Tablet comprising atorvastatin and ezetimibe

Abstract

Disclosed herein are a bilayer tablet, a pharmaceutical composition of the same, and a method of preparing the same. The bilayer tablet comprises: a first layer comprising atorvastatin or a salt thereof, a binder, and a disintegrant; and a second layer comprising ezetimibe or a salt thereof and microcrystalline cellulose.

Description

Tablets containing atorvastatin and ezetimibe

[0001] The present invention relates to a bilayer tablet comprising atorvastatin and ezetimibe, a composition of each layer for the tablet, and a method for preparing the same.

[0002]

[0003] Atorvastatin or a pharmaceutically acceptable salt thereof is a selective and competitive HMG-CoA reductase inhibitor, among which atorvastatin calcium (chemical name: [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-hydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)) of the following chemical formula 1 has been used to treat hyperlipidemia:

[0004] [Formula 1]

[0005]

[0006] Ezetimibe is known as a lipid-lowering compound that selectively inhibits the intestinal absorption of cholesterol and related phytosterols.

[0007] The superiority of the pharmacological effect of atorvastatin when administered in combination with ezetimibe has been proven in many studies (Non-patent literature 1), and the combined tablet is marketed as a cholesterol-lowering drug, such as a treatment for primary hypercholesterolemia and homozygous familial hypercholesterolemia, in the form of a double-layer tablet under the trade names Atozet or Liptruzet.

[0008] Since combination tablets must contain two active ingredients, the tablet size inevitably becomes larger. In this case, not only patients who have difficulty swallowing but also normal adult patients may experience resistance or pressure due to the size, which may reduce compliance. The tablets of the above Atozet or Liptruzet were large, which caused problems such as resistance to medication or reduced compliance when taking them.

[0009] In terms of tablets, reducing the size can be considered by increasing the compression pressure during tablet manufacturing or reducing the content of excipients. However, it is not easy to achieve this in practice because, depending on the type of excipient, the release rate characteristics required for tablets may be lowered or the friability required for tablet compression may be lowered.

[0010] In addition, in two-layer tableting, layer separation may occur between each layer, which may result in reduced productivity or tableting failure.

[0011]

[0012] [Patent Document]

[0013] International Publication No. WO2018 / 146302

[0014] [Non-patent literature]

[0015] Transl Clin Pharmacol Vol. 25, no. 4, Dec 15, 2017, 202-208

[0016]

[0017] Accordingly, one object of the present invention is to provide a bilayer tablet that reduces the size of the tablet by reducing the major axis diameter by 10% or more, specifically by 15% or more, and the weight of the tablet by 20% or more compared to a conventional bilayer tablet containing atorvastatin and ezetimibe, thereby improving the convenience of taking the tablet and the compliance with taking the medication by the patient.

[0018] In addition, the present invention aims to provide a two-layer tablet that improves the layer separation phenomenon in the two-layer tablet, thereby improving the decrease in productivity and tableting difficulties caused by the same.

[0019] One aspect of the present invention is,

[0020] A first layer comprising atorvastatin or a salt thereof, a binder and a disintegrant; and

[0021] A bilayer tablet comprising a second layer comprising ezetimibe or a salt thereof and microcrystalline cellulose,

[0022] In the first layer, the weight ratio of the binder and the disintegrant is in the range of 1:4 to 1:6 based on the total weight of the first layer,

[0023] The present invention relates to a two-layer tablet, wherein the microcrystalline cellulose is present in the second layer at 10 to 20 wt% based on the total weight of the second layer.

[0024] The salt of atorvastatin may include a sodium salt, a calcium salt, a strontium salt, a hydrochloride salt, a magnesium salt, a phosphate salt, a tartrate salt, a potassium salt, an oxalate salt, or a succinate salt, and may be specifically a calcium salt, more specifically atorvastatin calcium trihydrate.

[0025] The atorvastatin or its salt may be present in an amount of 10 wt% to 20 wt%, specifically 10 wt% to 15 wt%, based on the total weight of the first layer. In one example, the atorvastatin or its salt may be present in an amount of 10 mg, 20 mg, 40 mg, or 80 mg per tablet based on the atorvastatin content.

[0026] The binder may be selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, ethyl cellulose, povidone, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, gelatin, starch, pregelatinized starch, and mixtures thereof, and specifically, hydroxypropylcellulose, hydroxyethylcellulose, and hydroxymethylcellulose may be mentioned. The binder may be present in an amount ranging from 0.5 wt% to 6 wt%, specifically, from 1 wt% to 5 wt%, based on the total weight of the first layer.

[0027] The disintegrant may be crospovidone, croscarmellose sodium, sodium carboxymethyl cellulose, colloidal silicon dioxide, alginic acid, sodium alginate, corn starch, microcrystalline cellulose, sodium starch glycolate, or a mixture thereof, and may be specifically croscarmellose sodium or crospovidone. The disintegrant may be present in an amount of 2 wt% to 36 wt%, specifically 4 wt% to 30 wt%, and more specifically 8 wt% to 15 wt%, based on the total weight of the first layer.

