KR20230000506A - Pharmaceutical combination preparation comprising candesartan, amlodipine and atorvastatin - Google Patents

Abstract

The present invention relates to a pharmaceutical combination preparation comprising candesartan, amlodipine, and atorvastatin as active ingredients. The pharmaceutical combination preparation according to the present invention comprises three active ingredients at the same time, wherein the elution pattern and PK profile of each active ingredient are the same as the elution pattern and PK profile in the administration of Lipito® tab., or a single preparation of atorvastatin and Cantabell® tab., or a combination preparation of candesartan and amlodipine and the equivalent pharmacological effects can be shown. Stability is high because the content of individual and total related substances does not increase significantly under long-term and accelerated conditions. Therefore, provided is the pharmaceutical combination preparation that can greatly improve the convenience of medicine administration.

Description

Pharmaceutical combination preparation containing candesartan, amlodipine and atorvastatin

The present invention relates to a pharmaceutical combination preparation containing candesartan, amlodipine and atorvastatin as active ingredients. The pharmaceutical combination preparation according to the present invention contains three active ingredients at the same time, and the dissolution pattern and PK profile of each active ingredient are ^Lipitor® tablets, a single formulation of atorvastatin, and ^Cantabel® tablets, a combination formulation of Candesartan and Amlodipine, when administered in combination. A drug that can show equivalent pharmacological effects by being equivalent to the dissolution pattern and PK profile of , and significantly improve the convenience of taking medicine due to its high stability because the content of individual related substances and total related substances does not increase significantly under long-term and accelerated conditions Provides a scientific combination preparation.

Hypertension is a condition in which blood pressure is maintained above the normal range. Hypertension causes many complications and can eventually lead to death. Hypertension is divided into primary hypertension and secondary hypertension depending on the cause of the increase in blood pressure. Primary hypertension is essential hypertension for which the cause of the increase in blood pressure is unknown, and secondary hypertension is secondary hypertension in which blood pressure rises as a result of a specific disease or disease. Secondary hypertension can be treated by identifying the factors that increase blood pressure, but the cause of primary hypertension, which accounts for about 95% of all hypertension, is not clearly known. based drug therapy.

In general, hypertensive patients are often accompanied by other types of cardiovascular diseases including hyperlipidemia, so the combination prescription rate of two or more drugs is high. In addition, since long-term drug use is required, care must be taken in the selection of treatment drugs. There is a need to reduce side effects that may occur by taking the drug.

Candesartan is known as an angiotensin II receptor blocker (ARB), and its use as a treatment for hypertension is expanding because it has effects such as preservation of ventricular function, prevention and prevention of fibrosis, as well as lowering blood pressure. .

Amlodipine is known as a calcium channel blocker (CCB) and is used to treat high blood pressure and other medical indications. (See WO 2006/059217)

Atorvastatin is known as an HMG-CoA reductase inhibitor. It prevents HMG-CoA from being reduced to mevalonate and has the effect of lowering blood lipid concentration and cholesterol, so it is used for hyperlipidemia, hypercholesterolemia and atherosclerosis. . (See US 4681893)

In order to more effectively treat cardiovascular diseases, including hypertension, a combined preparation containing candesartan, amlodipine, and atorvastatin with different mechanisms of action as above can be considered, but an alkalizer used to secure the stability of atorvastatin may increase the production of related substances of amlodipine and affect the solubility of candesartan.

Therefore, it is difficult to design a dosage form so that candesartan, amlodipine, and atorvastatin can exhibit an effective dissolution pattern, and unit dosage forms in the form of a combined preparation containing all of candesartan, amlodipine, and atorvastatin as active ingredients have not been commercialized.

International Publication No. 2006-059217 U.S. Publication No. 4681893

An object of the present invention is to provide a pharmaceutical combination preparation containing three active ingredients, specifically, candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof, and amlodipine. or a pharmaceutically acceptable salt thereof, comprising: a first compartment containing candesartan or candesartan cilexetil; and a second compartment containing atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein amlodipine or a pharmaceutically acceptable salt thereof includes atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof. It is a specific problem to provide a pharmaceutical combination preparation that is not included in the second compartment.

Furthermore, the pharmaceutical combination preparation of the present invention has a pH in the range of 8.0 to 10.0 when dissolved in distilled water as a more specific problem.

Furthermore, the pharmaceutical combination preparation of the present invention has a special problem in that the first and second compartments are formulated in a form separated from each other.

In order to solve the above problems, the present invention discloses the following means.

In one aspect, the present invention provides a pharmaceutical combination preparation comprising candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof,

The pharmaceutical combination preparation includes a first compartment containing candesartan or candesartan cilexetil; and a second compartment containing atorvastatin or a pharmaceutically acceptable salt or solvate thereof,

Disclosed is a pharmaceutical combination preparation in which amlodipine or a pharmaceutically acceptable salt thereof is not included in the second compartment containing atorvastatin, a pharmaceutically acceptable salt thereof, or a solvate thereof.

In another aspect, the present invention provides a pharmaceutical combination preparation comprising candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof,

The pharmaceutical combination preparation includes a first compartment containing candesartan or candesartan cilexetil; and a second compartment containing atorvastatin or a pharmaceutically acceptable salt or solvate thereof,

Amlodipine or a pharmaceutically acceptable salt thereof is not included in the second compartment containing atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof;

Disclosed is a pharmaceutical combination preparation characterized in that the pH when dissolved in distilled water is within the range of 8.0 to 10.0.

The pharmaceutical combination preparation according to the present invention contains active ingredients of candesartan, amlodipine, and atorvastatin at the same time, and the dissolution pattern and PK profile of each active ingredient are ^Lipitor® tablets, a single preparation of atorvastatin, and a combination preparation of candesartan and amlodipine. It is equivalent to the dissolution pattern and PK profile at the time of combined administration of Cantabel ^® tablets, and has an effect that can exhibit equivalent pharmacological effects.

The pharmaceutical combination preparation according to the present invention does not greatly increase the content of individual related substances and total related substances under long-term and accelerated conditions, so it is highly stable and can significantly improve the convenience of taking medicine, so it is used for preventing or treating hypertension and hyperlipidemia. As such, it can be used as a useful complex preparation.

