KR101992400B1 - Pharmaceutical formulation - Google Patents

Abstract

The present invention relates to a pharmaceutical formulation capable of remarkably improving drug convenience, which comprises: a first layer including fimasartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof; and a second layer including 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.

Description

[0001] PHARMACEUTICAL FORMULATION [0002]

The present invention relates to a combination preparation comprising as an active ingredient piasmartan, amlodipine and rosuvastatin. More particularly, the present invention relates to a unit dosage form containing as an active ingredient pimazartan, amlodipine and rosuvastatin, exhibiting excellent dissolution pattern and stability, and improving convenience of administration.

It is important to maintain hypertension in the normal range of blood pressure rather than to treat blood pressure itself, so it is important to prevent coronary artery disease and cardiovascular complications such as life-threatening strokes, heart failure, myocardial infarction, It is important to adjust.

In general, hypertensive patients are often accompanied by other types of cardiovascular diseases including hyperlipidemia, so the combined prescription rate of two or more drugs is high. In addition, because of the long-term need to take drugs, care should be taken in choosing therapeutic drugs. As a result, by using drugs with different mechanisms of action and reducing the use of single drugs rather than choosing one drug, There is a need to reduce the side effects that may be caused by drug use.

Pimersartan is known to be an angiotensin II receptor antagonist developed to treat hypertension and other medical indications. (Registered patent 10-1058284)

Amlodipine is known as a calcium channel blocker developed to treat hypertension and other medical indications.

Rosuvastatin is an HMG-CoA reductase inhibitor, which is effective in reducing HMG-CoA to mevalonate to lower blood lipid levels and cholesterol, and is therefore used for hyperlipidemia, hypercholesterolemia and atherosclerosis.

In order to more effectively treat the cardiovascular diseases including hypertension, a combination preparation containing both of the above-mentioned different mechanisms of action such as pimasartan, amlodipine and rosuvastatin can be considered. In this case, Which may affect the dissolution of each active ingredient. In particular, cannab which is commercially available as a single product of a pimarastine single agent has a low solubility at a low pH (for example, pH 1.2 to pH 1.4), and when it is combined with other pharmacologically active ingredients, it is lower than the dissolution rate And may indicate the dissolution rate.

In addition, since the solubility of each of the above-mentioned components is different, it is difficult to formulate the three components so that they exhibit an effective dissolution pattern. Thus, a unit dosage form of a complex preparation type comprising both of pimaractan, amlodipine and rosuvastatin as an active ingredient Has not been commercialized.

Korean Patent No. 10-1058284

The present invention provides a pharmaceutical composition comprising a first layer comprising a pimaserartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof or a hydrate or solvate thereof; And

A second layer 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, / RTI >

The second layer provides a formulation comprising Low Substituted Hydroxypropylcellulose.

Hereinafter, the present invention will be described in more detail.

The present invention

A first layer comprising a phamacartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof or a hydrate or solvate thereof; And

A second layer 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, ≪ / RTI &

The second layer provides a formulation comprising Low Substituted Hydroxypropylcellulose.

In the formulation of the present invention, the second layer comprising low-substituted hydroxypropylcellulose rapidly swells upon contact with water to separate the first layer and the second layer immediately, and thus the first and second layers are separated from each other Respectively.

As a result, the first layer and the second layer are not affected by each other, and the respective layers are disintegrated so that the active component belonging to each layer can be eluted. That is, even if the disintegration pattern of the first layer and the second layer is different, the pharmaceutically acceptable carrier, disintegrating additive or pharmacologically active ingredient belonging to each layer may affect the disintegration pattern and elution of the other layer I can not go crazy. Particularly, since each layer can be immediately separated even in acidic stomachs having a pH of 3 or less, disintegration of the first layer and the second layer does not affect the disintegration and elution of the active ingredient of the other layer, Elution pattern. As a result, the three pharmacologically active ingredients included in the formulations of the present invention can exhibit an elution pattern that is approximately the same as or similar to a single formulation comprising each ingredient.

