JP7660352B2 - Tablets containing atorvastatin calcium hydrate and ezetimibe - Google Patents

Description

The present invention relates to a tablet containing atorvastatin calcium hydrate and ezetimibe, which exhibits good dissolution properties of atorvastatin.

Atorvastatin calcium hydrate has the chemical name: Monocalcium bis{(3R,5R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate} trihydrate, and ezetimibe has the chemical name: (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4- It is known that a combination tablet containing atorvastatin calcium hydrate and ezetimibe as active ingredients is a therapeutic agent for hypercholesterolemia and familial hypercholesterolemia, and further, it is described that the combination tablet contains precipitated calcium carbonate (Non-Patent Document 1).

However, the average particle size of the precipitated calcium carbonate is not described.

Package insert "Atozet (registered trademark) Combination Tablets LD/HD", revised in March 2019 (5th edition)

An object of the present invention is to provide a tablet comprising atorvastatin calcium hydrate and ezetimibe which exhibits good dissolution properties.

The present invention relates to a tablet containing atorvastatin calcium hydrate, ezetimibe, and calcium carbonate having a mean particle size of 10 μm or more.

That is, the present invention provides
(1) A tablet comprising atorvastatin calcium hydrate, ezetimibe, and calcium carbonate having an average particle size of 10 μm or more;
(2) The tablet according to (1), wherein the calcium carbonate having an average particle size of 10 μm or more has an average particle size of 20 μm or less.
(3) The tablet according to any one of (1) to (2) above, which contains at least atorvastatin calcium hydrate and granules of calcium carbonate having an average particle size of 10 μm or more.
(4) The tablet according to any one of (1) to (3), comprising a layer containing atorvastatin calcium hydrate and a layer containing ezetimibe.
(5) The tablet according to any one of (1) to (4) above, which contains 100 to 300% by weight of calcium carbonate having an average particle size of 10 μm or more, based on 100% by weight of atorvastatin calcium hydrate.

According to the present invention, it is possible to provide a tablet containing atorvastatin calcium hydrate and ezetimibe, which contains calcium carbonate and thereby exhibits a rapid dissolution behavior of atorvastatin.

The tablet containing atorvastatin calcium hydrate and ezetimibe of the present invention will be described below.

The atorvastatin calcium hydrate used in the present invention is used for the treatment of hypercholesterolemia and familial hypercholesterolemia. In the case of treating hypercholesterolemia, adults are usually orally administered 10 mg of atorvastatin once a day. The dosage may be increased or decreased depending on age and symptoms, but in severe cases, the dosage may be increased up to 20 mg per day. In the case of treating familial hypercholesterolemia, adults are usually orally administered 10 mg of atorvastatin once a day. The dosage may be increased or decreased depending on age and symptoms, but in severe cases, the dosage may be increased up to 40 mg per day.

Ezetimibe used in the present invention is used to treat hypercholesterolemia, familial hypercholesterolemia, and homozygous sitosterolemia. Usually, 10 mg of ezetimibe is orally administered to adults once a day after a meal. The dosage may be appropriately reduced depending on age and symptoms.

The atorvastatin calcium hydrate and ezetimibe used in the present invention can be separated when producing tablets. Specifically, a bilayer tablet can be formed by dividing the tablet into a layer containing atorvastatin calcium hydrate and a layer containing ezetimibe.

The calcium carbonate used in the present invention is pharma- ceutical acceptable and includes calcium carbonate having a particle size of 10 μm or more. Specific examples of the calcium carbonate include precipitated calcium carbonate (precipitated calcium carbonate B, Bihokufunka Kogyo Co., Ltd.) and precipitated calcium carbonate (precipitated calcium carbonate, Merck Co., Ltd.).

The term "average particle size" as used herein refers to the volume-based average particle size measured by a laser diffraction method. In principle, it refers to the particle size at the time when particles of a certain volume are sieved in ascending order of size and the particles that make up 50% of the volume are separated.

