Pharmaceutical combination formulation comprising atorvastatin and ezetimibe

Abstract

The present invention discloses a pharmaceutical combination formulation comprising atorvastatin and ezetimibe. The pharmaceutical combination formulation in the form of a bilayer tablet, comprises: a first layer comprising atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient; and a second layer comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

PHARMACEUTICAL COMBINATION FORMULATION COMPRISING ATORVASTATIN AND EZETIMIBE

[0001] The present invention relates to a pharmaceutical combination formulation comprising atorvastatin and ezetimibe, and more particularly, to a pharmaceutical combination formulation comprising as active ingredients atorvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor that inhibits cholesterol synthesis and treats dyslipidemia, and ezetimibe, a drug that inhibits cholesterol reabsorption in the small intestine.

[0002] Hyperlipidemia is a condition in which lipid components increase in the blood, and lipid components may accumulate on the blood vessel walls and cause atherosclerosis or other diseases. A similar term, dyslipidemia, is also used to refer to abnormal blood lipid conditions.

[0003] Atorvastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor represented by Chemical Formula 1 below, and it is sold under the trade name LIPITOR™. Atorvastatin is used for hyperlipidemia, hypercholesterolemia, and atherosclerosis, since it has the effect of lowering blood lipid concentration and cholesterol by preventing HMG-CoA from being reduced to mevalonate (Refer to US Patent No. 4,681,893).

[0004] [Chemical Formula 1]

[0005]

[0006] Statin-based drugs such as atorvastatin are known to reduce bad cholesterol (low-density lipoprotein (LDL) cholesterol) by more than 50% and increase good cholesterol (high-density lipoprotein (HDL) cholesterol) by about 15%.

[0007] Ezetimibe is a selective cholesterol absorption inhibitor represented by Chemical Formula 2 below, and it is sold under the trade name EZETROL™. Ezetimibe has a mechanism to inhibit cholesterol reabsorption in the small intestine, and it is well known to exhibit an advantageous therapeutic effect when used in combination with rosuvastatin, which is an HMG-CoA reductase inhibitor (Refer to US Patent Publication No. 2014 / 0287042).

[0008] [Chemical Formula 2]

[0009]

[0010] For this reason, ezetimibe is used alone or in combination with statin-based drugs for patients with hyperlipidemia.

[0011] However, it is generally known that rosuvastatin, a statin-based drug, is unstable under strongly acidic conditions, so a prescription is suggested to comprise an alkaline stabilizer to stabilize it.

[0012] However, since ezetimibe is unstable in a strongly alkaline environment, many related substances are generated when preparing a combination formulation of these two drugs, making it difficult to ensure the stability of the active ingredients (Refer to Korean Patent Publication No. 10-2014-0192374).

[0013] Therefore, it is necessary to develop a pharmaceutical combination formulation comprising atorvastatin and ezetimibe as active ingredients that can ensure the same level of content uniformity and drug release as the reference drug while improving the stability of the active ingredients ezetimibe and atorvastatin.

[0014] [Related Art Documents]

[0015] [Patent Documents]

[0016] (Patent Document 1) US Patent No. 4681893

[0017] (Patent Document 2) US Patent Publication No. 2014 / 0287042

[0018] (Patent Document 3) Korean Patent Publication No. 10-2014-0192374

[0019] An object of the present invention is to provide a pharmaceutical combination formulation in the form of a bilayer tablet comprising atorvastatin and ezetimibe as active ingredients, thereby increasing the convenience of taking the drug for patients with hyperlipidemia.

[0020] Another object of the present invention is to provide a pharmaceutical combination formulation having improved content uniformity, improved release, and improved stability through an optimal combination of additives.

[0021] More specifically, an object of the present invention is to provide a pharmaceutical combination formulation in the form of a bilayer tablet capable of improving the stability of the active ingredients atorvastatin and ezetimibe, while physically separating the active ingredients, thereby minimizing the impact of an alkalizing agent and blocking external factors that affect the increase of related substances of ezetimibe.

[0022] In order to achieve the above-described technical tasks, the present invention discloses the following means.

[0023] In one aspect, the present invention discloses a pharmaceutical combination formulation in the form of a bilayer tablet comprising: a first layer comprising atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient; and a second layer comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient.

[0024] The pharmaceutical combination formulation according to the present invention has the advantage of increasing the convenience of taking a drug for patients with hyperlipidemia, by developing a combination formulation in the form of a bilayer tablet comprising atorvastatin and ezetimibe as active ingredients.