Effects of the present invention are not limited to the effects mentioned above, and various effects may be included within a range apparent to those skilled in the art from the contents to be described below.

Hereinafter, this specification will be described in more detail.

A detailed description of this is as follows. The terms used in this specification have been selected from general terms that are currently widely used as much as possible while considering the functions in the present invention, but these may vary depending on the intention of a person skilled in the art, precedent, or the emergence of new technologies. In addition, in a specific case, there is also a term arbitrarily selected by the applicant, and in this case, the meaning will be described in detail in the description of the invention. Therefore, the term used in the present invention should be defined based on the meaning of the term and the overall content of the present invention, not simply the name of the term.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related art, and unless explicitly defined in this application, it should not be interpreted in an ideal or excessively formal meaning. don't

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

Hereinafter, each description and embodiment disclosed in the present invention can also be applied to other descriptions and embodiments for each. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be seen that the scope of the present invention is limited by the specific descriptions described below.

Expressions such as “comprising” used in this specification are understood as open-ended terms that include the possibility of including other embodiments, unless specifically stated otherwise in a phrase or sentence in which the expression is included. It should be.

The inventors of the present invention have developed a drug-drug interaction (DDI) for each combination drug to develop a three-component combination formulation containing ARB-based candesartan, CCB-based amlodipine, and a statin-based atorvastatin, a hyperlipidemia treatment among hypertension drugs. Efforts were made to design formulations that minimize stability, stability, and interactions.

The inventors of the present invention designed the formulation of a pharmaceutical combination formulation to solve the above problems, and as a result, the dissolution pattern and PK profile of each active ingredient were Lipitor ^® tablets, a single formulation of atorvastatin, and a combination formulation of candesartan and amlodipine. The present invention was completed by confirming that the dissolution pattern and PK profile of Cantabel ^® tablets are equivalent to the combined administration, so that they can exhibit equivalent pharmacological effects, and that the stability in long-term and accelerated conditions can significantly improve the convenience of taking medication. It became.

Hereinafter, the present invention will be described in detail.

Pharmaceutical combination preparation

In order to solve the above problems, the present invention discloses the following means.

In one aspect, the present invention provides a pharmaceutical combination preparation comprising candesartan or candesartancilexetil, atorvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical combination preparation a first compartment containing candesartan or candesartan cilexetil; and a second compartment containing atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein amlodipine or a pharmaceutically acceptable salt thereof includes atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof. It provides a pharmaceutical combination preparation that is not included in the second compartment.

In another aspect, the present invention provides a pharmaceutical combination preparation comprising candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof, The combination preparation includes a first compartment containing candesartan or candesartan cilexetil; and a second compartment containing atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein amlodipine or a pharmaceutically acceptable salt thereof includes atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof. It is not included in the second compartment, and provides a pharmaceutical combination preparation characterized in that the pH is within the range of 8.0 to 10.0 when dissolved in distilled water.

In the present invention, the term "candesartan" refers to angiotensin II receptor blocker (ARB), which is a benzimidazole-based drug represented by the following formula (1) and is mainly used for the treatment of hypertension. Its specific chemical name is 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl ]-1H-benzimidazole-7-carboxylic acid.

[Formula 1]

In the present invention, the term "candesartan cilexetil" is a prodrug of candesartan cilexetil represented by the following formula (2), which shows activity by being hydrolyzed into candesartan due to ester hydrolysis when absorbed in the gastrointestinal tract. means that Its specific chemical name is 1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimi dazole-7-carboxylate.

[Formula 2]

The candesartan or candesartan cilexetil can be easily chemically synthesized and prepared by a person skilled in the art according to a known synthesis method, or can be purchased and used as a commercially produced product.

In the present invention, the term "amlodipine" is a compound represented by the following formula (3) and refers to a calcium channel blocker mainly used for the treatment of hypertension and angina pectoris. Its specific chemical name is 3-ethyl-5methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridine dicar It is a voxylate.

[Formula 3]

The amlodipine may be easily chemically synthesized and prepared by a person skilled in the art according to a known synthesis method, or a commercially produced product may be purchased and used.

In the present invention, the term "atorvastatin" is a compound represented by the following Chemical Formula 4 and refers to an HMG-CoA reductase inhibitor mainly used for the treatment of hyperlipidemia, hypercholesterolemia and atherosclerosis. Its specific chemical name is [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[ (phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.

[Formula 4]

The atorvastatin may be easily chemically synthesized and prepared by a person skilled in the art according to a known synthesis method, or may be purchased and used as a commercially produced product.

In the present invention, the term “pharmaceutically acceptable salt” means a salt derived from a pharmaceutically acceptable acid or base. In the present invention, a pharmaceutically acceptable salt is a concentration that has a relatively non-toxic and harmless effective effect on patients, and means any organic or inorganic addition salt in which the side effects caused by the salt do not reduce the beneficial efficacy of the active pharmacological ingredient. do.

In the present invention, the term "solvate" means a hydrate, an acetone solvate, a methanol solvate, an ethanol solvate, and the like.

Specifically, the pharmaceutically acceptable salts of ampyrodine may be used in the form of hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartate, citrate, and besylate, Amlodipine besylate may be preferably used, but is not limited thereto.

Specifically, a pharmaceutically acceptable salt of atorvastatin may be used in the form of a calcium salt, magnesium salt, sodium salt, potassium salt, or aluminum salt, and as a solvate, it may be used in the form of a hydrate. In the present invention, atorvastatin is 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.

In the present invention, the terms "first", "second", "third", etc. do not indicate a particular order, and are simply intended to indicate that the meanings of terms to be described later are different from each other.

In the present invention, the pharmaceutical combination preparation may be formulated in a form in which the first and second compartments are separated from each other, but is not limited thereto.

In the present invention, the term "separated form" means that the first compartments are separated from each other and separated from the second compartment by one or more additional compartments.

At this time, in order to be formulated in a separated form, between the first and second compartments A third compartment containing only additives or not including atorvastatin or a pharmaceutically usable salt or solvate thereof, candesartan or candesartan cilexetil may be further included, but is not limited thereto.

In the present invention, the term "third compartment" is located between the first compartment and the second compartment to separate the first and second compartments, and means a compartment consisting only of pharmaceutical additives in the third compartment, or , means a compartment comprising pharmaceutical additives and pharmacologically active substances.