The method for adjusting the average particle size of calcium carbonate is not particularly limited and can be appropriately selected depending on the purpose. For example, a method using a jet mill, a method using a pin mill, a method using a feather mill, a method using a ball mill, a method using a hammer mill, a method using a mortar, etc. can be mentioned.

The average particle size of calcium carbonate used in the present invention is, in one embodiment, 10 μm or more, and in another embodiment, 10 μm to 20 μm (10 μm or more and 20 μm or less).

The content of calcium carbonate is 100 to 300% by weight in one embodiment, and 200 to 250% by weight in another embodiment, when atorvastatin calcium hydrate is taken as 100% by weight.

In the tablet containing atorvastatin calcium hydrate and ezetimibe of the present invention, various pharmaceutical additives are appropriately used to prepare the tablet within the range in which the desired effect of the invention is achieved. Such pharmaceutical additives are not particularly limited as long as they are pharmaceutical and pharmacologically acceptable. For example, excipients, binders, disintegrants, acidulants, effervescent agents, sweeteners, flavorings, colorants, buffers, antioxidants, surfactants, lubricants, coating agents, etc. may be used.

Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, crystalline cellulose, low-substituted hydroxypropylcellulose, carmellose sodium, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate.

Examples of binders include gum arabic, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, and the like.

Examples of disintegrants include corn starch, potato starch, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone.

Examples of acidulants include citric acid, tartaric acid, malic acid, etc.

The foaming agent may, for example, be sodium bicarbonate.

Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin.

Examples of the flavoring include lemon, lemon lime, orange, menthol, and the like.

Examples of coloring agents include Food Yellow No. 4, Food Yellow No. 5, Food Red No. 3, Food Red No. 102, Food Blue No. 3, and the like.

Examples of the buffer include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or a salt thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or a salt thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or a salt thereof, and the like.

Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, and propyl gallate.

Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

Examples of lubricants include magnesium stearate, sodium stearyl fumarate, stearic acid, sodium stearate, calcium stearate, hardened oil, and sucrose fatty acid esters.

Examples of coating agents include hypromellose, hydroxypropyl cellulose, methyl cellulose, polyethylene glycol, and the like.

These pharmaceutical additives can be added in appropriate amounts, either alone or in combination of two or more.

With regard to the blending ratio, any pharmaceutical additive is used in an amount within a range in which the desired effects of the present invention are achieved.

The tablet in the present invention may be a plain tablet, a coated tablet, or an orally disintegrating tablet. It may also be a multi-layer tablet such as a two-layer tablet or a three-layer tablet, or a single-layer tablet consisting of a single layer.

The tablet of the present invention can be manufactured by a normal tablet manufacturing method, and in some embodiments, it can be manufactured into a bilayer tablet. More specifically, the atorvastatin calcium hydrate and ezetimibe-containing tablet of the present invention is, for example, prepared by putting atorvastatin calcium hydrate, lactose hydrate, crystalline cellulose, croscarmellose sodium, and calcium carbonate into a stirring granulator and stirring, and then spraying a binder solution in which hydroxypropyl cellulose and polysorbate 80 are dissolved in purified water, and granulating. After granulation, the mixture is sieved through a sieve, dried using a fluidized bed granulation dryer, and sieved again. Croscarmellose sodium is added to the obtained sieved product and mixed, and magnesium stearate is added and mixed to obtain a tableting powder containing atorvastatin calcium hydrate. Also, ezetimibe, a disintegrant (e.g., croscarmellose sodium), and a surfactant (e.g., sodium lauryl sulfate) are put into an agitation granulator and agitated, and a binder solution obtained by dissolving a binder (e.g., povidone) in purified water is dropped and granulated. After completion of granulation, the mixture is sieved through a sieve, dried using a fluidized bed granulation dryer, and sized again using a sieve. To the resulting sized product, an excipient (e.g., crystalline cellulose) and a disintegrant (e.g., crospovidone) are added and mixed, and then a lubricant (e.g., magnesium stearate) is added and mixed to obtain a tableting powder containing ezetimibe. Next, the tableting powder containing atorvastatin calcium hydrate and the tableting powder containing ezetimibe are tableted using a single-shot tableting machine to obtain atorvastatin calcium hydrate and ezetimibe-containing plain tablets. Furthermore, a film-coated tablet containing ezetimibe and atorvastatin calcium hydrate can be obtained by spraying a film-coating liquid containing hypromellose, polyethylene glycol, etc. onto the atorvastatin calcium hydrate and ezetimibe-containing uncoated tablet.

