WO2019209058A1

WO2019209058A1 - Pharmaceutical formulation

Info

Publication number: WO2019209058A1
Application number: PCT/KR2019/005029
Authority: WO
Inventors: 박준홍; 김민정; 차진선; 박유빈; 김예린
Original assignee: 제일약품주식회사
Priority date: 2018-04-25
Filing date: 2019-04-25
Publication date: 2019-10-31
Also published as: KR20190124071A; KR102108396B1

Abstract

The present invention provides a formulation comprising telmisartan, amlodipine, and rosuvastatin as active ingredients. The present invention provides the formulation in which each of the active ingredients has an excellent dissolution rate, high stability, and excellent bioavailability.

Description

Pharmaceutical preparations

The present invention relates to a pharmaceutical combination comprising telmisartan, rosuvastatin and amlodipine as active ingredients. More specifically, the present invention includes a first mixing portion containing telmisartan as an active ingredient and a second mixing portion containing rosuvastatin and amlodipine as an active ingredient, and relates to a pharmaceutical combination preparation having excellent dissolution rate and stability. will be.

Drugs used in the treatment of hypertension are divided into diuretics, sympathetic inhibitors, and vasodilators, depending on the mechanism of action, and the most widely used vasodilators are angiotensin 2 receptor blockers, ACE inhibitors, and calcium channel blockers.

Angiotensin 2 receptor blockers are primarily used in hypertensive patients who are unable to use ACE excipients and are also used to treat diabetic kidney disease and congestive heart failure. This substance blocks the binding of angiotensin 2 and angiotensin 2-AT1 receptors to inhibit the activation of angiotensin 2-AT1 receptors. Representative drugs include telmisartan, balsatan, olmesartan, candesartan, and ibesatan. .

Amlodipine, a representative dihydropyridine-based calcium channel blocker, relaxes smooth muscle in the arterial wall when the drug is absorbed, thereby lowering blood pressure and increasing blood flow to the myocardium. Amlodipine is commercially available in the form of various salts such as besylic acid, maleic acid, and camsylic acid, and amlodipine besylate is the most widely used.

Meanwhile, HMG-CoA reductase inhibitor (HMG-CoA reductase inhibitor) is the most widely used in the treatment of hyperlipidemia and is involved in the conversion of HMG-CoA to Mevalonate, a rate determining step in the process of cholesterol biosynthesis in hepatocytes. Examples of drugs that inhibit the synthesis of cholesterol in the liver by inhibiting enzymes include rosuvastatin, atorvastatin, and pitavastatin, and these compounds lower total cholesterol and LDL-cholesterol in the human body. And to elevate HDL-cholesterol levels in some individuals.

Hypertension and hyperlipidemia are representative cardiovascular diseases, and more than 50% of hypertension patients have hyperlipidemia and more than 50% of hyperlipidemia patients have high blood pressure. It is also clinically reported to be effective in the treatment of cardiovascular diseases, such as reducing the death and preventing diabetes. (American Journal of Cardiology, 93, 5, 603-606, 2004)

Recently, a combination of hypertension and hyperlipidemia with different mechanisms of action has been reported to be more effective in preventing or treating cardiovascular diseases including hypertension and hyperlipidemia than conventional single-component formulations. There are many difficulties in the implementation.

In formulating several active ingredients in combination, the physical and chemical properties of each of the ingredients, as well as the effects on bioavailability and stability due to in vivo / vitro interactions between the active ingredients, must be considered.

As a representative angiotensin 2 receptor blocker, telmisartan is a poorly soluble drug having a very low solubility in the pH range of 3 to 9 or an alkalizing agent or a solubilizing agent because the drug should be rapidly released and absorbed in the stomach at a Tmax value of about 0.3 to 1.0 hours. It is customary to prepare formulations.

Amlodipine is an unstable free base that is greatly affected by light, heat, and water, and thus has a disadvantage in that its therapeutic effect is poor. Therefore, amlodipine is used in combination with various acid addition salts to maintain stability, but it is stable. Is still needed.

As a representative HMG-CoA reductase inhibitor, rosuvastatin is a drug belonging to the biopharmaceutical classification system II or III, and its bioavailability is very easily affected by the dissolution rate depending on the degree of ionization of the drug released at a specific pH. The composition of the combination is difficult. When exposed to certain physicochemical conditions (acid, moisture, light), it is easy to decompose or oxidize, making it difficult to secure stability. It has been reported that the absorption rate of rosuvastatin decreases by about 50% when the pH of the body changes due to an alkalizing agent. (Curr Med Res Opin. 2008, 24, 4, 1231-1235)

Such properties of drugs are a major obstacle to the development of co-formulations with other ingredients, and even if the formulation or composition is stable in a single-component formulation, it cannot guarantee the stability of the preparation in combination with other drug components. And may not meet the required bioavailability.

Under these circumstances, it is necessary to develop a dispersing pattern and a stable dissolution pattern capable of securing bioavailability of each component by supplementing the problems of the formulation.