Therefore, the respective components contained in the first layer and the second layer of the combination preparation of the present invention can sufficiently exert their respective pharmacological activities without interfering with each other, and there is no problem such as a decrease in stability due to drug mutual interference It is possible to remarkably improve the convenience of medicines and to mass-produce easily.

In addition, the preparation of the present invention exhibits excellent stability and can maintain a stable state for a long period without separating the layers.

In the present specification, the terms first, second, etc. are used for distinguishing between different layers, films, steps, etc., and are not intended to represent the order or importance, and the first, The terms such as layer, film, and step are not limited by the term. Therefore, the terms first, second, etc. may not be used equally in the detailed description, examples, claims, and the like of the invention, and it is sufficient if they can be distinguished from each other by the first and second terms .

As used herein, the term " pharmaceutically acceptable " means physiologically acceptable and non-toxic, non-toxic, non-toxic, non-toxic, non- May mean that it is conventionally used in manufacture.

As used herein, the term "hydrate" refers to a pharmaceutically acceptable salt of pimersartan, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, amlodipine, a pharmaceutically acceptable salt or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, , Or an optical isomer thereof, and water in a stoichiometric or non-stoichiometric amount in which water is bonded with non-conjugated intermolecular forces. Specifically, the hydrate may comprise from about 0.25 mole to about 10 mole percent of water based on 1 mole of active ingredient, and more specifically about 0.5 mole, about 1 mole, about 1.5 moles, about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, and the like.

As used herein, the term "solvate" refers to a pharmaceutically acceptable salt of pimersartan, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, amlodipine, a pharmaceutically acceptable salt or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, A salt, or an optical isomer thereof and a non-water solvent, are bound to each other by an intermolecular force, and the solvent can be contained in a stoichiometric or non-stoichiometric amount. Specifically, the solvate may comprise from about 0.25 mole to about 10 mole percent of solvent molecules based on 1 mole of active ingredient, and more specifically about 0.5 mole, about 1 mole, about 1.5 moles, about 2 moles , About 2.5 moles, about 3 moles, about 5 moles, and the like.

As used herein, the term "comprising as an active ingredient" may refer to a "pimaseartan free base, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof" . For example, the term "layer comprising as an active ingredient" refers to a layer comprising a free base of a pimarastane, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof , &Quot; a mixture comprising pimaractan as an active ingredient " refers to a mixture comprising a free base of a pimarastane, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof.

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

As used herein, the term "comprising rosuvastatin as an active ingredient" may mean "comprising rosuvastatin free base, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof" . For example, the term " layer containing 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 , A 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 embodiments of the present invention, the preparation may be a unit dosage form containing both pimicatan, rosuvastatin and amlodipine as an active ingredient.

In embodiments of the present invention, the second layer may comprise from 3% to 50% by weight of low-substituted hydroxypropylcellulose based on the weight of the second layer, specifically from 5% 40% by weight of low-substituted hydroxypropylcellulose. When the low-substituted hydroxypropyl cellulose is contained in a stomach content, the swelling of the second layer can proceed rapidly, and as a result, the first layer and the second layer can be separated more quickly. Therefore, even if the second layer disintegrates faster than the first layer, the first layer is not affected by the disintegration of the second layer, and each active ingredient contained in the first and second layers has an excellent dissolution pattern .

In addition, when the low-substituted hydroxypropylcellulose is contained in a stomach content, the tablets can be maintained in an appropriate size, thereby improving the patient's convenience of medication and facilitating tableting. In addition, the uniformity of content of each component contained in each tablet can be maintained to be excellent, and mass production can be easily performed economically.

In embodiments of the present invention, the first and second layers may exhibit different rates of disintegration in the eluting medium. At this time, the elution medium may be a hydrochloric acid aqueous solution having a pH of 1.2.

