JP2022136252A - Ezetimibe-containing oral preparation and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ezetimibe-containing oral preparation having excellent leachability, and a method of producing the same.

SOLUTION: An ezetimibe-containing oral preparation contains ezetimibe particles with d90 of 8.0 μm or less.

SELECTED DRAWING: None

COPYRIGHT: (C)2022,JPO&INPIT

Description

TECHNICAL FIELD The present invention relates to an ezetimibe-containing oral preparation having excellent dissolution properties and a method for producing the same.

Ezetimibe (chemical name: (3R,4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl]-(4-hydroxyphenyl)-2-azetidinone) is a compound represented by the following formula (1), and is a medicinal active ingredient that suppresses cholesterol absorption from the small intestine and lowers blood cholesterol levels.

Ezetimibe is marketed in Japan under the product name of "Zetia tablet 10 mg" as a small intestine cholesterol transporter inhibitor and hyperlipidemia therapeutic agent that lowers the amount of cholesterol in the blood.

Improving the bioavailability of active ingredients is important for obtaining effective pharmaceuticals, and high dissolution of active ingredients is required in order to provide oral preparations with high bioavailability.

So far, it has been reported that the particle size is adjusted for the purpose of enhancing dissolution in preparations containing ezetimibe. For example, Patent Document 1 discloses that in a combined preparation of ezetimibe and rosuvastatin, the average particle size (d(0.9)) of ezetimibe is 10 μm or less. It has also been reported that the primary particle size distribution, d(0.5), of ezetimibe, etc., is less than about 5 μm in a method of preparing a pharmaceutical composition containing a low-solubility active pharmaceutical ingredient, such as ezetimibe.

Japanese Patent Publication No. 2017-500303 Japanese Patent Publication No. 2014-500294

It has been found that the dissolution of ezetimibe is indeed improved by micronization. However, the present inventors' research has revealed that there is a limit to the dissolution-improving effect of simply pulverizing. In other words, in order to further improve the efficient dissolution properties of ezetimibe by pulverization, it was considered necessary to devise a method other than pulverization.

The present invention has been made in view of the above points, and a main object of the present invention is to provide an ezetimibe-containing oral preparation with even better dissolution than conventional preparations and a method for producing the same.

The inventors of the present invention have made intensive studies and found that the above problems can be solved by a formulation having the following constitution.

An ezetimibe-containing oral preparation according to one aspect of the present invention is characterized by containing ezetimibe particles having a d90 of 8.0 μm or less and a sugar alcohol of 50.0% by weight or more based on the total weight of the preparation.

Moreover, in the ezetimibe-containing oral preparation, the sugar alcohol is preferably D-mannitol.

Furthermore, it preferably contains at least one of polyvinyl alcohol and povidone as a binder.

In addition, a method for producing an ezetimibe-containing oral preparation according to a further aspect of the present invention comprises a step of pulverizing ezetimibe particles until d90 is 8.0 μm or less, and adding 50.50 μm of ezetimibe particles to the pulverized ezetimibe particles relative to the total weight of the preparation. and a step of mixing sugar alcohol in an amount to be added to be 0% by weight or more.

Furthermore, in the production method, the pulverization method in the pulverization step is preferably dry pulverization or wet pulverization.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide an ezetimibe-containing oral preparation with even better dissolution than conventional preparations and a method for producing the same.

Embodiments according to the present invention will be described below, but the present invention is not limited to these.

The ezetimibe-containing oral preparation of the present embodiment is characterized by containing ezetimibe particles having a d90 of 8.0 μm or less and a sugar alcohol of 50.0% by weight or more based on the total weight of the preparation.

The present inventors have found that dissolution is remarkably improved by the composition as described above, that is, by adding a high amount of sugar alcohol to micronized ezetimibe particles.

(active ingredient)
Ezetimibe, which is the active ingredient in the oral preparation of the present embodiment, is (3R,4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4 -fluorophenyl)propyl]-(4-hydroxyphenyl)-2-azetidinone.