[Preceding technical literature]

(Non-Patent Document 1) American Journal of Cardiology, 93, 5, 603-606, 2004

(Non-Patent Document 2) Curr Med Res Opin. 2008, 24, 4, 1231-1235

The present invention, in order to achieve the storage stability and excellent dissolution rate of the co-formulation comprising two or more drugs, the first mixing part and the second mixing part included in the co-formulation includes an excipient suitable for the properties of the drug, the first mixing It is to provide a pharmaceutical combination formulation in which the portion and the second mixing portion are present in physically separated form.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

The present invention

A first mixing portion comprising telmisartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof;

A second mixing portion comprising rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof and amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof Including,

It provides a pharmaceutical combination formulation wherein the first mixing portion and the second mixing portion are present in physically separated form.

The present invention

A first mixing portion comprising telmisartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof, and a sugar or sugar alcohol;

The present invention

Rosuvastatin, pharmaceutically acceptable salts thereof, optical isomers thereof, or hydrates or solvates thereof and amlodipine, pharmaceutically acceptable salts thereof, optical isomers thereof, or hydrates or solvates thereof, and microcrystalline cellulose A second mixing portion,

The present invention

Rosuvastatin, its pharmaceutically acceptable salts, its optical isomers, or its hydrates or solvates and amlodipine, its pharmaceutically acceptable salts, its optical isomers, or its hydrates or solvates, and croscarmellose sodium Including a second mixing unit comprising a,

The present invention

Rosuvastatin, its pharmaceutically acceptable salts, its optical isomers, or its hydrates or solvates and amlodipine, its pharmaceutically acceptable salts, its optical isomers, or its hydrates or solvates, and microcrystalline cellulose and croscarmell A second mixing part comprising sodium rose,

In the combination formulation of the present invention, the first mixing portion and the second mixing portion are present in physically separated form, specifically, in two-layered form, and do not affect the dissolution rate of the three pharmacologically active ingredients included in the formulation of the present invention. It can be eluted quickly.

Specifically, the preparation of the present invention by physically separating the first mixing unit and the second mixing unit due to the physical contact of telmisartan, an active ingredient of the first mixing unit and rosuvastatin and amlodipine, an active ingredient of the second mixing unit. Drug interactions can be inhibited. In particular, when the active ingredient is composed of one part without separation, an alkalizing agent is used to improve the absorption in vivo due to the characteristics of telmisartan having high solubility at high pH. In the case of rosuvastatin, which is rapidly disintegrated and absorbed in the gastrointestinal tract, Disintegration is delayed and dissolution rate is lowered by the alkalizing agent as described above. However, the formulations of the present invention are not only good for in vivo absorption of telmisartan at low pH, but also can achieve excellent dissolution rate and stability of rosuvastatin and amlodipine. Since the first mixing portion and the second mixing portion are present in a physically separated form, specifically, in a two-layered crystal form, the disintegration rate may be controlled due to the physicochemical characteristics of the active ingredient and the excipient constituting each layer. The second mixing portion may disintegrate and elute before the first mixing portion.

In the co-formulation of the present invention, the first mixing part may include sugar or sugar alcohol.

Specifically, even if the first mixing part containing sugar or sugar alcohol is present with the second mixing part in the composite preparation of the present invention, the sugar or sugar alcohol is not only the pharmacologically active ingredient of the first mixing part but also the two mixing parts. As it does not affect the dissolution rate of the pharmacologically active ingredient, the three pharmacologically active ingredients included in the formulation of the present invention may exhibit almost the same or similar dissolution pattern as the single agent containing the respective ingredient.

In addition, in the composite preparation of the present invention, the second mixing part may include microcrystalline cellulose, croscarmellose sodium, or a mixture thereof.

Specifically, the microcrystalline cellulose, croscarmellose sodium or a mixture thereof even if the second mixed portion comprising microcrystalline cellulose, croscarmellose sodium or a mixture thereof is present with the first mixing portion in the composite formulation of the present invention It does not affect the dissolution rate of the two pharmacologically active ingredients of the second mixing part as well as the pharmacologically active ingredients of the first mixing part, so that the three pharmacologically active ingredients included in the formulation of the present invention contain a single ingredient. Elution pattern can be almost the same or similar to the above.

In particular, the composite formulation of the present invention shows excellent stability due to little generation of flexible substances even under accelerated conditions.

Thus, a composite formulation comprising a first mixing portion containing a sugar or sugar alcohol and a second mixing portion containing microcrystalline cellulose, croscarmellose sodium or a mixture thereof is used as a pharmacological agent of the first mixing portion and the second mixing portion. The active ingredient exhibits an excellent dissolution rate, can sufficiently exhibit its pharmacological activity, no problems such as deterioration of stability can occur at all, can significantly improve the convenience of medication, and mass production is easy.

In the present specification, the terms such as the first and the second are only used to distinguish the various layers, the films, the steps, and the like, respectively, but are not intended to indicate the order or the importance. The terminology does not limit the features of layers, films, steps, and the like. Therefore, the terms such as the first and the second may not be used the same in the detailed description, the examples, the claims, and the like, and it is sufficient that the terms such as the first and the second can be distinguished from each other. .

As used herein, `` pharmaceutically acceptable '' is a pharmacologically acceptable autologous pharmaceutical agent having ordinary skill in the art, when administered to humans, typically without causing an allergic reaction such as gastrointestinal disorders, dizziness or the like. It may mean that the conventional use in the manufacture.

As used herein, 'hydrate' is telmisartan, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, rosuvastatin, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or amlodipine, a pharmaceutically acceptable salt thereof. , Or an optical isomer thereof, and the like, are combined with water by a non-covalent intermolecular force, and may include a stoichiometric or non-stoichiometric amount of water. Specifically, the hydrate may include about 0.25 moles to about 10 moles of water based on 1 mole of the active ingredient, and more specifically about 0.5 moles, about 1 moles, about 1.5 moles, about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, and the like.