In embodiments of the present invention, in the elution medium, the second layer may be disintegrated prior to the first layer, wherein the elution medium may be an aqueous hydrochloric acid solution at pH 1.2.

In the embodiments of the present invention, the preparation may be tablets, and specifically may be a two-layer tablet. In embodiments of the present invention, the two-layer defined first layer may comprise pimasartan as an active ingredient and the second layer may comprise amlodipine and rosuvastatin as an active ingredient, And the active ingredient of the second layer, amlodipine and rosuvastatin, are isolated from each other without mixing.

 Generally, in the case of two-layered structure, two layers having different physical properties are coupled by physical force, and when the two layers are separated from each other at the interface between the two layers at the time of disintegration, the components contained in each layer are disintegrated and eluted There arises a problem of deteriorating the reliability.

However, the preparations of the present invention can exhibit an excellent dissolution pattern even when the three components are contained in one tablet in a bilayer form, and as a result, they can be obtained by taking all the preparations including pimazartan, amlodipine and rosuvastatin The same or similar dissolution pattern and bioavailability can be markedly improved.

In embodiments of the present invention, the first layer may contain granules containing the pimarastane as an active ingredient. The granules may be dry granules or wet granules, and in particular may be wet granules.

In embodiments of the present invention, the second layer comprises 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 solvate thereof, may be mixed.

The formulation of the present invention is simple mixture of each component in the above two layers, but can exhibit excellent stability. In particular, rosuvastatin, which is an effective ingredient, can maintain a stable state for a long period of time. In addition, since the active ingredient contained in the second layer is not required to be produced in the form of granules, the production is simple, and the production efficiency is high and mass production is easy.

In embodiments of the present invention, the pharmaceutically acceptable salts of the pimarastine may be selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonic acid salts, amino acid salts and amine salts. Specifically, pharmacologically acceptable salts of phimarsartan include inorganic acid salts prepared from calcium, potassium, sodium or magnesium, inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, , Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid , Organic acid salts such as ascorbic acid, carbonic acid, vanillic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid or succinic acid and the like, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, benzenesulfonic acid, p- , Camphorsulfonic acid, naphthalene disulfonic acid, or naphthalene sulfonic acid, amino acid salts prepared with glycine, arginine, lysine, or the like, or trimethylamine , Meglumine, triethylamine, ammonia, pyridine, picoline or the like, but the salt produced in such choline, not a salt type, which means in the present invention by the enumeration of these salts is not limited. Specifically, the pharmaceutically acceptable salt of the above-mentioned pimasartan may be potassium pimarsatan, pimasartan toluenesulfonate or pimasartan ammonium salt, and more specifically, it may be a potassium salt of pimasartan.

In embodiments of the present invention, the paramsartan, a pharmaceutically acceptable salt thereof or an optical isomer thereof hydrate may be a monohydrate or a trihydrate, and more specifically, monohydrate or trihydrate of potassium < RTI ID = 0.0 > And more specifically may be a trihydrate of potassium < RTI ID = 0.0 > parasamartan. ≪ / RTI >

In embodiments of the present invention, a daily dose of a polymercaptan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof is about 0.5 mg to about 240 < RTI ID = 0.0 > mg, more specifically from about 10 mg to about 180 mg, more specifically from about 20 mg to about 120 mg, and still more specifically from about 30 mg to about 60 mg, for example, About 30 mg or about 60 mg as potassium palmitate potassium.

In embodiments of the present invention, the amlodipine in the second layer may comprise a racemate of amlodipine, (S) -amlodipine or (R) -amlodipine, specifically a racemate of amlodipine or (S ) -Amlodipine. ≪ / RTI >

In embodiments of the present invention, the pharmaceutically acceptable salt of amlodipine which may be included in the second layer is selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonic acid salts, amino acid salts and amine salts . Specifically, the pharmaceutically acceptable salt of amlodipine may be one prepared from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, gluconic acid, More specifically, it may be amlodipine besylate.