[0028] The weight ratio of the above binder and the above disintegrant is in the range of about 1:4 to about 1:6, and within this range, the dissolution rate is good, and further, the friability required for tableting can be provided.

[0029] The above dissolution rate is tested according to the dissolution test method among the general test methods of the Korean Pharmacopoeia, but can be tested using the second method, the paddle method. When a double-layer tablet is dissolved for 15 minutes under the conditions of pH 6.8 + 0.3% PSB 900 mL, 50 rpm, and 37℃, the dissolution rate of atorvastatin is 65% or more, and after 30 minutes, the dissolution rate can be 80% or more, specifically 85% or more.

[0030] The first layer may additionally comprise a pharmaceutically acceptable excipient.

[0031] Examples of the above excipients may be fillers, lubricants, solubilizers, stabilizers or mixtures thereof.

[0032] Examples of the filler include microcrystalline cellulose, lactose hydrate, starch, sucrose, glucose, dextrose, natural and synthetic gums, or gelatin, and specifically, microcrystalline cellulose and lactose hydrate. The filler may be present in an amount of 30 wt% to 65 wt%, specifically, 40 wt% to 50 wt%, and more specifically, 41 wt% to 48 wt%, based on the total weight of the first layer. In one example, the filler may be lactose hydrate and microcrystalline cellulose, and adding a high ratio of lactose hydrate relative to microcrystalline cellulose is more advantageous in securing a desirable dissolution rate. In one example, the lactose hydrate may be present in an amount of 20 wt% to 50 wt%, specifically, 30 wt% to 45 wt%, and more specifically, 35 wt% to 40 wt%, based on the total weight of the first layer. In one example, the microcrystalline cellulose may be present in an amount ranging from 2 wt% to 20 wt%, specifically from 3 wt% to 18 wt%, and more specifically from 3.5 wt% to 7.5 wt%, based on the total weight of the first layer.

[0033] Examples of the above-mentioned lubricant include magnesium stearate, sodium stearyl fumarate, colloidal silica anhydride, talc, polyethylene glycol, stearic acid, aluminum silicate, or mixtures thereof, and specifically, magnesium stearate or sodium stearyl fumarate can be used. The above-mentioned lubricant can be present in a range of 0.05 wt% to 5 wt%, specifically, in a range of 0.1 wt% to 2 wt%, based on the total weight of the first layer.

[0034] Examples of the solubilizing agent include sodium lauryl sulfate, polysorbate (e.g., polysorbate 80), polyethylene oxide, polypropylene oxide, etc., and specifically, polysorbate can be used. The solubilizing agent can be in the range of 0.05 wt% to 2 wt% based on the total weight of the first layer.

[0035] Examples of the above stabilizer include calcium carbonate, calcium sulfate, calcium acetate, magnesium carbonate, magnesium sulfate, magnesium acetate, calcium hydroxide, magnesium hydroxide, etc., and specifically, precipitated calcium carbonate or magnesium carbonate may be mentioned. The stabilizer may be present in an amount ranging from 15 wt% to 40 wt%, specifically, from 20 wt% to 35 wt%, based on the total weight of the first layer.

[0036] The total weight of the first layer may vary depending on the content of atorvastatin per tablet, and may range from 70 mg to 700 mg per tablet. In the present invention, the weight of the atorvastatin layer per tablet can be significantly reduced by adjusting the content ratio of the binder and disintegrant as described above.

[0037] The second layer comprises ezetimibe and microcrystalline cellulose. The microcrystalline cellulose is present in an amount of 10 to 20 wt% based on the total weight of the second layer. Including the microcrystalline cellulose in the above range is advantageous in terms of reducing the size of the tablet, preventing layer separation in a two-layer tablet, and ensuring content uniformity.

[0038] The above ezetimibe may be present in a range of 4 wt% to 10 wt%, specifically 5 wt% to 9 wt%, based on the total weight of the second layer.

[0039] The second layer may additionally comprise pharmaceutically acceptable excipients. Examples of the excipients include disintegrants, binders, fillers, glidants, solubilizers, or mixtures thereof.

[0040] The binder may be selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, gelatin, povidone, starch, pregelatinized starch and mixtures thereof, and specifically, povidone or hydroxypropylcellulose may be mentioned. The binder may be present in an amount ranging from 0.5 wt% to 6 wt%, specifically, from 1 wt% to 5 wt%, based on the total weight of the second layer.

[0041] The disintegrant may be crospovidone, croscarmellose sodium, sodium carboxymethyl cellulose, colloidal silicon dioxide, alginic acid, sodium alginate, corn starch, microcrystalline cellulose, sodium starch glycolate, or a mixture thereof, and may be specifically croscarmellose sodium or crospovidone. The disintegrant may be present in an amount ranging from 2 wt% to 10 wt%, specifically from 4 wt% to 8 wt%, based on the total weight of the second layer.