At this time, the third compartment may include pharmaceutical additives such as a binder, a diluent, a disintegrant, and a lubricant, but is not limited thereto.

Specifically, the binder may be at least one selected from the group consisting of polyvinylpyrrolidone (PVP), methyl cellulose, and hydroxypropylmethyl cellulose (HPMC), but is not limited thereto.

In addition, the diluent may be at least one selected from the group consisting of anhydrous calcium hydrogen phosphate, microcrystalline cellulose, xylitol, trehalose, sorbitol, maltose, sorbitol, erythritol, glucose, maltitol, mannitol, sucrose, lactose, and hydrates thereof. It is not.

In addition, the disintegrant may be at least one selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, alginic acid or a sodium salt thereof, and mixtures thereof. It is not limited.

In addition, the lubricant is sodium stearyl fumarate, magnesium stearate, calcium stearate, white sugar, fatty acid stearate, sucrose fatty acid ester, talc, hydrogenated vegetable oil, high melting point wax, glyceryl fatty acid esters, glyceryl behe It may be at least one selected from the group consisting of nates and mixtures thereof, but is not limited thereto.

In the present invention, preferably, the third compartment may include polyvinylpyrrolidone (PVP), anhydrous calcium hydrogen phosphate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, but is not limited thereto.

In the present invention, the third compartment may include 5 to 40% by weight, specifically 10 to 30% by weight based on the weight of the total pharmaceutical combination formulation, but is not limited thereto.

As described above, by including the third compartment in the pharmaceutical combination preparation of the present invention, the first compartment and the second compartment are formulated in a form separated from each other, and candesartan or candesartan for the alkalizing agent included in the second compartment to be described later Since the increase in absorption of tancilexetil can be minimized, it does not affect the solubility of candesartan or candesartan cilexetil, so there is an advantage in that a pharmaceutical combination preparation can be designed.

In the present invention, the pharmaceutical combination preparation comprises a first layer comprising candesartan or candesartan cilexetil and amlodipine or a pharmaceutically acceptable salt thereof; a second layer comprising atorvastatin or a pharmaceutically acceptable salt or solvate thereof; And it may be a three-layer tablet formulation composed of a third layer containing an additive between the first layer and the second layer, but is not limited thereto.

Specifically, the inventors of the present invention recognized the need to design a formulation that minimizes the interaction between an alkalizing agent of atorvastatin or a pharmaceutically acceptable salt or solvate thereof and candesartan or candesartan cilexetil, By designing to include an additive layer between the first layer and the second layer through necessity, the first layer and the second layer are formulated in a form separated from each other, so that candesartan or candesartan cilexetil can be absorbed by the alkalizing agent. As the increase can be minimized, bioequivalence can be secured.

In the present invention, the pharmaceutical combination preparation comprises a first layer containing candesartan or candesartan cilexetil; a second layer comprising atorvastatin or a pharmaceutically acceptable salt or solvate thereof; and a third layer including an additive and amlodipine or a pharmaceutically acceptable salt thereof between the first layer and the second layer, but is not limited thereto.

In the present invention, the pharmaceutical combination preparation comprises a first layer comprising candesartan or candesartan cilexetil and amlodipine or a pharmaceutically acceptable salt thereof; and a second layer containing atorvastatin or a pharmaceutically acceptable salt or solvate thereof, but is not limited thereto.

In the present invention, the second compartment containing atorvastatin or a pharmaceutically acceptable salt or solvate thereof may contain an alkalizing agent, but is not limited thereto.

In the present invention, the term "alkalizing agent" means an alkaline compound for stabilizing atorvastatin or a pharmaceutically acceptable salt or solvate thereof.

Specifically, in an acidic environment, atorvastatin degrades into the corresponding lactone. When formulated into tablets, powders or other dosage forms, it may exist in contact with pharmaceutical additives such as binders and diluents, or may be destabilized in contact with additives. At this time, the alkalinizing agent is to control the solubility and bioavailability by preventing the decomposition of atorvastatin or a pharmaceutically acceptable salt or solvate thereof, which is an active substance, and is used to control atorvastatin or a pharmaceutically acceptable salt or solvate thereof. It can be used to modulate pharmacokinetic parameters by influencing solubility.

In the present invention, the alkalinizing agent is magnesium hydroxide (Mg(OH) ₂ ), magnesium carbonate (MgCO ₃ ), calcium carbonate (CaCO ₃ ), sodium carbonate (Na ₂ CO ₃ ), meglumine (C ₇ H ₁₇ NO ₅ ), arginine (C ₆ H ₁₄ N ₄ O ₂ ) and sodium hydroxide (NaOH) may be one or more selected from the group consisting of, but is not limited thereto.

In the present invention, the density of the alkalizing agent may be 0.2 to 1.5 g / cm ³ , specifically, the density of the alkalizing agent may be 0.5 to 1.3 g / cm ³ , and the optimum density within the above range is 0.8 to 1.3 g/cm ³ or 0.5 to 0.7 g/cm ³ , but is not limited thereto.

In the present invention, the alkalinizing agent may be included in an amount of 10 to 50% by weight based on the total weight of the second compartment containing atorvastatin or a pharmaceutically acceptable salt or solvate thereof, specifically 20 to 45%. It may be included in % by weight, but is not limited thereto. That is, in the case of an alkalinizing agent, by satisfying the conditions of particle size, surface area, and density, the dissolution rate of ^Lipitor® -defined atorvastatin calcium trihydrate can be expressed at a level equivalent to that of atorvastatin calcium trihydrate.

In the present invention, the pharmaceutical combination formulation may have a pH in the range of 8.0 to 10.0 when dissolved in distilled water.

Specifically, when an alkalizing agent is used in the second compartment containing atorvastatin or a pharmaceutically acceptable salt or solvate thereof, the in vivo absorption of candesartan or candesartan cilexetil contained in the first compartment is not affected. Therefore, it is necessary to adjust the pH of the pharmaceutical combination preparation, and specifically, when the pH of the pharmaceutical combination preparation when dissolved in distilled water is adjusted within the range of 8.0 to 10.0, specifically within the range of 8.5 to 9.5, Bell ^® definition can be expressed at a level equivalent to the dissolution rate of Candesartan.