As used herein, a 'solvate' means telmisartan, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, rosuvastatin, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or amlodipine, a pharmaceutically acceptable salt thereof. A salt, or an optical isomer thereof, and a solvent other than water are bound by intermolecular force, and may include a solvent in stoichiometric or non-stoichiometric amounts. Specifically, the solvate may include a solvent molecule in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, and more specifically about 0.5 mol, about 1 mol, about 1.5 mol, and about 2 mol , About 2.5 moles, about 3 moles, about 5 moles, and the like.

In the present specification, 'telmisartan' is 4 '-((1,4'-dimethyl-2'-propyl (2,6'-bi-1H-benzimidazol) -1'-yl) methyl)- It is a representative ARB (Angiotensin II Receptor Blockers) family of drugs having the chemical formula (1,1'-biphenyl) -2-carboxylic acid, which inhibits the final stage of the binding of the enzyme angiotensin 2 to AT1 receptor, which causes an increase in blood pressure. Lowering is a typical antihypertensive drug.

In the present specification, 'comprising telmisartan as an active ingredient' may mean 'comprising telmisartan free base, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof. . For example, 'layer comprising telmisartan as an active ingredient' refers to a layer comprising free base of telmisartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof. , 'Mixture comprising telmisartan as an active ingredient' refers to a mixture comprising a free base of telmisartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.

In the present specification, 'Rosuvastatin' is [(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R , 5S) -3,5-dihydroxyhept-6-enoic acid], which is a representative HMG-CoA reductase inhibitor or a lipid lowering agent called 'statin', which is used for hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. Used for treatment.

In the present specification, 'including rosuvastatin as an active ingredient' may mean 'including rosuvastatin free base, pharmaceutically acceptable salt thereof, optical isomer thereof, or hydrate or solvate thereof. . For example, 'layer comprising rosuvastatin as an active ingredient' refers to a layer comprising a free base of rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof. , 'Mixture comprising rosuvastatin as an active ingredient' refers to a mixture comprising a free base of rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.

In the present specification, 'Amlodipine' is (RS) -3-ethyl-5-methyl-2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -6-methyl-1,4- It is a representative long-acting dihydropyridine-type calcium channel blocker with the formula of dihydropyridine-3,5-dicarboxylate, which expands peripheral arteries to reduce total peripheral blood vessel resistance, lowers heart rate, lowers blood pressure and reduces angina pain. It is a mechanism used to treat hypertension and angina.

In the present specification, 'including amlodipine as an active ingredient' may mean 'including amlodipine free base, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof. For example, 'layer comprising amlodipine as an active ingredient' refers to a layer comprising a free base of amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof. A mixture comprising as an active ingredient 'refers to a mixture comprising a free base of amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.

In the embodiments of the present invention, the first mixing portion, including the sugar, sugar alcohol, or sugar and sugar alcohol, the dissolution rate of the two pharmacologically active ingredients of the second mixing portion as well as the pharmacologically active ingredient of the first mixing portion Effect can be achieved.

In embodiments of the present invention, the sugar included in the first mixing portion may be any one or more selected from the group comprising lactose, sucrose, fructose, maltose and mixtures thereof. In addition, the sugar alcohol contained in the first mixing part is mannitol, sorbitol, xylitol, maltitol, trytol, adonitol, isomalt, erythritol, arabitol, psylitol, dulcitol, inositol, trehalose, ribitol, It may be any one or more selected from the group comprising galactitol, lactitol and mixtures thereof. Specifically, the first mixing unit may include at least one of mannitol and sorbitol.

In embodiments of the present invention, the sugar or sugar alcohol may be 30 to 80% by weight, specifically 45 to 75% by weight based on the total weight of the first mixing portion. When the sugar or sugar alcohol exhibits the weight ratio in the above range based on the total weight of the first mixing portion, the formation of a wet channel in the preparation according to the present invention promotes the dissolution of the pharmacologically active ingredient gradually, thereby achieving the desired elution within a limited time. Aspects can be achieved.

In embodiments of the present invention, the first mixing unit may further include an alkalizing agent.

In embodiments of the present invention, the alkalizing agent is selected from the group consisting of sodium or potassium hydroxide as alkali metal hydroxide, arginine or lysine as basic amino acid, and meglumine (N-methyl-D-glucamine) It may be any one or more, specifically sodium hydroxide or meglumine.

In embodiments of the present invention, the second mixing part may include microcrystalline cellulose and croscarmellose sodium to achieve excellent dissolution rate effects of two pharmacologically active ingredients of the second mixing part.

In embodiments of the present invention, the microcrystalline cellulose may be 10 to 80% by weight, specifically 20 to 70% by weight based on the total weight of the second mixing portion. In addition, the croscarmellose sodium may be 2 to 30% by weight, specifically 5 to 25% by weight, based on the total weight of the second mixing portion. When the microcrystalline cellulose or croscarmellose sodium has a weight ratio in the above range based on the total weight of the second mixing portion, a smooth formulation may be formed during the tableting operation for preparing the preparation according to the present invention, and the second mixing The part disintegrates quickly to ensure a high initial dissolution rate.