[0042] Examples of the filler include, in addition to the microcrystalline cellulose, lactose hydrate, starch, sucrose, glucose, dextrose, natural and synthetic gums, or gelatin, and specifically, lactose hydrate. The filler, excluding microcrystalline cellulose, may be present in an amount of 50 wt% to 80 wt%, specifically, 55 wt% to 75 wt%, and more specifically, 60 wt% to 70 wt%, based on the total weight of the second layer. In one example, the filler may be lactose hydrate, and in this case, the lactose hydrate may be present in an amount of 55 wt% to 75 wt%, specifically, 60 wt% to 70 wt%, based on the total weight of the second layer. The above range is more advantageous in securing a desirable dissolution rate.

[0043] Examples of the above-mentioned lubricant include magnesium stearate, sodium stearyl fumarate, colloidal silica anhydride, talc, polyethylene glycol, stearic acid, aluminum silicate, or mixtures thereof, and specifically, magnesium stearate or sodium stearyl fumarate can be used. The above-mentioned lubricant can be in the range of 0.05 wt% to 5 wt%, specifically, in the range of 0.1 wt% to 2 wt%, based on the total weight of the second layer.

[0044] Examples of the solubilizing agent include sodium lauryl sulfate, polysorbate (e.g., polysorbate 80), polyethylene oxide, polypropylene oxide, etc., and specifically, polysorbate can be used. The solubilizing agent can be in the range of 0.5 wt% to 5 wt%.

[0045] The total weight of the second layer may be 120 mg to 160 mg per tablet.

[0046] The first layer and the second layer may be compressed together to form a bilayer tablet. In addition, the bilayer tablet may be further coated with a coating agent. Examples of the coating agent include lactose, hydroxypropyl methyl cellulose, polyethylene glycol, triacetin, titanium dioxide, titanium oxide, polyvinyl alcohol, talc, polyvinylpyrrolidone, lecithin, polyethylene glycol, and the like. The coating agent may be present in an amount ranging from 0.05 wt% to 8 wt%, specifically, from 0.1 wt% to 5 wt%, based on the total weight of the bilayer tablet.

[0047] The total weight of the bilayer tablet of the present invention may be from 200 mg to 830 mg per tablet. For example, the weight of the bilayer tablet containing 10 mg of atorvastatin / 10 mg of ezetimibe may be from about 210 mg to about 240 mg; the weight of the bilayer tablet containing 20 mg of atorvastatin / 10 mg of ezetimibe may be from about 290 mg to about 325 mg; the weight of the bilayer tablet containing 40 mg of atorvastatin / 10 mg of ezetimibe may be from about 460 mg to about 490 mg; and the weight of the bilayer tablet containing 80 mg of atorvastatin / 10 mg of ezetimibe may be from about 800 mg to about 830 mg. The weight of the bilayer tablet is effectively reduced by at least 20% compared to the weight of the corresponding tablet of the commercially available Atozet bilayer tablet.

[0048] The major axis diameter of the bilayer tablet of the present invention may be 16 mm or less. For example, the major axis diameter of the bilayer tablet containing 10 mg of atorvastatin / 10 mg of ezetimibe may be 9 mm to 11 mm; the major axis diameter of the bilayer tablet containing 20 mg of atorvastatin / 10 mg of ezetimibe may be 11 mm to 13 mm; the major axis diameter of the bilayer tablet containing 40 mg of atorvastatin / 10 mg of ezetimibe may be 13 mm to 14 mm; and the major axis diameter of the bilayer tablet containing 80 mg of atorvastatin / 10 mg of ezetimibe may be 15 mm to 16 mm. The major axis diameter of the bilayer tablet has the effect of being reduced by 10% or more, specifically, 15% or more, compared to the major axis diameter of the corresponding commercially available Atozet bilayer tablet.

[0049] The two-layer tablet of this invention has a dissolution rate of atorvastatin of 65% or more when dissolved for 15 minutes under the conditions of pH 6.8 + 0.3% PSB 900 mL, 50 rpm, and 37℃ according to the dissolution test method among the general test methods of the Korean Pharmacopoeia, and after 30 minutes, the dissolution rate can be 80% or more, specifically 85% or more.

[0050]

[0051] In one specific embodiment of the above aspect, a two-layer tablet having the following composition may be provided:

[0052] 1st floor:

[0053] Based on the total weight of the first layer, atorvastatin calcium trihydrate comprises 10 wt% to 20 wt%; a weight ratio of a binder and a disintegrant is 1:4 to 1:6, and the combined content of the binder and the disintegrant is 10 wt% to 30 wt%; a filler comprising lactose hydrate and microcrystalline cellulose, wherein the lactose hydrate is in the range of 20 wt% to 50 wt% and the microcrystalline cellulose is in the range of 2 wt% to 20 wt%, and the filler content is 30 wt% to 50 wt%; a lubricant is 0.05 wt% to 5 wt%; a stabilizer is 15 wt% to 40 wt%; and a solubilizer is 0.05 wt% to 2 wt%.