Ezetimibe used in the present embodiment is ezetimibe particles that have been micronized to have a d90 of 8.0 μm or less. If the ezetimibe particles have a d90 of more than 8.0 μm, there is a risk that sufficient dissolution cannot be ensured. A more preferred particle size of ezetimibe has a d90 in the range of 1.0-5.0 μm, more preferably a d90 in the range of 2.0-3.5 μm. The lower limit of the particle size (d90) of ezetimibe is not particularly limited, but is 1.0 μm or more, preferably 2.0 μm or more, as described above, from the viewpoint of improving fluidity during the manufacturing process.

The amount of ezetimibe in the oral preparation of the present embodiment is preferably such that the daily dose of ezetimibe for human patients is usually about 10 mg (once) per day.

Thus, the oral formulation of this embodiment contains 10.0 mg of ezetimibe.

(sugar alcohol)
Next, the oral preparation of this embodiment contains 50.0% by weight or more of sugar alcohol relative to the total weight of the preparation. By including a sugar alcohol in such a high amount in the formulation, the dissolution of the micronized ezetimibe is further improved.

Specific examples of sugar alcohols include D-mannitol, D-sorbitol, xylitol, erythritol, maltitol and the like. Among them, it is preferable to use D-mannitol from the viewpoint of the stability of the main agent and the hygroscopic stability. These may be used individually by 1 type, and may use 2 or more types together.

As described above, the content of sugar alcohol in the oral preparation of the present embodiment is not particularly limited as long as it is 50.0% by weight or more relative to the total weight of the preparation, but from the viewpoint that if the tablet is too large, it becomes difficult to take. Therefore, it is preferably 90.0% by weight or less. A more preferable range is 55.0% by weight or more and 85.0% by weight or less, and a further preferable range is 60.0% by weight or more and 80.0% by weight or less.

Furthermore, the oral preparation of this embodiment may contain pharmaceutically acceptable additives. Specifically, commonly used binders, excipients, disintegrants, lubricants, surfactants, colorants and the like can be used.

(binder)
Binders that can be used in the present embodiment include, for example, polyvinyl alcohol, povidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, and methyl cellulose. These may be used individually by 1 type, and may use 2 or more types together. It preferably contains at least one of polyvinyl alcohol or povidone. Although not particularly limited, the content of the binder is preferably in the range of 0.1 to 10.0% by weight based on the total weight of the formulation.

(Excipient)
Examples of excipients that can be used in this embodiment include sugar alcohols, lactose hydrates, crystalline cellulose, anhydrous lactose, corn starch, and calcium hydrogen phosphate. Sugar alcohol, crystalline cellulose, etc. can be preferably used. These may be used individually by 1 type, and may use 2 or more types together. Although not particularly limited, the content of excipients is preferably in the range of 5.0 to 90.0% by weight based on the total weight of the formulation.

(Disintegrant)
Examples of disintegrants that can be used in the present embodiment include crystalline cellulose, corn starch, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, and the like. is mentioned. It is more preferably selected from carmellose, carmellose calcium, croscarmellose sodium and crospovidone, and most preferably croscarmellose sodium. These may be used individually by 1 type, and may use 2 or more types together. Although not particularly limited, the disintegrant is preferably contained in the range of 3.0 to 50.0% by weight with respect to the total weight of the uncoated tablet.

(Surfactant)
Examples of surfactants that can be used in the present embodiment include sucrose fatty acid esters, polysorbate, macrogol, sodium lauryl sulfate, lauromacrogol and the like. Sodium lauryl sulfate is preferred. The surfactant is preferably contained in the uncoated tablet in the range of 0.5 to 5.0% by weight based on the total weight of the preparation.

(lubricant)
Lubricants that can be used in the present embodiment include, for example, magnesium stearate, calcium stearate, sodium stearyl fumarate, and the like. Magnesium stearate is preferred. These may be used individually by 1 type, and may use 2 or more types together. Lubricants are preferably contained in the range of 0.1 to 5.0% by weight based on the total weight of the formulation.

The dosage form of the oral preparation of the present embodiment is not particularly limited, and may be granules, tablets, powders, capsules, and the like. Granules or tablets are preferred.

In the oral preparation of the present embodiment, the ezetimibe is preferably contained in the oral preparation as drug granules together with sugar alcohols, other excipients, etc. (that is, contained within granules).

When the oral preparation of the present embodiment is granules, the granules can be used as they are.

Moreover, when the pharmaceutical composition of the present embodiment is a tablet, the mixture containing the granules and other additives can be tableted into tablets. Further, the tablet may be coated or the like to obtain a coated tablet or the like.