[0025] The pharmaceutical combination formulation in the form of a bilayer tablet according to the present invention has the advantage of improving content uniformity, release, and stability through an optimal combination of additives.

[0026] Specifically, the pharmaceutical combination formulation in the form of a bilayer tablet according to the present invention has the advantage of improving the stability of the active ingredients, atorvastatin and ezetimibe, by physically separating the active ingredients, thereby minimizing the impact of an alkalizing agent and blocking external factors that affect the increase of related substances of ezetimibe.

[0027] The effects of the present invention are not limited to the above-mentioned effects, and various effects may be comprised within a range obvious to those skilled in the art from the contents that will be described below.

[0028] FIG. 1 shows the dissolution rate of ezetimibe in film-coated tablets according to Examples 2, 4, and 5 and Comparative Example 4 under the dissolution test solution conditions of pH 1.2 and 0.1% polysorbate 80.

[0029] FIG. 2 shows the dissolution rate of ezetimibe in film-coated tablets according to Examples 2, 4, and 5 and Comparative Example 4 under the dissolution test solution conditions of pH 4.5 and 0.1% polysorbate 80.

[0030] FIG. 3 shows the dissolution rate of ezetimibe in film-coated tablets according to Examples 2, 4, and 5 and Comparative Example 4 under the dissolution test solution conditions of pH 6.8 and 0.1% polysorbate 80.

[0031] FIG. 4 shows the dissolution rate of ezetimibe in film-coated tablets according to Examples 1 and 6 to 9 under the dissolution test solution conditions of pH 6.8 and 0.1% polysorbate 80.

[0032] Hereinafter, the present specification will be described in more detail.

[0033] The present specification is described in more detail as follows. The terms used herein are selected as general terms that are currently widely used as much as possible while considering the functions in the present invention, but they may vary depending on the intention or precedent of those of ordinary skill in the art, the emergence of new technology, or the like.　In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meaning will be described in the corresponding part of the detailed description of the invention.　Therefore, the terms used in the present invention should be defined based on the meaning of the terms and the overall content of the present invention, rather than simply the names of the terms.

[0034] Unless otherwise defined, all terms, comprising technical and scientific terms used herein, have the same meaning as generally understood by one of ordinary skill in the art to which the present invention pertains.　Terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and are not interpreted in an idealized or overly formal sense unless clearly so defined in the present invention.

[0035] Numerical ranges are inclusive of the values defined therein. Every maximum numerical limitation given throughout the present specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written. Every minimum numerical limitation given throughout the present specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written. Every numerical limitation given throughout the present specification will include every better numerical range within the broader numerical range, as if the narrower numerical limitations were expressly written.

[0036] Hereinafter, each description and embodiment disclosed in the present invention may also be applied to other descriptions and embodiments for each. In other words, all combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention may not be considered as being limited by the specific description described below.

[0037] Expressions such as "comprising" as used herein should be understood as open-ended terms implying the possibility of including other embodiments, unless otherwise specifically stated in the phrase or sentence in which the expression is included.

[0038] While conducting research and development to develop a pharmaceutical combination formulation comprising as active ingredients atorvastatin and ezetimibe, which are therapeutics for hyperlipidemia, the present inventors confirmed that the convenience of taking a drug for patients can be increased by preparing two drugs (LIPITOR™ and EZETROL™) as a single combination formulation, and that the content uniformity, release, and stability can be improved through an optimal combination of additives, thereby completing the present invention.

[0039] Hereinafter, the present invention will be described in detail.

[0040] The term 'atorvastatin' as used herein may refer to atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof. Therefore, a pharmaceutical combination formulation / granule comprising atorvastatin herein may refer to a pharmaceutical combination formulation / granule comprising atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0041] The term 'ezetimibe' as used herein may refer to ezetimibe or a pharmaceutically acceptable salt thereof. Therefore, a pharmaceutical combination formulation / granule comprising ezetimibe herein may refer to a pharmaceutical combination formulation / granule comprising ezetimibe or a pharmaceutically acceptable salt thereof.

[0042] Pharmaceutical combination formulation

[0043] To achieve the above-described technical task, the present invention discloses a means described below.

[0044] In one aspect, the present invention provides a pharmaceutical combination formulation in the form of a bilayer tablet, comprising: a first layer comprising atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient; and a second layer comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient.

[0045] In the present invention, the active ingredient, atorvastatin, is a compound represented by Chemical Formula 1 below and refers to a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor mainly used for the treatment of hyperlipidemia, hypercholesterolemia, and atherosclerosis. The specific chemical name thereof is [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.