[0054] 2nd floor:

[0055] Based on the total weight of the second layer, 4 to 10 wt% of ezetimibe; 10 to 20 wt% of microcrystalline cellulose; 0.5 to 6 wt% of a binder; 2 to 10 wt% of a disintegrant; 50 to 80 wt% of a filler excluding the microcrystalline cellulose, wherein the filler comprises lactose hydrate and the lactose hydrate is in the range of 55 to 75 wt%; 0.05 to 5 wt% of a lubricant; and 0.5 to 5 wt% of a solubilizer.

[0056] The two-layer tablet composed of the first layer and the second layer may be additionally coated with a coating agent.

[0057] In another specific embodiment of the above aspect, a two-layer tablet having the following composition may be provided:

[0058] 1st floor:

[0059] Based on the total weight of the first layer, atorvastatin calcium trihydrate is 10 wt% to 20 wt%; the weight ratio of hydroxypropylcellulose and croscarmellose is 1:4 to 1:6, and the combined content thereof is 10 wt% to 30 wt%; the lactose hydrate is 20 wt% to 50 wt%, and the microcrystalline cellulose is 2 wt% to 20 wt%, and the combined content thereof is 30 wt% to 50 wt%; magnesium stearate is 0.05 wt% to 5 wt%; calcium carbonate is 15 wt% to 40 wt%; and polysorbate 80 is 0.05 wt% to 2 wt%.

[0060] 2nd floor:

[0061] Based on the total weight of the second layer, ezetimibe 4 to 10 wt%; microcrystalline cellulose 10 to 20 wt%; povidone 0.5 to 6 wt%; croscarmellose sodium 2 to 10 wt%; lactose monohydrate 55 to 75 wt%; magnesium stearate 0.05 to 5 wt%; and sodium lauryl sulfate 0.5 to 5 wt%.

[0062] The two-layer tablet composed of the first layer and the second layer may be additionally coated with a coating agent.

[0063] Another aspect of the present invention is:

[0064] A first layer composition comprising atorvastatin or a salt thereof, a binder and a disintegrant; and

[0065] A two-layer tablet composition comprising a second-layer composition comprising ezetimibe or a salt thereof and microcrystalline cellulose, wherein the weight ratio of the binder and the disintegrant is in the range of 1:4 to 1:6 based on the total solid weight of the first-layer composition,

[0066] The present invention relates to a two-layer tablet composition comprising microcrystalline cellulose in an amount of 10 wt% to 20 wt% based on the total solid weight of the second layer composition.

[0067] A detailed description of the above aspect is as in the aforementioned aspect.

[0068] Another aspect of the present invention is to form granules for forming a first layer from the first layer composition comprising atorvastatin or a salt thereof, a binder and a disintegrant,

[0069] Forming granules for forming a second layer from the second layer composition comprising ezetimibe or a salt thereof and microcrystalline cellulose,

[0070] The present invention relates to a method for manufacturing a bilayer tablet, which comprises compressing the granules for forming the first layer and the granules for forming the second layer to form a bilayer tablet. The detailed description of the composition and content of the tablet is as described above.

[0071] The above manufacturing method comprises mixing atorvastatin or a salt thereof, which is the active ingredient of the first layer, with pharmaceutically acceptable excipients (including disintegrants and binders) and a solvent to make a granulated composition,

[0072] Preparing granules from the above granulating composition,

[0073] Dry and sieve the above granules,

[0074] A first layer forming granule is prepared by mixing a disintegrant, a lubricant, or both into the above granules,

[0075] The active ingredient of the second layer, ezetimibe, is mixed with pharmaceutically acceptable excipients and solvents to form a granulated composition.

[0076] Preparing granules from the above granulating composition,

[0077] Dry and sieve the above granules,

[0078] A granule for forming a second layer is prepared by mixing microcrystalline cellulose and a lubricant into the above granules,

[0079] It includes manufacturing a two-layer tablet by compressing the granules for forming the first layer and the granules for forming the second layer.

[0080] After manufacturing the above two-layer tablet, it can be additionally coated with a coating agent.

[0081] Solvents that can be used in the manufacture of the above two-layer tablet may be purified water, ethanol, etc.

[0082] The above-mentioned pressing pressure may be 5 kp to 30 kp in hardness, and the hardness may also be appropriately increased as the content of the granules for forming the first layer and the content of the granules for forming the second layer increase.

[0083] The two-layer tablet of the present invention can be used as a cholesterol-lowering agent, such as a treatment agent for primary hypercholesterolemia or homozygous familial hypercholesterolemia.