Coated tablets are produced by applying a coating layer to a plain tablet.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples in any way.

(Atorvastatin section)
43.4 g of atorvastatin calcium hydrate, 161 g of lactose hydrate (Pharmatose 200M DFE), 60 g of crystalline cellulose (PH-101 Asahi Kasei), 12 g of croscarmellose sodium (Kiccolate ND-2HS Asahi Kasei), and 100 g of calcium carbonate (precipitated calcium carbonate (≦0.002% Fe) Merck) were charged into a stirring granulator and stirred, and then a binder solution in which 8 g of hydroxypropylcellulose (HPC-SL Nippon Soda) and 1.6 g of polysorbate 80 (Polysorbate 80 Sanyo Chemical Industries) were dissolved in 120 g of purified water was sprayed and granulated. After completion of granulation, the mixture was sieved through a sieve with a mesh size of 1.0 mm, dried using a fluidized bed granulation dryer, and sized again using a sieve with a mesh size of 0.5 mm. 12 g of croscarmellose sodium (Kiccolate ND-2HS, Asahi Kasei) was added to the resulting sized product and mixed, and then 2 g of magnesium stearate (magnesium stearate (vegetable), Taihei Chemical Industry) was added and mixed to obtain a powder for tableting.
(Ezetimibe part)
5 kg of ezetimibe, 72 kg of excipient (lactose hydrate), 4 kg of disintegrant (croscarmellose sodium) (Kiccolate ND-2HS, Asahi Kasei), and 1 kg of surfactant (sodium lauryl sulfate) (SLS-P, Nikko Chemicals) are charged into a stirring granulator and stirred, and then a binder solution obtained by dissolving 3 kg of binder (povidone) (Plasdone K-29/32, Ashland) in 12 kg of purified water is dropped and granulated. After completion of granulation, the mixture is sized using a screen with an opening of 3.175 mm, dried using a fluidized bed granulation dryer, and subsequently sized using a screen with an opening of 1.575 mm. The above process is repeated for two batches, and the mixture is used as a sized product. To the obtained sized product, 25 kg of excipient (crystalline cellulose) (KG-1000, Asahi Kasei) and 4 kg of disintegrant (crospovidone) (CL-SF, BASF) were added and mixed, and then 1 kg of lubricant (magnesium stearate) (magnesium stearate (vegetable), Taihei Chemical Industry) was added and mixed to obtain a powder for tableting.
(Atorvastatin part + Ezetimibe part)
A bilayer tablet was obtained using a single punch tablet press (CRUX, manufactured by Kikusui Seisakusho) with tablet powder containing atorvastatin calcium hydrate and tablet powder containing ezetimibe, with a total mass of 400 mg, with 200 mg of atorvastatin and 200 mg of ezetimibe per tablet. After dissolving 72.8 g of hypromellose (TC-5R, Shin-Etsu Chemical Co., Ltd.) and 14.4 g of propylene glycol (JP Propylene Glycol, ADEKA) in 920 g of purified water, 15 mg of each tablet was coated with a film coating machine while spraying a dispersion of 21.6 g of titanium oxide (NA-61, Toho Titanium Co., Ltd.) and 11.2 g of talc (Crown Talc, Matsumura Sangyo Co., Ltd.) to obtain a film-coated tablet (weight per tablet: 415 mg).