Since the ezetimibe-containing oral preparation of the present embodiment has the effect of reducing the amount of cholesterol in the blood, it can be effectively used for the treatment and/or prevention of hyperlipidemia.

(Production method)
Next, the method for producing an ezetimibe-containing oral preparation of the present embodiment includes at least a step of pulverizing ezetimibe particles until d90 becomes 8.0 μm or less, and adding 50.0 μm to the pulverized ezetimibe particles with respect to the total weight of the preparation. and mixing the sugar alcohol in an amount added to be 0% by weight or more.

The production method of the present embodiment will be described below using a plain tablet as a specific example, but the production method of the oral preparation of the present invention is not limited to these.

In the production method of the present embodiment, first, ezetimibe particles are pulverized until d90 becomes 8.0 μm or less. The method of pulverization is not particularly limited, and dry pulverization (rotary impact mill (pin mill, hammer mill, etc.), jet mill, ball mill, etc.) or wet pulverization (rotor-stator mixing, ball mill, high-pressure homogenizer, etc.) is desired. can be ground to a particle size of

Next, the ezetimibe particles pulverized as described above are mixed with a sugar alcohol in an amount of 50.0% by weight or more based on the total weight of the formulation.

Then, for example, ezetimibe and sugar alcohol mixed in a fluidized bed granulator, and if necessary, further charged with a diluent, disintegrant, etc., sprayed with a binder dissolved in purified water, granulated, and then dried. - Granules are prepared by sizing, a disintegrant and a lubricant are further mixed with the granules to obtain a mixed powder, which can be compression-molded into uncoated tablets. For tableting, for example, a hydraulic hand press machine, a single-shot tableting machine, a rotary tableting machine, or the like can be used. The tableting pressure can be appropriately set according to the tablet weight of the tablet to be manufactured.

The shape of the oral preparation of the present embodiment is not particularly limited, but may be disk-shaped, doughnut-shaped, polygonal plate-shaped, spherical, elliptical, or the like.

EXAMPLES The present invention will be described in more detail below with reference to Examples, but the scope of the present invention is not limited to these.

<Test Example 1: Micronization effect of ezetimibe under the use of mannitol>
(Examples 1 to 4)
Povidone, ezetimibe and sodium lauryl sulfate were added to the purified water. Next, this ezetimibe dispersion (granulation liquid) is wet pulverized with a high-pressure homogenizer (“Microfluidizer M-110P” (device name), manufactured by Powrex) (Example 1: untreated, Example 2: 3 treatments, Example 3: 5 treatments, Example 4: 10 treatments), dispersions of ezetimibe having particle sizes (d10, d50, d90) shown in Table 1 below were prepared.

Furthermore, D-mannitol and croscarmellose sodium are put into a fluidized bed granulator (“MP-01” (device name), manufactured by Powrex), and the micronized dispersion of ezetimibe of each example is sprayed. It was granulated and dried to obtain granules. Microcrystalline cellulose, croscarmellose sodium and magnesium stearate were added to the obtained granules and mixed to obtain a mixed powder. The resulting mixed powder was compressed into tablets weighing 90 mg using a rotary tableting machine (“VIRGO” (apparatus name), manufactured by Kikusui Seisakusho) to obtain uncoated tablets.

Each component was added so that the composition of each component in the uncoated tablet would be the composition (% by weight) shown in Table 2 below.

The particle size of ezetimibe in the dispersion in each example was measured by a laser diffraction scattering method (LS13 320, Beckman Coulter).

The obtained ezetimibe-containing uncoated tablets of each example were subjected to an ezetimibe dissolution test under the following conditions.
・Dissolution test method: Based on dissolution test method 2 of the Japanese Pharmacopoeia ・Test solution: 2nd dissolution test solution with 0.1% polysorbate 80 added ・Test solution volume: 900 mL
・Tester temperature: 37°C
- Paddle rotation speed: 50 times per minute The results are shown in Table 3.

From the results in Table 3, it was found that when the sugar alcohol content in the granules was 50% by weight or more, the dissolution properties were remarkably improved by making the particle size of ezetimibe smaller.