[0084]

[0085] The bilayer tablet of the present invention can reduce the size of the tablet by reducing the major axis diameter by 10% or more, specifically 15% or more, and the weight of the tablet by 20% or more compared to the conventional bilayer tablet containing atorvastatin and ezetimibe, thereby improving the convenience of taking the tablet and the compliance with taking the medication by the patient.

[0086] In addition, the layer separation phenomenon in the above-mentioned two-layer tablet can be improved to improve the decrease in productivity or tableting difficulties caused by it, and provide suitable content uniformity, suitable dissolution rate, and tablet friability.

[0087]

[0088] Figure 1 is a photograph comparing the size of a two-layer tablet manufactured in one embodiment of the present invention with the size of a commercially available two-layer tablet of Comparative Example 1 (Comparative Example 1-3).

[0089]

[0090] Hereinafter, the present invention will be described in more detail through examples. However, these examples are intended to exemplify the present invention and the scope of the present invention is not limited to these examples.

[0091]

[0092] Example 1: Preparation of a two-layer tablet

[0093] A two-layer tablet was manufactured using the following process with the composition described in Table 1 below:

[0094] 1st floor:

[0095] Atorvastatin calcium trihydrate, microcrystalline cellulose, precipitated calcium carbonate, lactose monohydrate, and croscarmellose sodium were mixed in a kneader to prepare mixture 1. Afterwards, polysorbate 80, hydroxypropyl cellulose, and purified water were added to a beaker and stirred until the above components were completely dissolved to prepare a kneading solution 1. After adding the kneading solution 1 to the mixture 1, wet granulation was performed using a kneading device (High Speed ​​mixer; Diosna mixer, agitator 200 ± 20 rpm, chopper 3500 ± 300 rpm, kneading time 2 minutes ± 30 seconds), and then drying using a dryer (Tray dryer, drying temperature 60°C) until the moisture content became 0.8 to 1.5%, and then using a sieving device (Quadro comil, sieve size 050G) to prepare granules. Thereafter, croscarmellose sodium and magnesium stearate were sequentially added to the above-mentioned manufactured granules and mixed to manufacture granules for forming the first layer.

[0096] 2nd floor:

[0097] Ezetimibe and lactose monohydrate were mixed together, and additional lactose monohydrate and croscarmellose sodium were added and mixed to prepare mixture 1. Povidone, sodium lauryl sulfate, and purified water were placed in a beaker and stirred until the above ingredients were completely dissolved to prepare mixture 1. After adding mixture 1, mixture 1 was wet-granulated using a mixer (High Speed ​​mixer; Diosna mixer, agitator 100 ± 10 rpm, chopper 1750 ± 150 pm, mixing time 1 minute ± 20 seconds), and then dried using a dryer (Tray dryer, drying temperature 50°C) until the moisture content became 0.8 to 1.5%, and then granules were prepared using a sizing machine (Quadro comil, sieve size 040G). Afterwards, microcrystalline cellulose and magnesium stearate were sequentially added to the above-mentioned manufactured granules and mixed to manufacture granules for forming a second layer.

[0098] Double layer tablets:

[0099] The granules for forming the first layer and the granules for forming the second layer were compressed to a hardness of 17 to 25 kp (tableting machine: KORSCH 29 / 35 double-layer tablet machine) to produce double-layer tablets. Opadry white, purified water, and ethanol were sufficiently mixed using a mixer to produce a coating solution, and the double-layer tablets thus manufactured were film-coated with the coating solution to produce coated double-layer tablets. The size of the double-layer tablets thus manufactured was compared with the size of the commercially available double-layer tablets of Comparative Example 1 (Comparative Example 1-3) (see Fig. 1).

[0100] Ingredients Content (mg / 1 tablet) Atorvastatin layer (1st layer) Atorvastatin calcium trihydrate (40 mg as atorvastatin) 43.4 Polysorbate 80 1.2 Hydroxypropyl cellulose 6.8 Lactose hydrate 120.0 Microcrystalline cellulose 20.0 Precipitated calcium carbonate 90.0 Sodium croscarmellose 36.0 Magnesium stearate 2.6 Atorvastatin layer weight 320.0 mg / 1 tablet Ezetimibe layer (2nd layer) Ezetimibe 10.0 Sodium lauryl sulfate 2.4 Povidone 4.8 Lactose hydrate 93.2 Microcrystalline cellulose 20.0 Sodium croscarmellose 8.4 Magnesium stearate 1.2 Ezetimibe layer weight 140.0 mg / 1 tablet Uncoated tablet total weight 460.0 mg / 1 tablet Film coating layer Opadry white (03B28796)18.4 coated tablets, total weight 478.4 mg / 1 tablet

[0101]

[0102] Example 2: Preparation of a two-layer tablet

[0103] In the above Example 1, the content of atorvastatin calcium trihydrate was set to 10 mg as atorvastatin, the compression hardness was set to 6 kp to 15 kp, and the amount of additives mixed in the first layer was reduced to 1 / 4 of the amount in the above Example 1 (i.e., the first layer weight was 80 mg / 1 tablet and the second layer weight was 140.0 mg / 1 tablet, and the total weight of the double-layer uncoated tablet was 220 mg / 1 tablet), except that the coated double-layer tablet of Example 2 was manufactured in the same manner as in Example 1.