In the present invention, candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof may be in the form of granules, specifically, the first compartment. Candesartan or candesartan cilexetil and amlodipine or a pharmaceutically acceptable salt thereof included in the second compartment and atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof included in the second compartment are in the form of granules. may be, but is not limited thereto.

In the present invention, the third compartment containing only additives or not containing atorvastatin or a pharmaceutically usable salt thereof or a solvate thereof, candesartan or candesartan cilexetil may be in the form of granules, and is limited thereto. it is not going to be

In the present invention, the granules may be prepared by conventional granulation methods including dry granulation and wet granulation, preferably by wet granulation.

The granules of the present invention may further include a binder, and a commonly used binder may be used as the binder.

In the present invention, the candesartan or candesartan cilexetil may be 8 to 16 mg based on a unit formulation, but is not limited thereto.

In the present invention, the amlodipine or a pharmaceutically acceptable salt thereof may be 5 to 10 mg based on a unit formulation, but is not limited thereto.

In the present invention, the amount of atorvastatin or a pharmaceutically acceptable salt or solvate thereof may be 10 to 40 mg based on a unit formulation, but is not limited thereto.

Specifically, the pharmaceutical composition comprises candesartan or candesartan cilexetil, amlodipine or a pharmaceutically acceptable salt thereof and atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof in the following doses based on a unit formulation. It can be done, but is not limited thereto.

(1) 8 mg of candesartan or candesartancilexetil, 5 mg of amlodipine or a pharmaceutically acceptable salt thereof, and 10 mg of atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof;

(2) 16 mg of candesartan or candesartancilexetil, 5 mg of amlodipine or a pharmaceutically acceptable salt thereof, and 20 mg of atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof;

(3) 16 mg of candesartan or candesartancilexetil, 10 mg of amlodipine or a pharmaceutically acceptable salt thereof, and 40 mg of atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof.

In the present invention, the pharmaceutical combination preparation may be for preventing or treating hypertension and hyperlipidemia, but is not limited thereto.

In the present invention, the pharmaceutical composition may exhibit a dissolution rate of candesartan or candesartan cilexetil equivalent to the dissolution rate of candesartan cilexetil in Cantabel ^® tablets.

In the present invention, the pharmaceutical composition may exhibit a dissolution rate of amlodipine or a pharmaceutically acceptable salt thereof equivalent to that of Cantabel ^® tablet amlodipine besylate.

In the present invention, the pharmaceutical composition may exhibit a dissolution rate of atorvastatin or a pharmaceutically acceptable salt or solvate thereof equivalent to that of atorvastatin calcium trihydrate defined in ^Lipitor® .

In the present invention, candesartan or candesartan cilexetil and amlodipine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition has a blood concentration-time curve at a bioequivalent level compared to Cantabel ^® tablets having the same active ingredient dose. It can represent the area under (hereinafter referred to as 'AUC').

In the present invention, atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof in the pharmaceutical composition exhibits a bioequivalent blood concentration-time area under the curve (AUC) compared to ^Lipitor® tablets having the same active ingredient dose. can

A method for preventing or treating hypertension and hyperlipidemia comprising administering a therapeutically effective amount of a pharmaceutical combination preparation to a subject in need thereof

The present invention is to provide a method for preventing or treating hypertension and hyperlipidemia comprising administering a therapeutically effective amount of the pharmaceutical combination preparation to a subject in need thereof.

The prophylactic or therapeutic method of the present invention includes not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding its symptoms by administering the pharmaceutical combination preparation. In the management of disease, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Dosage and frequency of dosing will vary according to the age, weight and response of the individual patient. A suitable dosage regimen can be readily selected by those skilled in the art who take these factors into account. In addition, the method for preventing or treating hypertension and hyperlipidemia of the present invention may further include the administration of a therapeutically effective amount of an additional active agent useful for disease treatment together with the pharmaceutical combination preparation, and the additional active agent Synergistic effects or auxiliary effects may be exhibited with pharmaceutical combination preparations.

Use of a pharmaceutical combination preparation for the manufacture of a drug having an effect of preventing or treating hypertension and hyperlipidemia

The present invention is to provide a use of a pharmaceutical combination preparation for the manufacture of a drug having the effect of preventing or treating hypertension and hyperlipidemia.

The pharmaceutical combination preparation for preparing a drug may be mixed with acceptable adjuvants, diluents, carriers, etc., and may be prepared as a combination preparation with other active agents to have a synergistic action of the active ingredients.

Use of a pharmaceutical combination preparation for preparing a drug having an effect of preventing or treating hypertension and hyperlipidemia

The present invention is to provide a use for the preparation of a drug having a preventive or therapeutic effect on hypertension and hyperlipidemia of a pharmaceutical combination preparation.

Matters mentioned in the pharmaceutical combination preparation of the present invention, the manufacturing method, prevention or treatment method, and use of the pharmaceutical combination preparation are equally applicable unless they contradict each other.

Hereinafter, the present invention will be described in detail based on examples. However, if the following examples are only for exemplifying the present invention, the scope of the present invention is not limited thereto.

Example: Preparation of Pharmaceutical Combination Formulations

Example 1

compartment ingredient name Example 1 Content (mg) candesartan cilexetil and
Amlodipine Besylate Granules candesartan cilexetil 16.00 amlodipine besylate
(as amlodipine) 13.88
(10.00) mannitol 148.32 microcrystalline cellulose 50.00 copovidone 12.00 Hydroxypropyl Cellulose 12.00 triethyl citrate 2.60 Sodium stearyl fumarate 2.60 Magnesium Stearate 2.60 Total weight of candesartan amlodipine besylate granules 260.00 atorvastatin
Calcium Trihydrate Granules Atorvastatin Calcium Trihydrate
(as atorvastatin) 43.40
(40.00) lactose hydrate 58.04 microcrystalline cellulose 39.16 Croscarmellose Sodium 25.00 Hydroxypropyl Cellulose 6.00 Precipitated Magnesium Carbonate 80.00 Polysorbate 80 2.40 Magnesium Stearate 2.00 Total Weight of Atorvastatin Calcium Trihydrate Granules 256.00

1) Preparation of candesartan cilexetil and amlodipine besylate granules

Hydroxypropyl cellulose and triethyl citrate were added to purified water to prepare a binder solution, and amlodipine besylate and mannitol were mixed and sieved, and then a mixture of candesartan cilexetil, microcrystalline cellulose and mannitol was added to the binder solution and kneaded. .