[0046] [Chemical Formula 1]

[0047]

[0048] In the present invention, the active ingredient, ezetimibe, is a compound represented by Chemical Formula 2 below and is a selective cholesterol absorption inhibitor. The specific chemical name thereof is (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one.

[0049] [Chemical Formula 2]

[0050]

[0051] In the present invention, the term "pharmaceutically acceptable salt" comprises salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. The pharmaceutically acceptable salt in the present invention refers to any organic or inorganic addition salt at a concentration having an effect that is relatively nontoxic and harmless to the patient, the side effects of which do not reduce the beneficial effects of the pharmacologically active ingredient. The term "hydrate" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0052] In the present invention, the pharmaceutically acceptable salt of atorvastatin may be used in the form of atorvastatin calcium salt, atorvastatin magnesium salt, atorvastatin sodium salt, atorvastatin potassium salt, and atorvastatin aluminum salt, and the hydrate of the pharmaceutically acceptable salt of atorvastatin may be atorvastatin calcium trihydrate (chemical name: (-)-monocalcium bis{(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate}trihydrate), but is not limited thereto.

[0053] The atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and the ezetimibe or a pharmaceutically acceptable salt thereof may be easily chemically synthesized and prepared by a synthetic method known to those skilled in the art to be used, or may be purchased and used as commercially prepared products.

[0054] In the present invention, the content of the active ingredient may be 5.0% to 10.0% by weight based on the total weight of the entire pharmaceutical combination formulation, specifically 5.5% to 8.0% by weight, but is not limited thereto.

[0055] In the present invention, the terms "first," "second," and the like do not specifically indicate an order, but are simply intended to indicate that the meanings of the terms described below are different from each other.

[0056] In the present invention, the dosage form of the pharmaceutical combination formulation is a bilayer tablet, which means that the first layer and the second layer are each prepared and then tableted to form a formulation.

[0057] In the present invention, the weight ratio of the second layer comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient and the first layer comprising atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient may be 1:3 to 3:1, but is not limited thereto.

[0058] Specifically, when the weight ratio of the second layer comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient and the first layer comprising atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient satisfies the above-described range, there is an advantage in that the content uniformity of ezetimibe and atorvastatin can be ensured at an appropriate level.

[0059] In the present invention, the first layer and the second layer may comprise a solubilizing agent and a binder, but are not limited thereto.

[0060] In the present invention, the second layer comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient may comprise a solubilizing agent and a binder in a weight ratio of 1:0.1 to 1:30, but is not limited thereto.

[0061] Specifically, when the solubilizing agent and the binder are comprised in the second layer in a weight ratio of 1:0.1 to 1:30, there is an advantage of exhibiting an excellent ezetimibe release effect and tableting properties.

[0062] In the present invention, the solubilizing agent may be one or more selected from the group consisting of sodium lauryl sulfate, polysorbate, polyethylene oxide, polypropylene oxide, and cetrimonium bromide, but is not limited thereto.

[0063] In the present invention, the content of the solubilizing agent may be 0.1% to 5.0% by weight based on the total weight of the entire pharmaceutical combination formulation, specifically 0.2% to 1.5% by weight, but is not limited thereto.

[0064] In the present invention, the binder may be one or more selected from the group consisting of hydroxypropyl cellulose, hypromellose, povidone, copovidone, ethyl cellulose, pregelatinized starch, and maltodextrin, but is not limited thereto.

[0065] In the present invention, the content of the binder may be 0.3% to 10.0% by weight based on the total weight of the entire pharmaceutical combination formulation, specifically 0.5% to 8.0% by weight, but is not limited thereto.

[0066] Specifically, within the above-described weight ratio range, there is an advantage in that excellent release effect and tableting properties of ezetimibe can be exhibited regardless of the types of solubilizing agent and binder. In other words, the excellent release effect and tableting properties of ezetimibe are not limited to the above-described types of solubilizing agent and binder.

[0067] In the present invention, the pharmaceutical combination formulation may further comprise one or more pharmaceutical additives consisting of an excipient, a disintegrating agent, a stabilizer, and a lubricant, but is not limited thereto.

[0068] In the present invention, the excipient may be lactose hydrate, microcrystalline cellulose, or a mixture thereof, but is not limited thereto.

[0069] In the present invention, the content of the excipient may be 50.0% to 75.0% by weight based on the total weight of the entire pharmaceutical combination formulation, and specifically 60.0% to 75.0% by weight, but is not limited thereto.

[0070] In the present invention, the disintegrating agent may be croscarmellose sodium, but is not limited thereto.