[0104] Example 3: Preparation of a two-layer tablet

[0105] In the above Example 1, the content of atorvastatin calcium trihydrate was set to 20 mg as atorvastatin, the compression hardness was set to 8 kp to 20 kp, and the amount of additives mixed in the first layer was reduced to half the amount of the above Example 1 (i.e., the first layer weight was 160 mg / 1 tablet and the second layer weight was 140.0 mg / 1 tablet, and the total weight of the double-layer uncoated tablet was 300 mg / 1 tablet), except that the coated double-layer tablet of Example 3 was manufactured in the same manner as in Example 1.

[0106] Example 4: Preparation of a two-layer tablet

[0107] Except that the content of atorvastatin calcium trihydrate in Example 1 was set to 80 mg as atorvastatin, the compression hardness was set to 24 kp to 30 kp, and the amount of additives in the first layer was doubled compared to that in Example 1 (i.e., the first layer weight was 640 mg / 1 tablet and the second layer weight was 140.0 mg / 1 tablet, and the total weight of the double-layered tablet was 780 mg / 1 tablet), the same procedure as in Example 1 was followed to manufacture a coated double-layer tablet of Example 4.

[0108] Example 5: Preparation of a two-layer tablet

[0109] A two-layer tablet of Example 5 was manufactured in the same manner as Example 1, except that the weights of the binder and disintegrant in the first layer were adjusted as shown in Table 2 below.

[0110] Example 6: Preparation of a two-layer tablet

[0111] A two-layer tablet of Example 6 was manufactured in the same manner as Example 1, except that the weights of the binder and disintegrant in the first layer were adjusted as shown in Table 2 below.

[0112] Hydroxypropylcellulose Crosscarmellose Sodium Weight ratio of hydroxypropylcellulose and croscarmellose sodium Example 16.8mg 36mg 1:5.3 Example 58mg 32mg 1:4 Example 66.8mg 40.8mg 1:6 Comparative Example 28mg 16mg 1:2 Comparative Example 38mg 20mg 1:2.5 Comparative Example 48mg 24mg 1:3 Comparative Example 56.8mg 48mg 1:7.1 Comparative Example 66.8mg 56mg 1:8.2

[0113]

[0114] Example 7: Preparation of a two-layer tablet

[0115] A two-layer tablet of Example 7 was manufactured in the same manner as Example 1, except that the microcrystalline cellulose content in the second layer of Example 1 was changed to 15 mg and the composition of the second layer was as shown in Table 3.

[0116] Example 8: Preparation of a two-layer tablet

[0117] A two-layer tablet of Example 8 was manufactured in the same manner as Example 1, except that the microcrystalline cellulose content of the second layer was changed to 30 mg and the composition of the second layer was as shown in Table 3.

[0118] Comparative Example 1: Commercially available double-layer tablet

[0119] Atojet (manufacturer: MSD) tablets with the following main ingredient contents were used as comparative example 1.

[0120] (Comparative Example 1-1): Atorvastatin 10 mg and ezetimibe 10 mg bilayer tablet;

[0121] (Comparative Example 1-2): Atorvastatin 20 mg and ezetimibe 10 mg bilayer tablet;

[0122] (Comparative Example 1-3): Atorvastatin 40 mg and ezetimibe 10 mg bilayer tablet; and

[0123] (Comparative Example 1-4): Atorvastatin 80 mg and ezetimibe 10 mg bilayer tablet.

[0124] Comparative Examples 2 to 6: Two-layer tablets

[0125] Except that the weight ratio of the binder and the disintegrant in Example 1 was adjusted as shown in Table 2, two-layer tablets of Comparative Examples 2 to 6 were manufactured in the same manner as in Example 1.

[0126] Comparative Example 7: Two-layer tablet

[0127] The same procedure as Example 1 was followed, except that the content of microcrystalline cellulose in the second layer was changed from 20 mg to 0 mg, and the composition of the second layer was changed as shown in Table 3.

[0128] Comparative Example 8: Two-layer tablet

[0129] A two-layer tablet of Comparative Example 8 was manufactured in the same manner as in Example 1, except that the microcrystalline cellulose content of the second layer was changed from 20 mg to 10 mg in Example 1 and the composition of the second layer was changed as shown in Table 3.

[0130] Comparative Example 9: Two-layer tablet

[0131] A two-layer tablet of Comparative Example 9 was manufactured in the same manner as in Example 1, except that the microcrystalline cellulose content of the second layer was changed from 20 mg to 80 mg in the above Example 1 and the composition of the second layer was changed as shown in the following table.