After granulating the union, drying in a cabinet dryer, and sizing in Comil, mannitol, copovidone, magnesium stearate and sodium stearyl fumarate were added and finally mixed to prepare granules of candesartan cilexetil and amlodipine besylate.

2) Preparation of atorvastatin calcium trihydrate granules

After adding hydroxypropyl cellulose and polysorbate 80 to purified water to prepare a binder solution, a mixture of alkalizing agents such as precipitated magnesium carbonate, croscarmellose sodium, atorvastatin calcium trihydrate, lactose hydrate and microcrystalline cellulose and a binder solution United.

The kneaded material was granulated, dried in a fluidized bed granulator, and sized in Comil, and atorvastatin calcium trihydrate granules were prepared by adding croscarmellose sodium and magnesium stearate.

3) tableting

Tablets were prepared by tableting granules of candesartan cilexetil and amlodipine besylate and granules of atorvastatin calcium trihydrate.

4) coating

The colorant was suspended in purified water, coated using a coating machine, and then dried to prepare one coated tablet.

Example 2

In Example 1, 8 mg of candesartan cilexetil as active ingredients, 5 mg of amlodipine (6.94 mg of amlodipine besylate) and 10 mg of atorvastatin (10.85 mg of atorvastatin calcium trihydrate) were used, and the content of magnesium carbonate was 12 mg. , and the pharmaceutical additives included in the candesartan cilexetil and amlodipine besylate granules and the atorvastatin calcium trihydrate granules were adjusted in the same manner according to the reduced ratio of the main ingredient, in the same manner as in Example 1. A pharmaceutical combination formulation in the form of a double layer was prepared.

Example 3

In Example 1, 8 mg of candesartan cilexetil as active ingredients, 5 mg of amlodipine (6.94 mg of amlodipine besylate) and 10 mg of atorvastatin (10.85 mg of atorvastatin calcium trihydrate) were used, and carbonic acid was used instead of magnesium carbonate. Calcium (33 mg, particle size: 0.5 to 45 μm, surface area: 3,500 cm ² /g, density: 0.8 to 1.3 g/cm ³ of heavy calcium carbonate) is used, and granules of candesartan cilexetil and amlodipine besylate are used. A double-layered pharmaceutical combination preparation was prepared in the same manner as in Example 1, except that the pharmaceutical additives included in the atorvastatin calcium trihydrate granules were equally adjusted according to the reduced ratio of the main component.

Example 4

In Example 1, calcium carbonate (33 mg, particle size: 0.5-45 μm, surface area: 3,500 cm ² /g, density: 0.8-1.3 g/cm ³ of heavy calcium carbonate) was used instead of magnesium carbonate, and 2) Between the preparation of atorvastatin calcium trihydrate granules and 3) the tableting step, the step of preparing the following additive layer granules was performed, and in the tableting step, candesartan cilexetil granules, additive layer granules and atorvastatin calcium trihydrate granules were sequentially prepared. A pharmaceutical combination preparation in the form of a three-layer tablet was prepared in the same manner as in Example 1, except that the mixture was placed and tableted.

<Preparation of additive layer granules>

Additive layer granules were prepared by mixing microcrystalline cellulose (82 mg), anhydrous calcium hydrogen phosphate (76 mg), copovidone (30 mg), croscarmellose sodium (10 mg) and magnesium stearate (2 mg). .

Example 5

Excluding the use of precipitated calcium carbonate (33 mg, particle size: 0.5-15 μm, surface area: 15,600 cm ² /g, density: 0.5-0.7 g/cm ³ precipitated calcium carbonate) instead of precipitated calcium carbonate in Example 4 Then, a pharmaceutical combination preparation in the form of a trilayer tablet was prepared in the same manner as in Example 4.

Example 6

In Example 5, amlodipine besylate, an active ingredient contained in candesartan cilexetil and amlodipine besylate granules, was applied to the additive layer granules to obtain candesartan cilexetil granules, additive layer granules containing amlodipine besylate, and atorvastatin calcium 3 A pharmaceutical combination preparation in the form of a trilayer tablet was prepared in the same manner as in Example 5, except that the hydrate granules were used.

Comparative Example: Control drug setting

In Comparative Example 1, ^Lipitor® tablets 40 mg, Comparative Example 2, ^Cantabel® tablets 16/10 mg, Comparative Example 3, ^Lipitor® tablets 10 mg, and Comparative Example 4, ^Cantabel® tablets 8/5 mg. did

Experimental example

Experimental Example 1: Evaluation of the effect of an alkalizing agent on candesartan cilexetil (high dose)

1) Experiment method

In order to secure the stability of atorvastatin calcium trihydrate, the pharmaceutical combination preparation in the form of a double tablet of Example 1 to which magnesium carbonate (MgCO ₃ ), an alkalizing agent, was added, and Comparative Example 1 ( ^Lipitor® tablets 40 mg) and Comparative Example 2 (Cantha Bell ^® tablets 16/10 mg) compared the pharmacokinetic behavior with concomitant administration.

Specifically, the pharmaceutical combination formulation (high dose) according to Example 1 was orally administered to healthy adult males, or Comparative Example 1 ( ^Lipitor® tablets 40mg) and Comparative Example 2 ( ^Cantabel® tablets 16/ Bioequivalence was confirmed after co-administration of 10 mg).

Blood was collected at the same time after single administration, and blood concentrations of atorvastatin calcium trihydrate, amlodipine besylate, and candesartan cilexetil were respectively quantified using LC-MS/MS. Atorvastatin calcium trihydrate and amlodipine besylate when administered orally in combination with the pharmaceutical combination formulation (high dose) according to Example 1 after quantification and Comparative Example 1 ( ^Lipitor® tablets 40mg) and Comparative Example 2 ( ^Cantabel® tablets 16/10mg) and AUC values of candesartan cilexetil were log-transformed, and then the geometric mean was obtained, and a 90% confidence interval for the ratio of the geometric mean was calculated. If the 90% confidence interval is 0.8 to 1.25, the two agents are considered to be bioequivalent.