In embodiments of the present invention, the sugar or sugar alcohol is 30 to 80% by weight based on the total weight of the first mixing portion, the microcrystalline cellulose is 10 to 80% by weight based on the total weight of the second mixing portion The croscarmellose sodium may be 2 to 30% by weight based on the total weight of the second mixing part, and in this case, an excellent dissolution rate effect of the three pharmacologically active ingredients included in the formulation may be achieved.

In embodiments of the present invention, the second mixing unit may further include a light shielding agent, and specifically, the light blocking agent may be any one or more selected from the group consisting of talc, titanium oxide, and a dye.

In embodiments of the present invention, rosuvastatin included in the second mixing part may be decomposed or oxidized upon prolonged exposure to light to generate a lactone decomposition product, in which case the light blocking agent is added to the second mixing part. Including with rosuvastatin, it is possible to achieve the effect of suppressing the decomposition products by light even in the uncoated state.

In embodiments of the present invention, the pharmaceutically acceptable salt of telmisartan included in the first mixing part may be selected from the group consisting of sodium salt, potassium salt, magnesium salt and calcium salt.

In embodiments of the invention, the daily dosage of telmisartan, its pharmaceutically acceptable salts, optical isomers thereof, or hydrates or solvates thereof may be from about 5 mg to about 240 mg, specifically And from about 10 mg to 180 mg, more specifically from about 20 mg to about 120 mg, and even more specifically from about 40 mg to about 80 mg.

In embodiments of the present invention, the pharmaceutically acceptable salt of rosuvastatin included in the second mixing part may be an inorganic salt having a polyvalent cation, and specifically, may be a rosuvastatin calcium salt. It is not limited.

In embodiments of the present invention, the daily dosage of rosuvastatin, a pharmaceutically acceptable salt thereof, optical isomer thereof, or a hydrate or solvate thereof may be about 0.3 mg to about 50 mg, specifically And from about 0.8 mg to 40 mg, more specifically from about 2.5 mg to about 30 mg, and even more specifically from about 5 mg to about 20 mg.

In the embodiments of the present invention, the amlodipine of the second mixing portion may include racemate of amlodipine, (S) -amlodipine or (R) -amlodipine, and specifically, racemate or (S) of amlodipine. ) -Amlodipine.

In the embodiments of the present invention, the pharmaceutically acceptable salt of amlodipine included in the second mixing part is in the group consisting of inorganic acid salts, organic acid salts, sulfonate salts, metal salts or alkaline earth metal salts, amino acid salts and amine salts. Can be selected. Specifically, pharmaceutically acceptable salts of amlodipine include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, Lactic acid, fumaric acid, maleic acid, salicylic acid, besylic acid, campylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lithium, sodium, potassium, calcium, magnesium, lysine, arginine, guanidine, dicysine It may be made of clohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline or triethylamine, and more specifically, it may be amlodipine besylate.

In embodiments of the present invention, the daily dosage of amlodipine, its pharmaceutically acceptable salts, optical isomers thereof, or hydrates or solvates thereof may be about 1 mg to about 40 mg, specifically About 1.5 mg to 30 mg, more specifically about 2 mg to about 20 mg, and even more specifically about 2.5 mg to about 10 mg.

In embodiments of the invention, the formulation comprises from about 5 mg to about 240 mg of telmisartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof as telmisartan per unit dosage form. May include, specifically about 10 mg to about 180 mg, more specifically about 20 mg to about 120 mg, even more specifically about 40 mg to about And 80 mg.

In embodiments of the invention, the formulation comprises from about 0.3 mg to about 50 mg of rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof as rosuvastatin per unit dosage form. May be included, specifically about 0.8 mg to about 40 mg, more specifically about 2.5 mg to about 30 mg, and more specifically about 5 mg to And about 20 mg.

In embodiments of the invention, the formulation may comprise from about 1 mg to about 40 mg of amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof as amlodipine per unit dosage form. It may include, specifically about 1.5 mg to about 30 mg, more specifically may include about 2 mg to about 20 mg, even more specifically about 2.5 mg to about 10 mg May be included.

In embodiments of the present invention, the preparation may be administered once to several times a day, specifically, once a day to three times a day, more specifically once a day or twice a day, More specifically, it may be administered once a day, but is not limited thereto, and may be appropriately adjusted according to the condition of the patient.

In embodiments of the present invention, the agent may treat or prevent cardiovascular disease, the cardiovascular disease may be hypertension, arterial spasm, deep vein, heart failure, cardiac hypertrophy, cerebral infarction, diabetes, obesity, hyperlipidemia, coronary artery disease , Chronic stable angina, vasospasmodic angina, stroke, myocardial infarction, transient ischemic attack, congestive heart failure, insulin resistance, impaired glucose tolerance, prediabetes, type 2 diabetes mellitus, diabetic nephropathy, dyslipidemia, cognitive decline, dementia Etc., specifically, hypertension, arterial spasm, deep vein, cardiac hypertrophy, cerebral infarction, hemostasis, coronary artery disease, chronic stable angina, vasoconstrictive angina, stroke, myocardial infarction, transient ischemic attack, congestive heart failure, and more. Specifically, it may be hypertension, hyperlipidemia and the like.

In embodiments of the invention, the formulation may be a tablet, specifically, may be a two-layer tablet.

In embodiments of the present invention, the first mixing part may contain granules containing telmisartan as an active ingredient. The granules may be dry granules or wet granules, specifically wet granules.