[0071] In the present invention, the content of the disintegrating agent may be 5.0% to 15.0% by weight based on the total weight of the entire pharmaceutical combination formulation, and specifically 7.0% to 10.0% by weight, but is not limited thereto.

[0072] In the present invention, the stabilizer may be precipitated calcium carbonate, but is not limited thereto.

[0073] In the present invention, the content of the stabilizer may be 3.0% to 25.0% by weight based on the total weight of the entire pharmaceutical combination formulation, and specifically 5.0% to 18.0% by weight, but is not limited thereto.

[0074] In the present invention, the lubricant may be magnesium stearate, but is not limited thereto.

[0075] In the present invention, the content of the lubricant may be 0.5% to 3.0% by weight based on the total weight of the entire pharmaceutical combination formulation, and specifically 1.0% to 2.0% by weight, but is not limited thereto.

[0076] In the present invention, the pharmaceutical combination formulation may be a film-coated tablet coated with a coating agent, but is not limited thereto.

[0077] In the present invention, the content of the coating agent may be 1.5% to 5.0% by weight based on the total weight of the entire pharmaceutical combination formulation, and specifically 2.5% to 4.0% by weight, but is not limited thereto.

[0078] In the present invention, the coating agent may not comprise polyvinyl alcohol, but is not limited thereto.

[0079] In the present invention, the coating agent is a hydroxypropyl methyl cellulose-based coating base material, but is not limited thereto.

[0080] Specifically, polyvinyl alcohol-based coating base materials are known to have good moisture blocking properties, but when polyvinyl alcohol-based coating base materials are used, there is a problem in that related substances of ezetimibe increase. However, when hydroxypropyl methyl cellulose-based coating base materials are used, there is an advantage in that external factors affecting the increase of ezetimibe related substances can be blocked, thereby improving the phenomenon of increasing ezetimibe related substances.

[0081] In the present invention, the pharmaceutical combination formulation may contain 5 to 80 mg of atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof as atorvastatin per unit dosage form, for example, 5 mg, 10 mg, 20 mg, 40 mg or 80 mg as atorvastatin.

[0082] In the present invention, the pharmaceutical combination formulation may contain 5 to 20 mg of ezetimibe or a pharmaceutically acceptable salt thereof as ezetimibe per unit dosage form, specifically, 10 mg as ezetimibe per unit dosage form.

[0083] In the present invention, the pharmaceutical combination formulation may be a pharmaceutical combination formulation for treating or preventing hyperlipidemia, but is not limited thereto.

[0084] Hereinafter, the present invention will be described in detail based on examples and experimental examples. However, the following examples and experimental examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

[0085] Examples and Comparative Examples

[0086] Examples 1 and 2 and Comparative Example 1. Prescription with different weight ratios of ezetimibe layer and atorvastatin layer

[0087] Example 1

[0088] (1) Preparation of atorvastatin calcium trihydrate granules

[0089] Hydroxypropyl cellulose and polysorbate 80 were added to purified water to prepare a binding solution, and then a mixture prepared by mixing precipitated calcium carbonate as an alkalizing agent, a part of croscarmellose sodium as a disintegrating agent, atorvastatin calcium trihydrate as an active ingredient, a part of lactose hydrate as an excipient, and microcrystalline cellulose was wetted with the binding solution.

[0090] After wet screening the wet granule, the resulting product were dried in a fluidized bed granulator, and after dry screening in Co-Mill, the remaining lactose hydrate, the remaining croscarmellose sodium, and magnesium stearate were added to prepare atorvastatin calcium trihydrate granules.

[0091] (2) Preparation of ezetimibe granules

[0092] Povidone and sodium lauryl sulfate were added to purified water to prepare a binding solution, and then a mixture prepared by mixing croscarmellose sodium as a disintegrating agent, ezetimibe as an active ingredient, and lactose hydrate as an excipient was wetted with the binding solution.

[0093] After wet screening the wet granule, the resulting product was dried in a fluidized bed granulator, and after dry screening in Co-Mill, microcrystalline cellulose and magnesium stearate were added to prepare ezetimibe granules.

[0094] (3) Preparation of uncoated tablets

[0095] The atorvastatin calcium trihydrate granules and the ezetimibe granules were tableted to prepared tablets (uncoated tablets) consisting of in the form of a bilayer with an atorvastatin calcium trihydrate layer and an ezetimibe layer.

[0096] (4) Preparation of film-coated tablets

[0097] Film-coated tablets were prepared by coating the uncoated tablets obtained by the above-described process (3) using Opadry.

[0098] Example 2

[0099] A film-coated tablet according to Example 2 was prepared in the same manner as Example 1 using each component and content according to Table 1 below.