-Test drug: Pharmaceutical combination preparation according to Example 1 (high dose)

- Control drug ①: ^Lipitor® tablets 40mg (Comparative Example 1)

- Control drug ②: ^Cantabel® tablets 16/10mg (Comparative Example 2)

2) Experimental results

Specifically, it was confirmed that the pharmaceutical combination preparation (high dose) according to Example 1 increased the absorption of candesartan cilexetil by about 20% based on AUC under the influence of magnesium carbonate (MgCO ₃ ) as an alkalizing agent.

T/R Example 1 (MgCO ₃ ) Atorvastatin Calcium Trihydrate AUC 1.02 amlodipine besylate AUC 1.05 candesartan cilexetil AUC 1.20

Experimental Example 2: Evaluation of the effect of alkalinizing agent types (low dose)

1) Experiment method

Comparative Example 3 In order to select the amount of alkalizing agent capable of maintaining the same pH as the pH of 1 tablet of 10 mg of Lipitor ^® tablet, candesartan cilexetil (8mg) according to the type and amount of alkalizing agent was added to 900 mL of distilled water. Then, the solubility was confirmed by dissolving for 3 hours while stirring at 200 rpm.

-Test drug ①: Pharmaceutical combination preparation according to Example 2

- Test drug ②: Pharmaceutical combination preparation according to Example 3

- Control drug ①: ^Lipitor® tablets 10mg (Comparative Example 3)

2) Experimental results

Referring to Table 3, it was confirmed that when using the alkalizer according to Examples 2 and 3, the pH at the same level as Comparative Example 3 (Lipitor ^® tablet 10mg) could be maintained.

alkalizing agent pH Candesartan content magnesium carbonate
(MgCO ₃ ) 20 mg
(Example 1) 9.6 82.6% 16mg 9.3 82.4% 12mg
(Example 2) 8.9 75.3% 10 mg 8.5 72.5% calcium carbonate
(CaCO ₃ ) Lipitor ^® tablets 10mg
(Comparative Example 3) 8.8 72.3% 33mg
(Example 3) 8.6 73.3%

Experimental Example 3: In vivo absorption effect of candesartan cilexetil (low dose)

1) Experiment method

When magnesium carbonate (MgCO ₃ ) and calcium carbonate (CaCO ₃ ) were used as alkalizing agents contained in the atorvastatin calcium trihydrate layer, the in vivo absorption of candesartan cilexetil was investigated in clinical trials at low doses (8/5/10 mg). Confirmed.

Specifically, after single administration of the pharmaceutical combination preparations according to Examples 2 and 3 to healthy adult males, blood was collected at the same time, and atorvastatin calcium trihydrate, amlodipine besylate and The blood concentration of candesartan cilexetil was quantified, respectively. After quantification, the AUC values of atorvastatin calcium trihydrate, amlodipine besylate, and candesartan cilexetil at each administration of the pharmaceutical combination preparations according to Examples 3 and 4 were log-transformed, and then the geometric mean was obtained, and the geometric mean ratio 90% confidence intervals were calculated.

- Test drug ①: Pharmaceutical combination preparation according to Example 2

- Test drug ②: Pharmaceutical combination preparation according to Example 3

In addition, the pH environment and the absorption behavior of candesartan due to the difference in the weight of the alkalizing agent at high and low doses of the pharmaceutical combination formulation were evaluated.

Specifically, the pharmaceutical combination preparations according to Examples 2 and 3 and the pharmaceutical combination preparations according to Comparative Examples 3 and 4 were added to 900 mL of distilled water and then dissolved for 3 hours while stirring at 200 rpm to confirm solubility.

-Test drug: Pharmaceutical combination preparation according to Examples 2 and 3

- Control drug ①: ^Lipitor® tablets 10mg (Comparative Example 3)

- Control drug ②: ^Cantabel® tablets 8/5mg (Comparative Example 4)

2) Experiment method

Table 4 shows the pharmacokinetic behavior according to the type of alkalizing agent at a low dose (8/5/10 mg) of a pharmaceutical combination formulation.

Referring to Table 4, it was confirmed that the pharmacokinetic behavior according to the type of alkalizing agent was similar at low doses (8/5/10 mg).

T/R Example 2 (MgCO ₃ ) Example 3 (CaCO ₃ ) atorvastatin
calcium trihydrate AUC 0.98 1.01 amlodipine besylate AUC 0.99 0.97 candesartan cilexetil AUC 0.93 0.93

In addition, Table 5 shows the pH environment and the absorption behavior of candesartan due to the weight difference of the alkalizing agent at high and low doses.

Referring to Table 5, it was confirmed that the pH environment and the absorption behavior of candesartan were different due to the difference in the weight of the alkalizing agent at high and low doses, and the solubility of candesartan cilexetil varied depending on the pH range. In order to exhibit drug absorption patterns similar to Examples 3 and 4, it was confirmed that adjustment to pH 8.0 to 10.0 was necessary.

division
(Can/Aml/Ato) Comparative Examples 3 and 4 Example 2
(MgCO ₃ ) Example 3
(CaCO ₃ ) CaCO ₃ pH solubility
(can) MgCO ₃ pH solubility
(can) CaCO ₃ pH solubility
(can) high dose
(16/10/40) 132mg 9.0 38.7% 48mg 10.0 50.2% 132mg 8.7 36.2% medium dose
(16/5/20) 66mg 8.9 58.2% 24mg 8.8 58.7% 66mg 8.9 49.3% low dose
(8/5/10) 33mg 8.8 72.3% 12 mg 8.7 67.8% 33mg 8.6 73.3%

(In Table 5, Can denotes candesartan cilexetil, Aml denotes amlodipine besylate, and Ato denotes atorvastatin calcium trihydrate.)

Experimental Example 4: Formulation design suitable for drug release (high dose)

1) Experiment method

It is necessary to design a formulation that minimizes the interaction between the alkalizing agent of the atorvastatin calcium trihydrate layer and candesartan.

A formulation was designed with calcium carbonate (CaCO ₃ ) showing a pH similar to that of Comparative Examples 3 and 4 and the solubility of candesartan cilexetil regardless of low, medium, and high doses. was designed and carried out.