(Atorvastatin section)
43.4 g of atorvastatin calcium hydrate, 161 g of lactose hydrate (Pharmatose 200M DFE), 60 g of crystalline cellulose (PH-101 Asahi Kasei), 12 g of croscarmellose sodium (Kiccolate ND-2HS Asahi Kasei), and 100 g of calcium carbonate (precipitated calcium carbonate (≦0.0001% Al) Merck) were charged into a stirring granulator and stirred, and then a binder solution in which 8 g of hydroxypropylcellulose (HPC-SL Nippon Soda) and 1.6 g of polysorbate 80 (Polysorbate 80 Sanyo Chemical Industries) were dissolved in 120 g of purified water was sprayed and granulated. After completion of granulation, the mixture was sieved through a sieve with a mesh size of 1.0 mm, dried using a fluidized bed granulation dryer, and sized again using a sieve with a mesh size of 0.5 mm. 12 g of croscarmellose sodium (Kiccolate ND-2HS, Asahi Kasei) was added to the resulting sized product and mixed, and then 2 g of magnesium stearate (magnesium stearate (vegetable), Taihei Chemical Industry) was added and mixed to obtain a powder for tableting.
(Ezetimibe part)
5 kg of ezetimibe, 72 kg of excipient (lactose hydrate), 4 kg of disintegrant (croscarmellose sodium) (Kiccolate ND-2HS Asahi Kasei), and 1 kg of surfactant (sodium lauryl sulfate) are charged into an agitation granulator and agitated, and then a binder solution obtained by dissolving 3 kg of binder (povidone) (Plasdone K-29/32 Ashland) in 12 kg of purified water is dropped and granulated. After completion of granulation, the mixture is sized using a screen with an opening of 3.175 mm, dried using a fluidized bed granulation dryer, and subsequently sized using a screen with an opening of 1.575 mm. The above process is repeated for two batches, and the mixture is used as a sized product. To the obtained sized product, 25 kg of excipient (crystalline cellulose) (KG-1000, Asahi Kasei) and 4 kg of disintegrant (crospovidone) (CL-SF, BASF) were added and mixed, and then 1 kg of lubricant (magnesium stearate) (magnesium stearate (vegetable), Taihei Chemical Industry) was added and mixed to obtain a powder for tableting.
(Atorvastatin part + Ezetimibe part)
A bilayer tablet was obtained using a single punch tablet press (CRUX, Kikusui Seisakusho) with tablet powder containing atorvastatin calcium hydrate and tablet powder containing ezetimibe, with a total mass of 400 mg, with 200 mg of atorvastatin and 200 mg of ezetimibe per tablet. After dissolving 72.8 g of hypromellose (TC-5R, Shin-Etsu Chemical Co., Ltd.) and 14.4 g of propylene glycol (JP Propylene Glycol, ADEKA) in 920 g of purified water, 15 mg of each tablet was coated with a film coating machine while spraying a dispersion of 21.6 g of titanium oxide (NA-61, Toho Titanium Co., Ltd.) and 11.2 g of talc (Crown Talc, Matsumura Sangyo Co., Ltd.) to obtain a film-coated tablet (weight per tablet: 415 mg).