[0132] Raw material name Content (mg / 1 tablet) Comparative Example 7 Comparative Example 8 Example 7 Example 8 Comparative Example 9 Ezetimibe layer (2nd layer) Ezetimibe 10.0 10.0 10.0 10.0 10.0 10.0 Sodium lauryl sulfate 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 Povidone 4.8 4.8 4.8 4.8 4.8 4.8 Lactose monohydrate 9 3.2 3.2 3.2 3.2 Microcrystalline cellulose-10.0 15.0 30.0 8 0.0 Sodium croscarmellose 8.4 8.4 4.8 4.8 4.8 4.8 4.8 4.8 Magnesium stearate 1.2 ...

[0133]

[0134] Experimental Example 1: Comparison of the size and content of two-layer tablets

[0135] The major axis diameter, minor axis diameter, and thickness of the two-layer tablets of Examples 1 to 4 and Comparative Example 1 were measured using a vernier caliper (manufactured by Mitutoyo), and the contents were also measured, and the results are shown in Table 4 below.

[0136] Comparative Example 1 ResultsExamples 1 to 4 ResultsComparative Example 1-1 Long axis diameter: 13 mm Short axis diameter: 5 mm Thickness: 4 mm Content: 309.4 mgExample 2 Long axis diameter: 10 mm Short axis diameter: 5.2 mm Thickness: 4 mm Content: 228.8 mgComparative Example 1-2 Long axis diameter: 15 mm Short axis diameter: 6 mm Thickness: 5 mm Content: 414.7 mgExample 3 Long axis diameter: 12 mm Short axis diameter: 5.9 mm Thickness: 4.1 mm Content: 312 mgComparative Example 1-3 Long axis diameter: 17 mm Short axis diameter: 7 mm Thickness: 7 mm Content: 625.7 mgExample 1 Long axis diameter: 14 mm Short axis diameter: 6.3 mm Thickness: 4.7 mm Content: 478.4 mg Comparative Example 1-4 Long axis diameter: 19 mm Short axis diameter: 9 mm Thickness: 8 mm Content: 1047.1 mg Example 4 Long axis diameter: 16 mm Short axis diameter: 6.3 mm Thickness: 6 mm Content: 811.2 mg

[0137] Experimental Example 2: Dissolution Rate

[0138] The dissolution rates of the bilayer tablets of Examples 1, 5, and 6 manufactured above and the bilayer tablets of Comparative Example 1 (Comparative Examples 1-3) and Comparative Examples 2 to 6 were measured using the following measurement method, and the results are shown in Table 5 below:

[0139] The dissolution test method among the general test methods of the Korean Pharmacopoeia was followed, but the test was conducted using the second method, the paddle method. The dissolution rate of atorvastatin was measured for 5 minutes, 10 minutes, 15 minutes, and 30 minutes when the two-layer tablet was dissolved in 900 mL of pH 6.8 + 0.3% PSB, 50 rpm, and 37℃.

[0140] Experimental Example 3: Friability of a two-layer tablet

[0141] The wear rate was measured for the uncoated tablets of Examples 1, 5, and 6 and Comparative Examples 2 to 6 manufactured above using the following method, and the results are shown in Table 5 below:

[0142] The test was conducted according to the general information test method of the Korean Pharmacopoeia, Appendix 6, and the mass of the tablets before and after the test was precisely measured to calculate the loss ratio after the test.

[0143] Dissolution rate (%) Wear (%) 5 minutes 10 minutes 15 minutes 30 minutes Example 132.66 8.88 4.39 4.10.2% or less Example 527.15 0.46 5.58 5.20.2% or less Example 633.87 7.39 0.99 8.80.2% or less Comparative example 1-3 (Atojet) 18.84 9.26 5.27 9.2 Comparative example 218.5 24.136.36 2.6 0.2% or less Comparative example 322.8 32.64 4.17 3.80.2% or less Comparative example 425.94 0.95 2.88 0.20.2% or less Comparative example 537.48 8.19 5.59 8.0 0.6~1.0% Comparative example 639.992.395.497.61.0~1.5%

[0144]

[0145] From the above results, it can be seen that the double-layer tablets of Examples 1, 5, and 6, in which the weight ratio of binder:disintegrant is in the range of 1:4 to 1:6, exhibited dissolution rates and friability results similar to or better than those of commercially available Atozet tablets, whereas the double-layer tablets of Comparative Examples 2 to 4, in which the weight ratio of binder:disintegrant is less than 1:4, exhibited dissolution rates inferior to those of Atozet tablets, and the double-layer tablets of Comparative Examples 5 and 6, in which the weight ratio of binder:disintegrant is greater than 1:6, exhibited improved dissolution rates but significantly reduced friability.

[0146] Experimental Example 4: Content Uniformity Experiment

[0147] The content uniformity of ezetimibe in the tablets of Examples 1, 7 and 8, and Comparative Examples 7 to 9 was evaluated (unit: %) using the content uniformity test method among the formulation uniformity items of the Korean Pharmacopoeia, and the results are shown in Table 6 below.