[0100] Example 3

[0101] A film-coated tablet according to Example 3 was prepared in the same manner as Example 1 using each component and content according to Table 1 below.

[0102] Comparative Example 1

[0103] A film-coated tablet according to Comparative Example 1 was prepared in the same manner as Example 1 using each component and content according to Table 1 below.

[0104] Comparative Example 2

[0105] A film-coated tablet according to Comparative Example 2 was prepared in the same manner as Example 1 using each component and content according to Table 1 below.

[0106] ComponentContent (mg / tablet)Comparative Example 1Example 1Example 2Example 3Comparative Example 2Ezetimibe layerEzetimibe10.0010.0010.0010.0010.00Lactose hydrate35.0035.0035.009.006.75Microcrystalline cellulose84.2584.2584.2524.0815.56Croscarmellose sodium15.0015.0015.005.003.75Povidone3.003.003.001.000.75Magnesium stearate2.002.002.000.670.50Sodium lauryl sulfate0.750.750.750.250.19Weight of ezetimibe layer150.00150.00150.0050.0037.50Atorvastatin layerAtorvastatin calcium trihydrate(as atorvastatin)5.425(5.00)5.425(5.00)5.425(5.00)5.425(5.00)5.425(5.00)Lactose hydrate12.77518.00528.97561.37561.375Precipitated calcium carbonate8.2511.0016.5033.0033.00Microcrystalline cellulose6.509.5015.0032.0032.00Croscarmellose sodium3.154.206.3012.6012.60Hydroxypropyl cellulose0.7501.0001.5003.0003.000Polysorbate 800.150.200.300.600.60Magnesium stearate0.500.671.002.002.00Weight of atorvastatin layer37.5050.0075.00150.00150.00Total weight of uncoated tablet187.50200.00225.00200.00187.50Film-coating layerOpadry White (03B28796)7.007.007.007.007.00Total weight of coated tablet194.50207.00232.00207.00194.50Ezetimibe layer:Atorvastatin layer (weight ratio)4 : 13 : 12 : 11 : 31 : 4

[0107] Experimental Example 1. Confirmation of content uniformity of Examples 1 to 3 and Comparative Examples 1 and 2

[0108] 1. Test method

[0109] Ten film-coated tablets each according to Examples 1 to 3 and Comparative Examples 1 and 2 were tested through the content uniformity test among the formulation uniformity items of the Korean Pharmacopoeia to evaluate the content uniformity of ezetimibe and atorvastatin, and the results are shown in Table 2 below.

[0110] <Sample analysis conditions>

[0111] Detector: UV spectrophotometer (measurement wavelength: 231 nm)

[0112] Column: Inertsil ODS4 (5 μm, 150 × 4.6 mm)

[0113] Flow rate: 1.0 mL / min

[0114] Injection amount: 20 μL

[0115] Column temperature: 30 ℃

[0116] Analysis time: 7 minutes

[0117] Mobile phase: Mixture of a pH 5.5 buffer and acetonitrile (45:55)

[0118] 2. Test results

[0119] Referring to Table 2, the film-coated tablets of Examples 1 to 3, in which the weight ratio of the ezetimibe layer and the atorvastatin layer was in the range of 1:3 to 3:1, showed an acceptable result with a content uniformity determination value of 15 or less, but the film-coated tablets of Comparative Examples 1 and 2, in which the weight ratio of the ezetimibe layer and the atorvastatin layer was out of the range of 1:3 to 3:1, showed a determination value of 15 or more, which is an unacceptable level.

[0120] Test result (%)Comparative Example 1Example 1Example 2Example 3Comparative Example 2Ezetimibe5.83.54.59.117.7Atorvastatin18.48.35.33.64.1Criterion: 15 or lessUnacceptableAcceptableAcceptableAcceptableUnacceptable

[0121] Examples 4 and 5 and Comparative Examples 3 and 4: Prescriptions with different ratios of binder and solubilizing agent

[0122] Purpose of new prescriptions

[0123] Ezetimibe is a poorly soluble drug, and thus low bioavailability may be exhibited, and the therapeutic efficacy may be reduced. There are various methods for increasing bioavailability of poorly soluble drugs. The present inventors attempted to increase the bioavailability of ezetimibe, a poorly soluble drug, and enhance the therapeutic efficacy thereof by appropriately adjusting the solubilizing agent (increasing solubility) and binder (controlling release) and set the weight ratio of the solubilizing agent and the binder to the range of 1:0.1 to 1:30, thereby deriving an optimal prescription.

