granulation step. In addition, after mixing, tablets can be obtained by tableting. Excipients, disintegrants and lubricants used are as described above. The locking method is not particularly limited, and for example, a hydraulic hand press machine, a single-shot locking machine, a rotary locking machine, etc. are used by using a locking mortar, a locking upper punch and a lower punch, and the like. A method 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.

The pharmaceutical composition obtained by the production method of the present invention is useful as a small intestinal cholesterol transporter inhibitor in the treatment of hypercholesterolemia, familial hypercholesterolemia, and homozygous cytosterolemia.

The dose of the pharmaceutical composition obtained by the production method of the present invention varies depending on the age, body weight, administration route, etc., and is, for example, 10 mg of ezetimibe per day for an adult. The route of administration is preferably enteric administration, particularly oral administration, from the mechanism of action of ezetimibe. Therefore, it is preferable to use tablets as the pharmaceutical composition as described above.

The tablets thus obtained can be further processed using conventional techniques to provide suitable coatings common in the art that do not affect the elution properties of the final formulation. For example, it can be a coated tablet such as a film-coated tablet made of a functional polymer. As the coating agent, hypromellose, macrogol and the like can be used. Further, a colorant such as titanium oxide and iron sesquioxide, a brightener such as carnauba wax, and the like can be appropriately added to the coating agent. It can also be a sugar-coated tablet.

The shape of the tablet thus obtained is not particularly limited, and may be, for example, a disk shape, a donut shape, a polygonal plate shape, a spherical shape, an elliptical shape, a caplet shape, or the like. The size is preferably small, for example, in the case of a caplet shape, the major axis is preferably about 8 to 9 mm, the minor axis is preferably 4 to 5 mm, and a score line can be inserted. The mass is preferably about 80 to 100 mg.

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.
Lactose monohydrate: Japan Bureau XVI
Crystalline Cellulose: Japan Bureau XVI
Povidone: Nikkei XVI
Croscarmellose Sodium: Japan Bureau XVI
Sodium Lauryl Sulfate: Japan Bureau XVI
Magnesium stearate: Japan Bureau XVI

In the above, the Japanese Pharmacopoeia XVI represents the 16th revised Japanese Pharmacopoeia.

Example 1
As the first pulverization step of ezetimibe, ezetimibe was pulverized by a pin mill under the conditions that the average particle size of the obtained fine powder was within the range of 10 to 30 μm and the particle size distribution was within the range of 5 to 50 μm. As the second pulverization step, the finely pulverized product obtained in the first pulverization step is jet milled under the condition that the average particle size of the obtained fine powder is within the range of 1 to 4 μm and the particle size distribution is within the range of 0.5 to 15 μm. Crushed. Using the obtained pulverized ezetimibe, caplet tablets were produced according to the composition shown in Table 1. First, povidone in Table 1 was added to an aqueous solution of sodium lauryl sulfate to obtain a granulated solution. Next, pulverized ezetimibe, lactose hydrate, and a part of croscarmellose sodium (3 mg / tablet) were mixed to obtain granulated nuclei. The flow of the fluidized bed granulator was started, and the granulated liquid was sprayed while fluidizing the obtained granulated nuclei to obtain a fluidized bed granulated product. The obtained granules were sieved through a 500 μm sieve to obtain sized granules.

Crystalline cellulose, the remaining sodium croscarmellose, and magnesium stearate are added to the obtained sized granules, mixed, and charged into a tableting machine (major axis: 8.1 mm, minor axis: 4.1 mm) for tableting. Then, a caplet tablet having a mass of 100 mg was obtained.

Example 2
The first pulverization step of ezetimibe was carried out by a jet mill under the conditions that the average particle size of the obtained fine powder was within the range of 1 to 4 μm and the particle size distribution was within the range of 0.5 to 15 μm, as in Example 1. I got a caplet tablet.

Comparative Example 1
The first pulverization step of ezetimibe was performed by a jet mill under the conditions that the average particle size of the obtained fine powder was within the range of 1 to 4 μm and the particle size distribution was within the range of 0.5 to 15 μm, and the second pulverization step was not performed. A caplet tablet was obtained in the same manner as in Example 1 except for the above.

Test Example 1: Particle size distribution measurement The particle size distribution of the pulverized ezetimib used in Examples 1 and 2 and Comparative Example 1 is measured by a dry measurement method of laser diffraction / scattering type particle size distribution measuring device (Partica manufactured by Horiba Seisakusho Co., Ltd.). LA-950, dispersion solvent: ethanol, sample refractive index 1.60) was measured on a volume basis. The results are shown in Table 2.

Average particle size = Σ {q (J) x X (J)} ÷ Σ {q (J)}
J: Particle size division number q (J): Frequency distribution value (%)
X (J): Representative diameter (μm) of the Jth particle size range

Test Example 2: Measurement of dissolution characteristics Ezetimibe tablets (n = 6 each) obtained in each Example and Comparative Example were subjected to an dissolution test. The dissolution test was performed in the dissolution tester (trade name: NTR-6000 series, manufactured by Toyama Sangyo Co., Ltd.) according to the Japanese Pharmacopoeia dissolution test method, as the dissolution test solution of the Japanese Pharmacopoeia dissolution test second solution (pH 6.8). ) With 0.1% polysorbate 80 added to the test solution 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 are shown in FIG.

From FIG. 1, in Comparative Example 1 using the ezetimibe drug substance that was crushed only once by a jet mill, the elution rate was lower than that of Examples 1 and 2 in which the crushing step was performed twice. It was. From the results of Test Example 1, considering that the particle size of Example 1 and the particle size (particle size distribution) of Comparative Example 1 are about the same, it is considered that the number of pulverization steps affects the elution rate. Be done.

Test Example 3: Measurement of stability The ezetimibe tablet obtained in Example 1 was immediately after production (n = 3) and wrapped in a PTP packaging material (polypropylene single layer) at 60 ° C. and a humidity of 75% RH. Stored in an incubator. The stability (amount of substance of related substances) of the tablets at the start of storage (n = 3), 1 week after storage (n = 3) and 2 weeks after storage was measured. The results are shown in Table 3.

The concentration of ezetimibe-related substances was measured by the liquid chromatograph method under the following conditions according to the 16th revised Japanese Pharmacopoeia.
Test conditions:
Detector: Ultraviolet absorptiometer (measurement wavelength: 232 nm)
Column: A stainless steel tube having an inner diameter of 3.9 mm and a length of 15 cm was filled with 5 μm of octylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 30 ° C Mobile phase: 20 mM KH ₂ PO ₄ / CH ₃ CN (1/1)
Flow rate: 1.0 mL / min Area measurement range: 7 minutes after sample injection Injection volume: 50 μL
Diluted solution: 0.05M Hydrochloric acid: Acetonitrile mixed solution (1: 1)

The amount of related substances was 0.131% for ketone bodies and 0.184% for the total amount of related substances after a storage period of 2 weeks, and very good results were obtained.

Claims (4)

(A) The first pulverization step of pulverizing ezetimibe with a pin mill or a jet mill,
(B) The second pulverization step of supplying the pulverized product obtained in the step (a) as a raw material and pulverizing it with a pin mill or a jet mill, and (c) producing the pulverized ezetimib obtained in the step (b). A method for producing an ezetimib-containing pharmaceutical composition, which comprises a step of granulating. The manufacturing method according to claim 1, wherein the second crushing step is performed by a jet mill. The production method according to claim 1 or 2, wherein the first pulverization step is performed by a jet mill. (D) The production method according to any one of claims 1 to 3, further comprising a step of tableting the granulated product obtained in the step (c) to obtain a tablet.

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