In embodiments of the present invention, the second mixing part may contain granules containing rosuvastatin and amlodipine as active ingredients. The granules may be dry granules or wet granules, but are not limited thereto.

In embodiments of the present invention, the composite formulation may further include a film layer on the outer surface, specifically, the film layer may be a light-shielding film layer, moisture-proof film layer or sugar film layer and the like.

In embodiments of the present invention, the film layer may be formed of a water-soluble material, specifically, as a water-soluble film layer forming material, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl Cellulose (HEC), cellulose acetate phthalate (CAP), ethyl cellulose (EC), methyl cellulose (MC), polymethacrylate, polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat (registered trademark); BASF) , Germany)), polyvinyl alcohol (PVA) (Opadry®; Colorcon, USA) and any one or more selected from the group consisting of a mixture thereof, but is not limited thereto.

Method for producing a formulation according to the present invention,

A first step of mixing telmisartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof, and a sugar or sugar alcohol to prepare a mixture;

Rosuvastatin, pharmaceutically acceptable salts thereof, optical isomers thereof, or hydrates or solvates thereof; Amlodipine, pharmaceutically acceptable salts thereof, optical isomers thereof, or hydrates or solvates thereof; And a second step of preparing a mixture by mixing microcrystalline cellulose and croscarmellose sodium; And

Tableting the mixture prepared in the first step and the mixture prepared in the second step.

In embodiments of the present invention, the agent may be present in a physically separated form of the layer containing telmisartan as an active ingredient, and the layer containing rosuvastatin and amlodipine as an active ingredient.

In embodiments of the present invention, the first step may include the step of further mixing the alkalizing agent.

In embodiments of the present invention, the first step may include preparing granules containing telmisartan as an active ingredient. Specifically, the step of preparing the granules may be by dry granulation method or wet granulation method, and more specifically by wet granulation method.

In embodiments of the present invention, the second step may include preparing a granule comprising rosuvastatin and amlodipine as an active ingredient. Specifically, the step of preparing the granules may be by dry granulation method or wet granulation method, but is not limited thereto.

The matters mentioned in the preparations of the present invention may be equally applied to the above production methods unless they contradict each other.

The present invention comprises a first mixing unit containing telmisartan as an active ingredient; And

It provides a pharmaceutical composition for treating or preventing a cardiovascular disease comprising a second mixture comprising rosuvastatin and amlodipine as an active ingredient.

The present invention provides a method for preventing or treating cardiovascular disease by administering a pharmaceutical composition comprising a second mixture comprising rosuvastatin and amlodipine as an active ingredient in a therapeutically effective amount.

It provides a therapeutic use of the cardiovascular disease of the composition comprising a second mixture comprising a rosuvastatin and amlodipine as an active ingredient.

The matters mentioned in the formulations of the present invention may equally apply to pharmaceutical compositions, methods of treatment and therapeutic uses, unless they contradict each other.

The present invention is a pharmaceutical combination formulation containing all of telmisartan, rosuvastatin and amlodipine as an active ingredient, although all three components are contained in one pharmaceutical combination formulation without the interference phenomenon It is stable and can be used as a safe and effective therapeutic agent for hypertension and hyperlipidemia.

1 is a graph showing that the telmisartan dissolution rate of the formulation of the example was excellent when comparing the formulation according to the example and the formulation according to the comparative examples.

Figure 2 is a graph showing the excellent rosuvastatin dissolution rate of the formulation of the Example when comparing the formulation according to the Example and the formulation according to the comparative examples.

3 is a graph showing that the amlodipine dissolution rate of the formulation of the example was excellent when comparing the formulation according to the example and the formulation according to the comparative examples.

4 is a graph showing that the telmisartan dissolution rate of the formulation of the example was excellent when comparing the formulation according to the example and the formulation according to the comparative examples.

Figure 5 is a graph showing that the rosuvastatin dissolution rate of the formulation of the Example is excellent when comparing the formulation according to the Example and the formulation according to the comparative examples.

6 is a graph showing that the amlodipine dissolution rate of the formulation of the example was excellent when comparing the formulation according to the example and the formulation according to the comparative examples.

7 is a graph showing that the telmisartan bioavailability of the formulation of the example is excellent when comparing the formulation according to the example and the formulation according to the comparative example.

8 is a graph showing the superior rosuvastatin bioavailability of the formulation of the Example when comparing the formulation according to the Example and the formulation according to the Comparative Example.

9 is a graph showing that the amlodipine bioavailability of the formulation of the Example is excellent when comparing the formulation according to the Example and the formulation according to the Comparative Example.

Hereinafter, examples will be described in detail to help understand the present invention. However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the present invention. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

실시예 1: 텔미사르탄, 로수바스타틴 및 암로디핀의 복합 이층정 제조Example 1 Preparation of Composite Two-Layered Tablets of Telmisartan, Rosuvastatin and Amlodipine

Preparation of the first mixing portion containing telmisartan as an active ingredient

According to the components and contents shown in Example 1 of Table 1 per unit formulation, a first mixing part including telmisartan as an active ingredient was prepared by the following method.

Specifically, telmisartan, meglumine and povidone were dissolved in purified water, and then sprayed on sorbitol to prepare granules. After granulating the granules in a 20 mesh sieve, magnesium stearate was added and finally mixed in a mixer to prepare a first mixing portion containing telmisartan.