[0124] Example 4

[0125] A film-coated tablet according to Example 4 was prepared in the same manner as Example 1 using each component and content according to Table 3 below.

[0126] Example 5

[0127] A film-coated tablet according to Example 5 was prepared in the same manner as Example 1 using each component and content according to Table 3 below.

[0128] Comparative Example 3

[0129] A film-coated tablet according to Comparative Example 3 was prepared in the same manner as Example 1 using each component and content according to Table 3 below.

[0130] Comparative Example 4

[0131] A film-coated tablet according to Comparative Example 4 was prepared in the same manner as Example 1 using each component and content according to Table 3 below.

[0132] ComponentContent (mg / tablet)Comparative Example 3Example 4Example 2Example 5Comparative Example 4Ezetimibe layerEzetimibe10.0010.0010.0010.0010.00Lactose hydrate35.0035.0035.0035.0035.00Microcrystalline cellulose85.9885.8084.2572.5062.50Croscarmellose sodium15.0015.0015.0015.0015.00Povidone0.020.203.0015.0025.00Magnesium stearate2.002.002.002.002.00Sodium lauryl sulfate2.002.000.750.500.50Weight of ezetimibe layer150.00150.00150.00150.00150.00Solubilizing agent:binder (weight ratio)1:0.011:0.11:41:301:50Atorvastatin layerAtorvastatin calcium trihydrate(as atorvastatin)5.425(5.00)5.425(5.00)5.425(5.00)5.425(5.00)5.425(5.00)Lactose hydrate28.97528.97528.97528.97528.975Precipitated calcium carbonate16.5016.5016.5016.5016.50Microcrystalline cellulose15.0015.0015.0015.0015.00Croscarmellose sodium6.306.306.306.306.30Hydroxypropyl cellulose1.5001.5001.5001.5001.500Polysorbate 800.300.300.300.300.30Magnesium stearate1.001.001.001.001.00Weight of atorvastatin layer75.0075.0075.0075.0075.00Total weight of uncoated tablet225.00225.00225.00225.00225.00Film-coating layerOpadry White (03B28796)7.007.007.007.007.00Total weight of coated tablet232.00232.00232.00232.00232.00

[0133] Experimental Example 2. Confirmation of the dissolution rate of ezetimibe

[0134] 1. Test method

[0135] It was confirmed in the case of Comparative Example 3, in which the weight ratio of the solubilizing agent and binder was lower than 1:0.1, the binding force of the ezetimibe granules was not good and the tablets could not be prepared, and therefore Comparative Example 3 was excluded.

[0136] Accordingly, the film-coated tablets of Comparative Example 4 and Examples 2, 4, and 5 were tested under the following conditions to confirm the dissolution rate of ezetimibe, and the results are shown in Tables 5 to 7 and FIGS. 1 to 3.

[0137] <Dissolution conditions>

[0138] The dissolution conditions are as shown in Table 4 below.

[0139] Test methodDissolution Test Methods Method 1 of Korean Pharmacopoeia General Test Methods (Rotating Basket Method)Test conditionspH 1.2 + 0.1% polysorbate 80900 mL, 50 rpm, 37 ℃pH 4.5 + 0.1% polysorbate 80pH 6.8 + 0.1% polysorbate 80Sampling points5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes

[0140] <Sample analysis conditions>

[0141] Detector: UV spectrophotometer (measurement wavelength: 231 nm)

[0142] Column: Inertsil ODS4 (5 μm, 150 × 4.6 mm)

[0143] Flow rate: 1.0 mL / min

[0144] Injection amount: 20 μL

[0145] Column temperature: 30 ℃

[0146] Analysis time: 7 minutes

[0147] Mobile phase: Mixture of a pH 5.5 buffer and acetonitrile (45:55)

[0148] 2. Test results

[0149] Referring to Table 5 and FIG. 1, Comparative Example 4 showed the results that the dissolution was delayed. This can be expected to show a low bioavailability due to the low dissolution rate due to the binder content being higher than 1:30 in the weight ratio of the solubilizing agent and binder.

[0150] However, unlike Comparative Example 4, it was confirmed that the film-coated tablets according to Examples 2, 4 and 5, in which the weight ratio of the solubilizing agent and the binder was in the range of 1:0.1 to 1:30, exhibited excellent ezetimibe release effects and tableting properties.