In embodiments of the present invention, the daily dosage of amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof may be from about 0.1 mg to about 20 mg as amlodipine, From about 3 to about 15 mg, and more specifically from about 5 to about 10 mg, for example, about 5 mg or about 10 mg as amlodipine.

In embodiments of the present invention, the pharmaceutically acceptable salt of rosuvastatin in the second layer may be selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonic acid salts, amino acid salts and amine salts have. Specifically, the pharmaceutically acceptable salt of rosuvastatin may be an inorganic ionic salt such as calcium, potassium, sodium or magnesium, and more specifically rosuvastatin calcium salt.

In embodiments of the present invention, a daily dosage of rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof may be about 1 mg to about 40 mg as rosuvastatin, Specifically about 3 mg to about 30 mg, and more specifically about 5 mg to about 20 mg, such as about 5 mg, about 10 mg, or about 20 mg as rosuvastatin.

In embodiments of the present invention, the formulation may comprise from about 0.5 mg to about 240 < RTI ID = 0.0 > (mg / kg) < / RTI > as the potassium < RTI ID = 0.0 > mg, more specifically from about 10 mg to about 180 mg, and more specifically from about 20 mg to about 120 mg, and still more specifically from about 30 mg to about 120 mg, mg to about 60 mg, such as about 30 mg or about 60 mg as potassium pimarate.

In embodiments of the present invention, the formulation may comprise from about 0.1 mg to about 20 mg of amlodipine per unit dosage form, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof as an amlodipine , Specifically from about 3 mg to about 15 mg, and more specifically from about 5 mg to about 10 mg, including, for example, about 5 mg or about 10 mg as amlodipine . ≪ / RTI >

In embodiments of the present invention, the formulation comprises from about 1 mg to about 40 mg of rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof as a rosuvastatin per unit dosage form , Specifically from about 3 mg to about 30 mg, and more specifically from about 5 mg to about 20 mg, for example, as rosuvastatin About 5 mg, about 10 mg, or about 20 mg.

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

In embodiments of the present invention, the agent may treat or prevent a cardiovascular disease, wherein the cardiovascular disease is selected from the group consisting of hypertension, arterial spasm, heart arrhythmia, heart failure, cardiomyopathy, cerebral infarction, diabetes, obesity, hyperlipidemia, coronary artery disease , Chronic stable angina pectoris, vasospastic angina pectoris, stroke, myocardial infarction, transient ischemic attack, congestive heart failure, insulin resistance, impaired glucose tolerance, pre-diabetes type 2 diabetes mellitus, diabetic nephropathy, dyslipidemia, And may be, for example, hypertension, arterial spasm, heart arrhythmia, cardiomyopathy, stroke, dyslipidemia, coronary artery disease, chronic stable angina pectoris, vasospastic angina pectoris, stroke, myocardial infarction, transient ischemic attack, congestive heart failure Specifically, it may be hypertension, hyperlipidemia, and the like.

In embodiments of the present invention, the first layer and the second layer may each further comprise a pharmaceutically acceptable additive. The pharmaceutically acceptable additives contained in the first layer and the second layer may be the same or different from each other.

The pharmaceutically acceptable excipient may be selected from the group consisting of carriers, excipients, diluents, extenders, antioxidants, stabilizers, solubilizers, buffers, fillers, anticoagulants, lubricants, disintegrants, wetting agents, fragrances, emulsifiers, suspending agents, Or a mixture thereof. The additive may be formulated to include a range of capacities by choice.

In embodiments of the present invention, the second layer may comprise a stabilizer as a pharmaceutically acceptable additive.