Preparation of the second mixing part containing rosuvastatin and amlodipine as active ingredients

According to the components and contents shown in Example 1 of Table 1 per unit formulation, a second mixing part including rosuvastatin and amlodipine as an active ingredient was prepared by the following method.

Specifically, rosuvastatin calcium, amlodipine besylate, calcium hydrogen phosphate hydrate, microcrystalline cellulose, pregelatinized starch and croscarmellose sodium were mixed and sieved to a 30 mesh sieve. Magnesium stearate was added and final mixed in a mixer to prepare a second mixing portion (granule) containing rosuvastatin and amlodipine.

Manufacture of Double-Layered Tablets

A double-layer tableting machine was used to prepare a composite double-layer tablet consisting of a first mixing portion containing telmisartan and a second mixing portion containing rosuvastatin and amlodipine.

비교예 1: 텔미사르탄, 로수바스타틴 및 암로디핀의 단층정 제조Comparative Example 1 Preparation of Monolayer Tablets of Telmisartan, Rosuvastatin and Amlodipine

According to the components and contents described in Comparative Example 1 of Table 1 per unit dosage form, a first mixing part including telmisartan and a second mixing part including rosuvastatin and amlodipine were prepared as in Example 1.

Thereafter, the first mixing portion and the second mixing portion were further mixed in a mixer, and then a monolayer tablet was prepared using a tablet press.

비교예 2: 텔미사르탄의 단층정 제조Comparative Example 2: Monolayer Tablet of Telmisartan

A monolayer tablet was prepared by a tablet press using only the first mixing part including telmisartan prepared in Comparative Example 1 per unit formulation as shown in Table 1 below.

비교예 3: 로수바스타틴 및 암로디핀의 단층정 제조Comparative Example 3: Preparation of Monolayer Tablet of Rosuvastatin and Amlodipine

Single-layer tablets were prepared with a tablet press using only the second mixing part including rosuvastatin and amlodipine prepared in Comparative Example 1 per unit formulation as shown in Table 1 below.

실험예 1 : 용출 시험Experimental Example 1 Dissolution Test

The dissolution test of telmisartan, rosuvastatin and amlodipine over time was performed using the tablets of Example 1 and Comparative Examples 1 to 3 prepared above under the following conditions. The control group was a cresto of telmisartan and amlodipine, twin star and rosuvastatin.

Eluent: pH 7.5 phosphate buffer, 900 mL

Device: Paddle Method 75 rpm

Temperature: 37 ℃

Elution time: 30 minutes

Column: Phenomenex Kinetex 5u C18, 4.6 × 150 mm (equivalent to this)

Mobile Phase A: A solution of pH 3.0 buffer, acetonitrile and methanol at 7: 2: 1

Mobile phase B: A mixture of water, acetonitrile and methanol in a 2: 5: 3

Detector: UV absorbance photometer (wavelength 238 nm)

Flow rate: 1.0 mL / min

Injection volume: 5 uL

Column Temperature: 40 ℃

The dissolution rate measurement results are shown in FIGS. 1 to 3. As shown in the figure, the dissolution of telmisartan, rosuvastatin and amlodipine was remarkably lowered in the monolayer tablet formulations of Comparative Examples 1 to 3. On the other hand, in the case of the bilayer tablet formulation of Example 1, the dissolution rate of each active ingredient was not lowered, and it was confirmed that the dissolution rate was equivalent to that of the control group.

Therefore, the combination preparations containing telmisartan, rosuvastatin and amlodipine are separated into portions containing telmisartan and portions containing rosuvastatin and amlodipine, respectively, without affecting the dissolution rate between the drugs. It was found that excellent dissolution rate could be maintained.

실시예 2: 만니톨을 포함하는 복합 이층정 제조Example 2: Preparation of Composite Two-Layered Tablet Containing Mannitol

Preparation of the First Mixing Part Containing Mannitol

According to the ingredients and contents shown in Example 2 of Table 2 per unit formulation, a first mixing part containing telmisartan as an active ingredient and containing D-mannitol was prepared by the following method.

Specifically, telmisartan, meglumine and povidone were dissolved in purified water, and then sprayed on D-mannitol to prepare granules. After granulating the granules in a 20 mesh sieve, magnesium stearate was added and finally mixed in a mixer to prepare a first mixing portion containing telmisartan.

Preparation of the second mixing part

According to the ingredients and contents shown in Example 2 of Table 2 per unit formulation, a second mixing part including rosuvastatin and amlodipine as an active ingredient was prepared by the following method.

Specifically, rosuvastatin calcium, amlodipine besylate, calcium hydrogen phosphate hydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, titanium oxide and mixed gray powder were mixed and sieved into a 30 mesh sieve. Magnesium stearate was added and final mixed in a mixer to prepare a second mixing portion comprising rosuvastatin and amlodipine.

Manufacture of Double-Layered Tablets

비교예 4: 크로스카르멜로오스나트륨 대신 크로스포비돈을 포함하는 복합 이층정 제조Comparative Example 4: Preparation of a composite bilayer tablet containing crospovidone instead of croscarmellose sodium

A composite bilayer tablet was prepared in the same manner as in Example 2, except that crospovidone was used instead of croscarmellose sodium in the preparation of the second mixing unit according to the ingredients and contents shown in Example 2 in Table 2 per unit dosage form. It was.