Candesartan cilexetil for the pharmaceutical combination formulation of Example 3 in which the granules containing candesartan cilexetil and amlodipine besylate and the granules containing atorvastatin calcium trihydrate were formulated into a double-layer tablet and the alkalizer of the atorvastatin layer The pharmaceutical combination formulation of Example 4 formulated as a triple-layer tablet in which an additive granule layer was added between the two layers to minimize the increase in absorption was designed.

Clinical trials were conducted according to Examples 3 and 4, and the results are shown in Table 5.

Specifically, after single administration of the pharmaceutical combination preparations according to Examples 3 and 4 to healthy adult males, blood was collected at the same time, and atorvastatin calcium trihydrate, amlodipine besylate and The blood concentration of candesartan cilexetil was quantified, respectively. After quantification, the AUC values of atorvastatin calcium trihydrate, amlodipine besylate, and candesartan cilexetil at each administration of the pharmaceutical combination preparations according to Examples 3 and 4 were log-transformed, and then the geometric mean was obtained, and the geometric mean ratio 90% confidence intervals were calculated.

-Test drug ①: Pharmaceutical combination preparation according to Example 3

-Test drug ②: Pharmaceutical combination preparation according to Example 4

2) Experimental results

Referring to Table 6, it was confirmed that the increase in absorption of candesartan or candesartan cilexetil to an alkalizing agent could be minimized in the triple-layer tablet according to Example 4 compared to the double-layer tablet of Example 3.

T/R Example 3 (bilayer tablet) Example 4 (trilayer tablet) atorvastatin
calcium trihydrate AUC 0.95 1.05 amlodipine besylate AUC 1.00 1.04 candesartan cilexetil AUC 0.84 0.91

Experimental Example 5: Elution pattern of atorvastatin calcium trihydrate according to the particle size of calcium carbonate (high dose)

1) Experiment method

In order to confirm that the dissolution pattern of the drug varies depending on the surface area and particle size of calcium carbonate, the dissolution pattern of the pharmaceutical combination preparation according to Examples 4 and 5 was confirmed.

Specifically, the dissolution rate measurement was tested based on the first method (rotating sample pass method) listed in the Korean Pharmacopoeia, and 900 mL of DW was used as the eluate, the elution temperature was 37 ± 0.5 ° C, and the rotation speed was 50 rpm. . After taking the elution solution at 5, 10, 15, 30, 45, 60, and 90 minutes after the start of elution, the filtered solution was used as the sample solution, and analyzed with a liquid chromatograph along with the standard solution to determine the elution rate. measured.

-Test drug ①: Pharmaceutical combination preparation according to Example 4

- Test drug ②: Pharmaceutical combination preparation according to Example 5

- Control drug ①: ^Lipitor® tablets 40mg (Comparative Example 1)

2) Experimental results

Table 8 shows the results of the dissolution pattern of the Lipitor ^® tablet 40mg according to Comparative Example 1 and the pharmaceutical combination formulations according to Examples 4 and 5.

Referring to Table 8, in the case of calcium carbonate, it was confirmed that the dissolution pattern of Comparative Example 1 and atorvastatin calcium trihydrate was similar to that of Comparative Example 1 as the particle size was smaller and the surface area was larger.

division Calcium Carbonate (Heavy) Calcium Carbonate (hard) Particle Size (μm) 0.5 to 45 0.5 to 15 Surface area (cm ² /g) 3,500 15,600 Density (g/cm ³ ) 0.8 to 1.3 0.5 to 0.7

ingredient division D.W. Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes Ator
Vastatin Calcium
trihydrate Comparative Example 1 61.9 67.4 70.7 75.0 78.0 79.3 95.9 Example 4
(medium quality) 8.1 34.7 48.8 64.1 68.4 71.0 84.8 Example 5
(reshuffle) 30.5 58.2 67.4 78.1 83.5 84.1 91.6

Experimental Example 6: Dissolution pattern according to the composition of the trilayer tablet of the amlodipine component (high dose)

1) Experiment method

In order to confirm that the dissolution pattern of the drug changes depending on the structure of the amlodipine besilate salt in the trilayer tablet, the dissolution pattern of the pharmaceutical combination preparation according to Examples 5 and 6 was confirmed.

Specifically, the dissolution rate measurement was tested based on the first method (rotating sample pass method) listed in the Korean Pharmacopoeia, the elution solution was 900 mL of DW, the elution temperature was 37 ± 0.5 ° C, and the rotation speed was 50 rpm. . The elution solution was taken at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes after the start of elution, and the filtered solution was used as a sample solution, and the dissolution rate was measured by analyzing the liquid chromatograph together with the standard solution.

-Test drug ①: Pharmaceutical combination preparation according to Example 5

- Test drug ②: Pharmaceutical combination preparation according to Example 6

2) Experimental results

The results of the dissolution pattern of the pharmaceutical combination preparations according to Examples 5 and 6 are shown in Table 9.

Referring to Table 9, it was confirmed that when amlodipine besylate was contained in the additive layer granules (third compartment), the dissolution rate was higher than when included in the candesartan cilexetil compartment (first compartment) due to rapid disintegration. At this time, , it was confirmed that there was no effect on the dissolution rates of candesartan cilexetil and atorvastatin calcium trihydrate. In the case of amlodipine besylate, the clinical effect of the in-vitro dissolution change is considered to be minimized because the clinical drug release was confirmed to be similar to that of the comparative example even though the prescription was changed in the examples.

ingredient division D.W. Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes amlodipine
besylate Example 5 0.1 1.4 6.4 21.1 29.1 32.5 Example 6 17.2 35.4 48.2 62.2 71.8 76.7 candesartan
cilexetil Example 5 0.1 0.3 1.2 3.0 4.5 6.2 Example 6 0.2 0.4 1.6 3.5 5.0 7.3 atorvastatin
calcium trihydrate Example 5 30.5 58.2 67.4 78.1 83.5 84.1 Example 6 32.7 60.3 69.6 80.2 85.8 87.3

Experimental Example 7: Securing equivalence in clinical trials (high dose)

1) Experiment method

Pharmacokinetic test (PK test) for single administration of the pharmaceutical combination preparation according to Example 5 of the present invention and the preparations of Comparative Example 1 ( ^Lipitor® tablets 40mg) and Comparative Example 2 ( ^Cantabel® tablets 16/10mg) was performed to evaluate bioequivalence with concomitant administration.