[0151] Dissolution test solutionpH 1.2 + 0.1% polysorbate 80Dissolution rate (%)5 minutes10 minutes15 minutes30 minutes45 minutes60 minutesExample 448.953.058.168.071.375.4Example 243.351.057.164.668.370.0Example 536.754.158.164.368.170.4Comparative Example 420.235.944.956.962.366.0

[0152] Dissolution test solutionpH 4.5 + 0.1% polysorbate 80Dissolution rate (%)5 minutes10 minutes15 minutes30 minutes45 minutes60 minutesExample 445.765.872.478.281.583.5Example 238.555.362.473.679.783.3Example 527.147.161.467.675.981.3Comparative Example 427.742.850.655.258.761.4

[0153] Dissolution test solutionpH 6.8 + 0.1% polysorbate 80Dissolution rate (%)5 minutes10 minutes15 minutes30 minutes45 minutes60 minutesExample 454.072.175.682.086.088.4Example 248.863.469.379.383.686.7Example 542.860.066.071.377.382.2Comparative Example 422.637.446.556.261.060.2

[0154] Examples 6 to 9. Prescriptions with different types of solubilizer and binder

[0155] Purpose of new prescriptions

[0156] Prescriptions with different types of solubilizer and binder are proposed in order to confirm whether excellent release effect and tableting properties are exhibited in a weight ratio of 1:0.1 to 1:30 regardless of the type of solubilizer and binder.

[0157] Example 6

[0158] A film-coated tablet according to Example 6 was prepared in the same manner as Example 1 using each component and content according to Table 8 below, except that hydroxypropyl cellulose was used instead of povidone as a binder in Example 1.

[0159] Example 7

[0160] A film-coated tablet according to Example 7 was prepared in the same manner as Example 1 using each component and content according to Table 8 below, except that hypromellose was used instead of povidone as a binder in Example 1.

[0161] Example 8

[0162] A film-coated tablet according to Example 8 was prepared in the same manner as Example 1 using each component and content according to Table 8 below, except that copovidone was used instead of povidone as a binder in Example 1.

[0163] Example 9

[0164] A film-coated tablet according to Example 9 was prepared in the same manner as Example 1 using each component and content according to Table 8 below, except that polysorbate 80 was used instead of sodium lauryl sulfate as a solubilizing agent in Example 1.

[0165] ComponentContent (mg / tablet)Example 2Example 6Example 7Example 8Example 9Ezetimibe layerEzetimibe10.0010.0010.0010.0010.00Lactose hydrate35.0035.0035.0035.0035.00Microcrystalline cellulose84.2584.2584.2584.2584.25Croscarmellose sodium15.0015.0015.0015.0015.00Povidone3.00---3.00Hydroxypropyl cellulose-3.00---Hypromellose--3.00--Copovidone---3.00-Magnesium stearate2.002.002.002.002.00Sodium lauryl sulfate0.750.750.750.75-Polysorbate 80----0.75Weight of ezetimibe layer150.00150.00150.00150.00150.00Atorvastatin layerAtorvastatin calcium trihydrate(as atorvastatin)5.425(5.00)5.425(5.00)5.425(5.00)5.425(5.00)5.425(5.00)Lactose hydrate28.97528.97528.97528.97528.975Precipitated calcium carbonate16.5016.5016.5016.5016.50Microcrystalline cellulose15.0015.0015.0015.0015.00Croscarmellose sodium6.306.306.306.306.30Hydroxypropyl cellulose1.5001.5001.5001.5001.500Polysorbate 800.300.300.300.300.30Magnesium stearate1.001.001.001.001.00Weight of atorvastatin layer75.0075.0075.0075.0075.00Total weight of uncoated tablet225.00225.00225.00225.00225.00Film-coating layerOpadry White (03B28796)7.007.007.007.007.00Total weight of coated tablet232.00232.00232.00232.00232.00

[0166] Experimental Example 3. Confirmation of Ezetimibe Dissolution Rate

[0167] 1. Test method

[0168] The analysis method was the same as that described in Experimental Example 2 above, and the results are shown in Table 9 and FIG. 4.

[0169] 2. Test results

[0170] Referring to Table 9 and FIG. 4, it was confirmed that excellent release effect and tableting properties were exhibited when the weight ratio was in the range of 1:0.1 to 1:30 regardless of the types of solubilizer and binder.

[0171] Dissolution test solutionpH 6.8 + 0.1% polysorbate 80Dissolution rate (%)5 minutes10 minutes15 minutes30 minutes45 minutes60 minutesExample 148.863.469.379.383.686.7Example 643.865.471.577.580.081.6Example 749.570.676.981.984.285.6Example 839.065.473.980.383.485.4Example 933.655.766.777.380.582.1

[0172] Comparative Example 5. Prescriptions with different types of coating base material

[0173] A film-coated tablet according to Comparative Example 5 was prepared in the same manner as Example 1 using each component and content according to Table 10 below, except that Opadry White (85F18422, PVA base) was used instead of Opadry White (03B28796, HPMC base) as the coating agent in Example 1.