Comparative Example 1
(Atorvastatin section)
43.4g of atorvastatin calcium hydrate, 61g of lactose hydrate (Pharmatose 200M DFE), 160g of crystalline cellulose (PH-101 Asahi Kasei), 12g of croscarmellose sodium (Kiccolate ND-2HS Asahi Kasei), and 100g of calcium carbonate (precipitated calcium carbonate A Bihoku Funka Kogyo) were charged into an agitation granulator and agitated, and then a binder solution in which 8g of hydroxypropylcellulose (HPC-SL Nippon Soda) and 1.6g of polysorbate 80 (Polysorbate 80 Sanyo Chemical Industries) were dissolved in 120g of purified water was sprayed and granulated. After completion of granulation, the mixture was sieved through a sieve with a mesh size of 1.0 mm, dried using a fluidized bed granulation dryer, and sized again using a sieve with a mesh size of 0.5 mm. 12 g of croscarmellose sodium (Kiccolate ND-2HS, Asahi Kasei) was added to the resulting sized product and mixed, and then 2 g of magnesium stearate (magnesium stearate (vegetable), Taihei Chemical Industry) was added and mixed to obtain a powder for tableting.
(Ezetimibe part)
5 kg of ezetimibe, 72 kg of excipient (lactose hydrate), 4 kg of disintegrant (croscarmellose sodium) (Kiccolate ND-2HS Asahi Kasei), and 1 kg of surfactant (sodium lauryl sulfate) are charged into an agitation granulator and agitated, and then a binder solution obtained by dissolving 3 kg of binder (povidone) (Plasdone K-29/32 Ashland) in 12 kg of purified water is dropped and granulated. After completion of granulation, the mixture is sized using a screen with an opening of 3.175 mm, dried using a fluidized bed granulation dryer, and subsequently sized using a screen with an opening of 1.575 mm. The above process is repeated for two batches, and the mixture is used as a sized product. To the obtained sized product, 25 kg of excipient (crystalline cellulose) (KG-1000, Asahi Kasei) and 4 kg of disintegrant (crospovidone) (CL-SF, BASF) were added and mixed, and then 1 kg of lubricant (magnesium stearate) (magnesium stearate (vegetable), Taihei Chemical Industry) was added and mixed to obtain a powder for tableting.
(Atorvastatin part + Ezetimibe part)
A bilayer tablet was obtained using a single punch tablet press (CRUX, manufactured by Kikusui Seisakusho) with tablet powder containing atorvastatin calcium hydrate and tablet powder containing ezetimibe, with a total mass of 400 mg, with 200 mg of atorvastatin and 200 mg of ezetimibe per tablet. After dissolving 72.8 g of hypromellose (TC-5R, Shin-Etsu Chemical Co., Ltd.) and 14.4 g of propylene glycol (JP Propylene Glycol, ADEKA) in 920 g of purified water, 15 mg of each tablet was coated with a film coating machine while spraying a dispersion of 21.6 g of titanium oxide (NA-61, Toho Titanium) and 11.2 g of talc (Crown Talc, Matsumura Sangyo Co., Ltd.) to obtain a film-coated tablet (weight per tablet: 415 mg).

The average particle sizes of calcium carbonate in Examples 1 and 2 and Comparative Example 1 are shown in Table 1.

The formulation amounts of the tablets obtained in Examples 1 and 2 and Comparative Example 1 are shown in Table 2.

Test Example 1: Dissolution test (atorvastatin)
The dissolution properties of atorvastatin from the reference formulation (ATOSET (registered trademark) combination tablet HD), the tablets obtained in Example 1, Example 2, and Comparative Example 1 were evaluated by a dissolution test (pH 6.8, 900 mL, 37°C, basket method, rotation speed 100 rpm, n=6). The results are shown in Table 3.

As a result, the tablets of Examples 1 and 2 showed better dissolution properties than those of Comparative Example 1 and the reference formulation.

Test Example 2: Dissolution test (ezetimibe)
The dissolution properties of ezetimibe from the reference formulation (ATOSET (registered trademark) combination tablet HD) and the tablets obtained in Example 1 and Example 2 were evaluated by a dissolution test (pH 1.2 (polysorbate 80 0.1%) 900 mL, 37°C, paddle method, rotation speed 50 rpm, n=6). The results are shown in Table 4.

As a result, the tablets of Examples 1 and 2 showed better dissolution properties than the reference formulation.

Claims (1)

A film-coated tablet comprising a layer containing atorvastatin calcium hydrate and a layer containing ezetimibe,
A film-coated tablet, wherein the layer containing atorvastatin calcium hydrate comprises granules containing atorvastatin calcium hydrate and calcium carbonate having an average particle size of 10 μm or more and less than 20 μm in an amount of 200 to 250% by weight relative to 100% by weight of atorvastatin calcium hydrate.