Specifically, after oral administration of the pharmaceutical combination preparation according to Example 5 to healthy adult males, or combined administration of Comparative Example 1 ( ^Lipitor® tablets 40mg) and Comparative Example 2 ( ^Cantabel® tablets 16/10mg) Bioequivalence was confirmed.

Blood was collected at the same time after single administration, and blood concentrations of atorvastatin calcium trihydrate, amlodipine besylate, and candesartan cilexetil were respectively quantified using LC-MS/MS. Atorvastatin calcium trihydrate, amlodipine besylate, and candesar at the time of combined oral administration of the pharmaceutical combination preparation according to Example 5 after quantification and Comparative Example 1 ( ^Lipitor® tablets 40mg) and Comparative Example 2 ( ^Cantabel® tablets 16/10mg) The AUC values of tancilexetil were logarithmically transformed, the geometric mean was obtained, and a 90% confidence interval for the ratio of the geometric mean was calculated. If the 90% confidence interval is 0.8 to 1.25, the two agents are considered to be bioequivalent.

-Test drug: Pharmaceutical combination preparation according to Example 5

- Control drug ①: ^Lipitor® tablets 40mg (Comparative Example 1)

- Control drug ②: ^Cantabel® tablets 16/10mg (Comparative Example 2)

2) Experimental results

The bioequivalence evaluation results performed as above are shown in Table 10 below. The ratio of the geometric mean of the AUC values of atorvastatin calcium trihydrate, amlodipine besylate, and candesartan cilexetil was suitable for the 90% confidence interval in the range of 0.8 to 1.25, and the pharmaceutical combination preparation according to Example 5 of the present invention and Comparative Example 1 and PK equivalence in concomitant oral administration of 2 was secured.

T/R Example 5 Atorvastatin Calcium Trihydrate AUC 1.05 amlodipine besylate AUC 1.00 candesartan cilexetil AUC 0.96

Claims (17)

A pharmaceutical combination preparation comprising candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof,
The pharmaceutical combination preparation includes a first compartment containing candesartan or candesartan cilexetil; and a second compartment containing atorvastatin or a pharmaceutically acceptable salt or solvate thereof,
Amlodipine or a pharmaceutically acceptable salt thereof is not included in the second compartment containing atorvastatin or a pharmaceutically acceptable salt or solvate thereof. According to claim 1,
The pharmaceutical combination preparation is a pharmaceutical combination preparation, characterized in that the first and second compartments are formulated in a form separated from each other. According to claim 1,
between the first and second compartments A pharmaceutical combination preparation characterized in that it further comprises a third compartment containing only additives or not containing atorvastatin or a pharmaceutically usable salt or solvate thereof, candesartan or candesartan cilexetil. According to claim 3,
In the third compartment,
A pharmaceutical combination preparation comprising a binder, a diluent, a disintegrant and a lubricant. According to claim 3,
The third compartment is a pharmaceutical combination formulation, characterized in that it comprises 5 to 40% by weight based on the weight of the total pharmaceutical combination formulation. According to claim 3,
The pharmaceutical combination preparation includes a first layer comprising candesartan or candesartan cilexetil and amlodipine or a pharmaceutically acceptable salt thereof;
a second layer comprising atorvastatin or a pharmaceutically acceptable salt or solvate thereof; and
A pharmaceutical combination formulation, characterized in that it is a three-layer tablet formulation composed of a third layer containing an additive between the first layer and the second layer. According to claim 3,
The pharmaceutical combination preparation includes a first layer containing candesartan or candesartan cilexetil;
a second layer comprising atorvastatin or a pharmaceutically acceptable salt or solvate thereof; and
A pharmaceutical combination preparation, characterized in that the three-layer tablet formulation consisting of a third layer containing an additive and amlodipine or a pharmaceutically acceptable salt thereof between the first layer and the second layer. According to claim 1,
The pharmaceutical combination preparation includes a first layer comprising candesartan or candesartan cilexetil and amlodipine or a pharmaceutically acceptable salt thereof; and
A pharmaceutical combination preparation characterized in that it is a two-layer tablet formulation composed of a second layer containing atorvastatin or a pharmaceutically acceptable salt or solvate thereof. According to claim 1,
A pharmaceutical combination preparation comprising an alkalizing agent in the second compartment containing atorvastatin or a pharmaceutically acceptable salt or solvate thereof. According to claim 9,
The alkalizer is magnesium hydroxide (Mg(OH) ₂ ), magnesium carbonate (MgCO ₃ ), calcium carbonate (CaCO ₃ ), sodium carbonate (Na ₂ CO ₃ ), meglumine (C ₇ H ₁₇ NO ₅ ), arginine ( C ₆ H ₁₄ N ₄ O ₂ ) And sodium hydroxide (NaOH) characterized in that at least one selected from the group consisting of a pharmaceutical combination preparation. According to claim 9,
The density of the alkalizing agent is 0.2 to 1.5 g / cm ³ Pharmaceutical combination preparation, characterized in that. According to claim 9,
The alkalizing agent is included in 10 to 50% by weight based on the total weight of the second compartment containing the atorvastatin or a pharmaceutically acceptable salt or solvate thereof. According to claim 1,
A pharmaceutical combination preparation, characterized in that candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof are in the form of granules. According to claim 1,
Candesartan or candesartan cilexetil is a pharmaceutical combination preparation, characterized in that 8 to 16 mg based on the unit formulation. According to claim 1,
Amlodipine or a pharmaceutically acceptable salt thereof is a pharmaceutical combination formulation, characterized in that 5 to 10 mg based on the unit formulation. According to claim 1,
A pharmaceutical combination preparation, characterized in that 10 to 40 mg of atorvastatin or a pharmaceutically acceptable salt or solvate thereof is based on a unit dosage form. A pharmaceutical combination preparation comprising candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof,
The pharmaceutical combination preparation includes a first compartment containing candesartan or candesartan cilexetil; and a second compartment containing atorvastatin or a pharmaceutically acceptable salt or solvate thereof,
Amlodipine or a pharmaceutically acceptable salt thereof is not included in the second compartment containing atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof;
A pharmaceutical combination preparation characterized in that the pH ranges from 8.0 to 10.0 when dissolved in distilled water.