(Comparative Examples 1 to 5)
Povidone, ezetimibe and sodium lauryl sulfate were added to purified water to prepare ezetimibe dispersions (granulation liquids) having particle sizes (d10, d50, d90) shown in Table 4 below.

Furthermore, lactose hydrate and croscarmellose sodium are put into a fluidized bed granulator ("MP-01" (device name), manufactured by Powrex), and the micronized dispersion of ezetimibe of each comparative example is sprayed. It was granulated and dried to obtain granules. Crystalline cellulose, croscarmellose sodium and magnesium stearate were added to the obtained granules and mixed to obtain a mixed powder. The resulting mixed powder was compressed into tablets weighing 90 mg using a rotary tableting machine (“VIRGO” (apparatus name), manufactured by Kikusui Seisakusho) to obtain uncoated tablets.

Each component was added so that the composition of each component in the uncoated tablet would be the composition (% by weight) shown in Table 5 below.

In addition, the particle size of ezetimibe in each comparative example was measured in the same manner as in Example 1.

The obtained ezetimibe-containing uncoated tablet of each comparative example was subjected to a dissolution test in the same manner as in Example 1. The results are shown in Table 6 below.

From the results in Table 6, it was found that when the particle size (d90) of ezetimibe is 8.0 μm or less, the improvement in dissolution slows even if the particle size of ezetimibe is reduced. In other words, it was shown that when the size of the ezetimibe particles is smaller than a certain particle size, the dissolution of ezetimibe cannot be improved simply by making the particle size smaller.

<Test Example 2: Confirmation of effects under different manufacturing methods>
(Examples 5-7)
First, it was dry pulverized by a jet mill (Example 5: treated twice in a nitrogen atmosphere, Example 6: treated once in a nitrogen atmosphere, Example 7: treated once in the atmosphere), and the particle sizes shown in Table 7 below. Ezetimibe particles with (d10, d50, d90) were prepared.

Then, the micronized ezetimibe particles of each example, D-mannitol, and croscarmellose sodium are charged into a fluidized bed granulator (“MP-01” (device name), manufactured by Powrex), and polyvinyl alcohol and sodium lauryl sulfate are added. was dissolved in 120 g of purified water (granulation liquid) to granulate and dried to obtain granules. Microcrystalline cellulose, croscarmellose sodium and magnesium stearate were added to the obtained granules and mixed to obtain a mixed powder. The resulting mixed powder was compressed into tablets weighing 100 mg using a rotary tableting machine (“VIRGO” (apparatus name), manufactured by Kikusui Seisakusho) to obtain uncoated tablets.

Each component was added so that the composition of each component in the uncoated tablet would be the composition (% by weight) shown in Table 8 below.

In addition, the particle size of ezetimibe in each example was measured in the same manner as in Example 1.

The obtained ezetimibe-containing uncoated tablet of each example was subjected to a dissolution test in the same manner as in Example 1. The results are shown in Table 9 below.

From the results in Table 9, even with different production methods (different pulverization methods and no active ingredient in the granulation liquid), ezetimibe particles with a d90 of 8.0 μm or less and a formulation containing a high content of sugar alcohol , it was confirmed that the dissolution was remarkably improved.

From the above, it was shown that the ezetimibe-containing oral preparation of the present invention is more excellent in dissolution than conventional ones.

Claims (7)

An ezetimibe-containing oral formulation comprising ezetimibe particles having a d90 of 8.0 μm or less. 2. The ezetimibe-containing oral preparation according to claim 1, further comprising 50.0% by weight or more of a sugar alcohol relative to the total weight of the preparation. 3. The ezetimibe-containing oral dosage form according to claim 2, wherein said sugar alcohol is D-mannitol. The ezetimibe-containing oral preparation according to any one of claims 1 to 3, further comprising at least one of polyvinyl alcohol and povidone as a binder. A method for producing an ezetimibe-containing oral preparation, comprising the step of pulverizing ezetimibe particles to a d90 of 8.0 μm or less. 6. The method for producing an ezetimibe-containing oral preparation according to claim 5, further comprising the step of mixing the pulverized ezetimibe particles with a sugar alcohol in an amount of 50.0% by weight or more based on the total weight of the preparation. . The method for producing an ezetimibe-containing oral preparation according to claim 5 or 6, wherein in the pulverization step, the pulverization method is dry pulverization or wet pulverization.