[0174] ComponentContent (mg / tablet)Comparative Example 5Example 2Ezetimibe layerEzetimibe10.0010.00Lactose hydrate35.0035.00Microcrystalline cellulose84.2584.25Croscarmellose sodium15.0015.00Povidone3.003.00Magnesium stearate2.002.00Sodium lauryl sulfate0.750.75Weight of ezetimibe layer150.00150.00Atorvastatin layerAtorvastatin calcium trihydrate(as atorvastatin)5.425(5.00)5.425(5.00)Lactose hydrate28.97528.975Precipitated calcium carbonate16.5016.50Microcrystalline cellulose15.0015.00Croscarmellose sodium6.306.30Hydroxypropyl cellulose1.5001.500Polysorbate 800.300.30Magnesium stearate1.001.00Weight of atorvastatin layer75.0075.00Total weight of uncoated tablet225.00225.00Film-coating layerOpadry White (03B28796, HPMC base)-7.00Opadry White (85F18422, PVA base)7.00-Total weight of coated tablet232.00232.00

[0175] Experimental Example 4. Confirmation of Related Substance

[0176] 1. Test method

[0177] In order to confirm the ezetimibe related substance of the film-coated tablets according to Comparative Example 5 and Example 2, ten film-coated tablets each according to Comparative Example 5 and Example 2 were packaged in bottles (HDPE), stored under severe conditions (approximately 80 ℃) for two weeks and under accelerated conditions (approximately 40 ℃, approximately 75% RH) for six months, and the ezetimibe related substance F was measured. The results are shown in Table 12.

[0178] <Sample analysis conditions>

[0179] Detector: UV spectrophotometer (measurement wavelength: 232 nm)

[0180] Column: Phenomenex Synergi Polar_RP 80 Å (4 μm, 250 × 4.6 mm)

[0181] Flow rate: 1.1 mL / min

[0182] Injection amount: 15 μL

[0183] Column temperature: 40 ℃

[0184] Analysis time: 65 minutes

[0185] Mobile phase: (A) a mixture of a pH 5.0 buffer and acetonitrile (67:33), (B) acetonitrile, and (C) tetrahydrofuran

[0186] Time (min)Mobile phase AMobile phase BMobile phase C09109159163208216225821625032662553266255.019109659109

[0187] 2. Test results

[0188] Referring to Table 12, it was confirmed that the phenomenon of increasing the related substance was improved in the HPMC-based coating agent compared to the PVA-based coating base material, which is known to have good moisture blocking properties.

[0189] ClassificationCriterionConcentration of ezetimibe related substance F (%)Comparative Example 5Example 2Under severe conditions for two weeks0.2% or less2.84%0.05%Under accelerated conditions for six months0.24%ND*

[0190] (In Table 12 above, *ND refers to 'Not Detected.')

[0191] While the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that these specific descriptions are merely preferred embodiments and that the scope of the present invention is not limited thereto. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1.A pharmaceutical combination formulation in the form of a bilayer tablet, comprising:a first layer comprising atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient; anda second layer comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient.2.The pharmaceutical combination formulation according to claim 1, wherein the weight ratio of the second layer comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient and the first layer comprising atorvastatin or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient is 1:3 to 3:1.3.The pharmaceutical combination formulation according to claim 1, wherein the first layer and the second layer comprise a solubilizing agent and a binder.4.The pharmaceutical combination formulation according to claim 3, wherein the second layer comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient comprises a solubilizing agent and a binder in a weight ratio of 1:0.1 to 1:30.5.The pharmaceutical combination formulation according to claim 3, wherein the solubilizing agent is one or more selected from the group consisting of sodium lauryl sulfate, polysorbate, polyethylene oxide, polypropylene oxide, and cetrimonium bromide.6.The pharmaceutical combination formulation according to claim 3, wherein the binder is one or more selected from the group consisting of hydroxypropyl cellulose, hypromellose, povidone, copovidone, ethyl cellulose, pregelatinized starch, and maltodextrin.7.The pharmaceutical combination formulation according to claim 1, wherein the pharmaceutical combination formulation is a film-coated tablet coated with a coating base material.8.The pharmaceutical combination formulation according to claim 7, wherein the coating agent does not comprise polyvinyl alcohol.9.The pharmaceutical combination formulation according to claim 7, wherein the coating agent is a hydroxypropyl methyl cellulose-based coating base material.

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