비교예 5: 미결정셀룰로오스 대신 만니톨을 포함하는 복합 이층정의 제조Comparative Example 5: Preparation of Composite Two-Layered Tablet Containing Mannitol Instead of Microcrystalline Cellulose

According to the components and contents shown in Example 2 of Table 2 per unit formulation, a composite bilayer tablet was prepared in the same manner as in Example 2, except that D-mannitol was used instead of microcrystalline cellulose in the preparation of the second mixing portion.

비교예 6: 만니톨 대신 미결정셀룰로오스를 포함하는 복합 이층정의 제조Comparative Example 6: Preparation of Composite Two-Layered Tablet Comprising Microcrystalline Cellulose Instead of Mannitol

According to the ingredients and contents shown in Example 2 in Table 2 per unit formulation, a composite bilayer tablet was prepared in the same manner as in Example 2, except that microcrystalline cellulose was used instead of D-mannitol in the preparation of the first mixing portion.

비교예 7: 복합 이층정의 제조Comparative Example 7: Preparation of Composite Two-Layered Tablet

Except for the use of microcrystalline cellulose instead of D-mannitol in the preparation of the first mixing portion according to the components and contents shown in Example 2 of Table 2 per unit dosage form, and the use of other excipients in the preparation of the second mixing portion, Composite bilayer tablets were prepared in the same manner as in Example 2.

실험예 2 : 용출 시험Experimental Example 2 Dissolution Test

The dissolution test of telmisartan, rosuvastatin and amlodipine over time was performed under the same conditions as in Experiment 1 using the tablets of Example 2 and Comparative Examples 4 to 7 prepared above. The control group was a cresto of telmisartan and amlodipine, twin star and rosuvastatin.

The dissolution rate measurement results are shown in FIGS. 4 to 6. As shown in the drawing, the first mixing portion containing telmisartan includes D-mannitol and the second mixing portion containing rosuvastatin and amlodipine layers includes microcrystalline cellulose and croscarmellose sodium. The purification of Example 2 did not lower the dissolution rate of all the active ingredients, it showed an excellent dissolution rate. On the other hand, in the case of the tablets of Comparative Examples 4 to 7, as a result of using excipients different from those of Example 2 in the preparation of the first mixing section or the second mixing section, disintegration of each mixing section is delayed and the dissolution rate of the active ingredients is reduced. It was confirmed.

Specifically, in the tablets of Comparative Example 4 using crospovidone instead of croscarmellose sodium in the second mixing part and Comparative Example 5 using D-mannitol instead of microcrystalline cellulose, the dissolution rate of rosuvastatin and amlodipine included in the second mixing part Not only was this drastically reduced, the dissolution rate of telmisartan in the first mixing portion also decreased, and it was confirmed that the first mixing portion also affected. In addition, even in the case of the tablet of Comparative Example 6 using microcrystalline cellulose instead of D-mannitol in the first mixing section, the dissolution rate of telmisartan included in the first mixing section was drastically reduced, as well as rosuvastatin and amlodipine in the second mixing section. It was also confirmed that the dissolution rate of was also reduced, affecting the second mixing section. Further, in Comparative Example 7 in which microcrystalline cellulose was used instead of D-mannitol in the first mixing part and crospovidone in place of croscarmellose sodium in the second mixing part, and D-mannitol instead of microcrystalline cellulose, the dissolution rate of all the active ingredients also decreased drastically. It was confirmed.

As confirmed in Comparative Examples 4 to 7 above, even if any one of the first mixing unit or the second mixing unit uses an appropriate excipient, in the case of using an inappropriate excipient in another part, not only the part containing the inappropriate excipient but also a suitable excipient It was confirmed that the dissolution rate of the active ingredient is reduced even in the part using.

Therefore, in order to achieve an excellent dissolution rate improvement effect for the active ingredients, the composite preparation including two or more active ingredients, it was found that the use of excipients according to the dissolution and biological absorption characteristics of each active ingredient.

실험예 3 : 유연물질 시험 (온도, 수분)Experimental Example 3 Flexible Material Test (Temperature, Moisture)

The tablets of Examples 2 and Comparative Examples 1 to 3 were stored under accelerated conditions (40 ° C., 75% RH) after Alu-Alu packaging, and the amount of lead increased compared to the initial value after 3 and 6 months after the start of the test. .

As shown in Table 3, the single tablets of Comparative Examples 2 and 3 are flexible even after 6 months storage under accelerated conditions using telmisartan (Comparative Example 2) or rosuvastatin and amlodipine (Comparative Example 3) as active ingredients. It was confirmed that the material is rarely generated and excellent in stability. On the other hand, the tablets of Example 2 and Comparative Example 1 is a composite formulation containing three active ingredients, in the case of Comparative Example 1 prepared by mixing all of the active ingredients in a single-layer tablet storage for 6 months under accelerated conditions compared to the initial In the case of Example 2 prepared in a two-layered tablet by separating the first mixed part of telmisartan and the second mixed part of rosuvastatin and amlodipine, the flexible material increased after the remarkable increase of the flexible material. It was confirmed that the stability was excellent because almost no flexible material occurred even after months of storage.