[0148] Experimental Example 5: Layer Separation Test

[0149] The occurrence of layer separation in the tablets of Examples 1, 7 and 8, and Comparative Examples 7 to 9 during tableting, transport, or coating was evaluated, and the results are shown in Table 6 below.

[0150] Example 1 Example 7 Example 8 Comparative Example 7 Comparative Example 8 Comparative Example 9 Content uniformity 5.35.910.32.15.215.8 Layer separation phenomenon not occurred not occurred not occurred occurred not occurred

[0151]

[0152] From the above results, the double-layer tablets of Examples 1, 7, and 8, in which the microcrystalline cellulose content was in the range of 10 wt% to 20 wt% in the second layer, had good content uniformity and no layer separation phenomenon, whereas the tablets of Comparative Examples 7 and 8, in which the microcrystalline cellulose content was less than 10 wt%, had good content uniformity results but layer separation phenomenon occurred, and the double-layer tablet of Comparative Example 9, in which the microcrystalline cellulose content was more than 20 wt%, did not have layer separation phenomenon but had a content uniformity exceeding 15%. Furthermore, since the double-layer tablet of Comparative Example 9 contained a large amount of microcrystalline cellulose, the tablet size and weight increased, which decreased medication compliance.

Claims

1. A first layer comprising atorvastatin or a salt thereof, a binder and a disintegrant; and A bilayer tablet comprising a second layer comprising ezetimibe or a salt thereof and microcrystalline cellulose, In the first layer, the weight ratio of the binder and the disintegrant is in the range of 1:4 to 1:6 based on the total weight of the first layer, A two-layer tablet, comprising microcrystalline cellulose in the second layer in an amount of 10 to 20 wt% based on the total weight of the second layer.

2. A two-layer tablet in the first paragraph, wherein the binder is selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, ethyl cellulose, povidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, methyl cellulose, gelatin, starch, pregelatinized starch, and mixtures thereof.

3. A two-layer tablet in claim 1, wherein the disintegrant is crospovidone, croscarmellose sodium, sodium carboxymethyl cellulose, colloidal silicon dioxide, alginic acid, sodium alginate, corn starch, microcrystalline cellulose, sodium starch glycolate, or a mixture thereof.

4. A two-layer tablet in claim 1, wherein the first layer further comprises 30 to 45 wt% of lactose hydrate and 3 to 18 wt% of microcrystalline cellulose based on the total weight of the first layer.

5. A two-layer tablet according to claim 1, wherein the second layer further comprises 55 to 75 wt% of lactose hydrate based on the total weight of the second layer.

6. A bilayer tablet according to any one of claims 1 to 5, wherein the weight of the bilayer tablet is 200 mg to 830 mg per tablet.

7. A bilayer tablet according to any one of claims 1 to 5, wherein each of the first layer and the second layer of the bilayer tablet further comprises a pharmaceutically acceptable excipient.

8. A two-layer tablet in accordance with claim 7, wherein the pharmaceutically acceptable excipient is a filler, a lubricant, a solubilizer, a stabilizer or a mixture thereof.

9. A two-layer tablet according to any one of claims 1 to 5, wherein the major axis diameter of the two-layer tablet is 16 mm or less.

10. In any one of clauses 1 to 5, the two-layer tablet, A two-layer tablet in which the dissolution rate of atorvastatin is 65% or higher when tested according to the dissolution test method among the general test methods of the Korean Pharmacopoeia, using the second method, the paddle method, when dissolving for 15 minutes under the conditions of pH 6.8 + 0.3% PSB 900 mL, 50 rpm, and 37℃.

11. Forming granules for forming the first layer from the first layer composition comprising atorvastatin or a salt thereof, a binder and a disintegrant, Forming granules for forming a second layer from the second layer composition comprising ezetimibe or a salt thereof and microcrystalline cellulose, A method for manufacturing a two-layer tablet according to claim 1, comprising compressing and compacting the first layer-forming granules and the second layer-forming granules to manufacture a two-layer tablet.

12. A method for manufacturing a two-layer tablet, wherein the two-layer tablet is additionally coated with a coating agent in claim 11.

13. In clause 11 or 12, the method, A granulated composition is prepared by mixing atorvastatin or a salt thereof with pharmaceutically acceptable excipients and solvents, including a binder and a disintegrant, Preparing granules from the above granulating composition, Dry and sieve the above granules, A granule for forming a first layer is prepared by mixing a disintegrant, a lubricant, or both into the above granules, A granulated composition is prepared by mixing ezetimibe with pharmaceutically acceptable excipients and solvents, Preparing granules from the above granulating composition, Dry and sieve the above granules, By mixing microcrystalline cellulose and a lubricant into the above granules, granules for forming a second layer are manufactured. A manufacturing method comprising: manufacturing a two-layer tablet by compressing and compacting the first layer-forming granules and the second layer-forming granules.