In the case of tablets prepared by the simple mixing method of the three active ingredients from the above results, while it is difficult to ensure sufficient stability according to the change over time under accelerated conditions by heat or moisture, the preparation according to the present invention is between drugs By minimizing contact with substances that affect the stability and stability, it can be seen that improved stability can be achieved in the preparation and storage of the telmisartan, rosuvastatin and amlodipine combinations.

실험예 4 : 생체이용률 평가Experimental Example 4 Evaluation of Bioavailability

In order to confirm the pharmacokinetic properties of the combination formulation, twinstar tablets 40/5 mg and Cresto tablet 20 mg were used as a control and compared with the tablets of Example 2 and Comparative Example 7.

Specifically, by using nine male Beagle dogs (Covance Beagles) of about 14 to 15 months, three tablets of the control, Example 2 or Comparative Example 7 were administered to cross each of three for three weeks (3 X 3 cross over test) The bioavailability of telmisartan, rosuvastatin calcium and amlodipine besylate was confirmed.

The bioavailability evaluation result was obtained by pharmacokinetic parameters were calculated by analyzing the sample taken according to a predetermined time after the administration of the tablet, the comparison between the control group and the test group was 90% confidence in the average ratio of these after logarithmic conversion of the evaluation item value The interval was calculated and evaluated. The results are shown in Table 4 and FIGS. 7 to 9, and Table 4 shows the lower limit and the upper limit of the test group individual values for the control mean. The T / R ratio was calculated by dividing the geometric mean of the endpoint for the test group by the geometric mean of the endpoint for the control group.

In the case of Example 2 in which the dissolution rate was equal to that of the control group, the bioavailability confirmed by the T / R ratio value was also confirmed to be equivalent to that of the control group. On the other hand, in Comparative Example 7, which showed a lower dissolution rate compared to the control group, both AUC and Cmax value was low, so that the absorption in vivo was not properly achieved, it was confirmed that the overall bioavailability is low.

From the above description, those skilled in the art will understand that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, it should be understood that the embodiments described above are exemplary in all respects and are not intended to limit the invention. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the following claims and equivalent concepts rather than the detailed description are included in the scope of the present invention.

Claims

A first mixing portion comprising telmisartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof, and a sugar or sugar alcohol;

A second mixing portion comprising rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof and amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof Including,

The pharmaceutical combination preparation wherein the first mixing portion and the second mixing portion are present in physically separated form.
The pharmaceutical combination according to claim 1, wherein the sugar comprises any one or more selected from the group consisting of lactose, sucrose, fructose, maltose and mixtures thereof.
The sugar alcohol according to claim 1, wherein the sugar alcohol is mannitol, sorbitol, xylitol, maltitol, trytol, adonitol, isomalt, erythritol, arabitol, psylitol, dulcitol, inositol, trehalose, ribitol, galactitol, lacx A pharmaceutical co-formulation comprising any one or more selected from the group comprising titol and mixtures thereof.
The pharmaceutical combination according to claim 1, wherein the sugar alcohol is mannitol or sorbitol.
According to claim 1, wherein the sugar or sugar alcohol is 30 to 80% by weight based on the total weight of the first mixing portion of the pharmaceutical combination formulation.
The method of claim 1, wherein the second mixing portion is rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof and amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a mixture thereof. A pharmaceutical combination comprising a hydrate or solvate and microcrystalline cellulose and croscarmellose sodium.
The pharmaceutical composite formulation of claim 6, wherein the microcrystalline cellulose is contained in an amount of 10 to 80 wt% based on the total weight of the second mixing portion.
The pharmaceutical combination according to claim 6, wherein the croscarmellose sodium is included in an amount of 2 to 30 wt% based on the total weight of the second mixing portion.
The pharmaceutical combination preparation according to claim 1, wherein the second mixing portion disintegrates and elutes before the first mixing portion.
The pharmaceutical combination according to claim 1, wherein the pharmaceutical combination is a bilayer tablet.
The pharmaceutical combination formulation of claim 1, wherein the first mixing portion further comprises an alkalizing agent.
The pharmaceutical combination formulation of claim 1, wherein the second mixing portion further comprises a light shielding agent.
The pharmaceutical combination preparation according to claim 12, wherein the light shielding agent is at least one selected from the group consisting of talc, titanium oxide and pigments.
The pharmaceutical combination according to claim 1, wherein the telmisartan is included in an amount of 5 to 240 mg.
The pharmaceutical combination according to claim 1, wherein the rosuvastatin is contained in an amount of 0.3 to 50 mg.
The pharmaceutical combination according to claim 1, wherein said amlodipine is included in an amount of 1 to 40 mg.
A first step of mixing telmisartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof, and a sugar or sugar alcohol to prepare a mixture;

Rosuvastatin, pharmaceutically acceptable salts thereof, optical isomers thereof, or hydrates or solvates thereof; Amlodipine, pharmaceutically acceptable salts thereof, optical isomers thereof, or hydrates or solvates thereof; And a second step of preparing a mixture by mixing microcrystalline cellulose and croscarmellose sodium; And

Tableting the mixture prepared in the first step and the mixture prepared in the second step.
18. The method of claim 17, wherein said first step further comprises mixing an alkalizing agent.
The method of claim 17, wherein the first step comprises preparing granules comprising telmisartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof. Process for the preparation of a pharmaceutical combination.
The method of claim 17, wherein the second step is rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof and amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or A method for producing a pharmaceutical complex preparation comprising hydrate or solvate and granules comprising microcrystalline cellulose and croscarmellose sodium.