Specifically, the additive is selected from the group consisting of lactose, dextrose, calcium silicate, corn starch, sodium starch glycolate, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, pregelatinized starch, Gelatin, calcium phosphate anhydride, calcium primary phosphate, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, croscarmellose sodium, crospovidone, colloidal silicon dioxide, povidone, copovidone, polyvinylpyrrolidone, Hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, light silicic anhydride, talc, talc, stearic acid, magnesium stearate, calcium stearate, hydrogenated castor oil Free, polyethylene glycol, colloids and silicon dioxide or mixtures thereof Be, but is not limited to these. For example, the additive may be a substance that does not react with pimazartan, rosuvastatin or amlodipine contained as an active ingredient of the preparation and does not lower the stability of the preparation.

More specifically, the stabilizer may be selected from the group consisting of meglumine, calcium phosphate anhydride, calcium monophosphate, calcium phosphate dibasic, tribasic magnesium phosphate, tribasic aluminum phosphate, meglumine, Specifically, it may be meglumine, calcium phosphate anhydride, calcium monophosphate, calcium phosphate diphosphate, or a mixture thereof. The binder may be selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, starch, gelatin, glucose syrup, polyvinylpyrrolidone, polyethylene glycol 6000, methylcellulose, ethylcellulose, carboxymethylcellulose, have. The disintegrant of the additive may be selected from starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch, clay such as bentonite, montmorillonite or veegum, microcrystalline cellulose or carboxymethylcellulose Alginates such as sodium alginate or alginic acid, cross-linked cellulose such as croscarmellose sodium, gums such as guar gum and xanthan gum; A cross-linked polymer such as crospovidone, sodium bicarbonate, citric acid, or a mixture thereof. The lubricant may be magnesium stearate, calcium stearate, stearic acid, sodium stearate fumarate, polyethylene glycol, silicon dioxide, or a mixture thereof. The diluent may be cellulose, lactose, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, dicalcium phosphate or a mixture thereof. The dissolution aid may be a polyoxyethylene sorbitan fatty acid ester such as sodium lauryl sulfate or polysorbate, sodium docusate, or a mixture thereof. Examples of the surfactant include sodium lauryl sulfate, cremopore, poloxamer, docusate, and pharmaceutically acceptable docusate salts or mixtures thereof.

In embodiments of the present invention, the first layer is a pharmaceutically acceptable additive and may include a binder, a disintegrant, a lubricant, a diluent, a lubricant, or a mixture thereof, In addition to doxorubicin propylcellulose, pharmaceutically acceptable additives may include disintegrants, lubricants, diluents, lubricants or mixtures thereof.

According to embodiments of the present invention, the second layer may contain, in addition to low-substituted hydroxypropylcellulose, various starches, sucrose, starch 1500, calcium monohydrogen phosphate, sorbitol, calcium phosphate, calcium carbonate, mannitol, Microcrystalline cellulose or a mixture thereof. Specifically, the second layer may further include mannitol, lactose, microcrystalline cellulose or a mixture thereof in addition to low-substituted hydroxypropyl cellulose, and may further include microcrystalline cellulose.

For example, the first layer comprising the pimasartan as an active ingredient may comprise croscarmellose sodium, hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, mannitol, lactose, lactose hydrate or mixtures thereof, The second layer comprising rosuvastatin and amlodipine as an active ingredient may contain, in addition to the low-substituted hydroxypropylcellulose, crospovidone, mannitol, microcrystalline cellulose, lactose, lactose hydrate, meglumine, colloidal silicon dioxide, magnesium stearate or And mixtures thereof.

In embodiments of the present invention, the tablet may further include an outer coating layer in addition to the first layer and the second layer. The method of forming the coating layer may be appropriately selected by a person skilled in the art from a method capable of forming a film-like coating layer on the surface of the tablet layer, and a fluid bed coating method, a pan coating method, a dry coating method, can do. The coating layer may include hydroxypropylmethylcellulose, ethylcellulose, polyvinyl acetate, polyethylene glycol, titanium dioxide, iron oxide, or the trade name Opadry (R). The coating layer may contain, for example, 0.5 to 10.0% by weight, specifically 1.0 to 6.0% by weight, more specifically 2.0 to 5.0% by weight, based on the total weight of the tablet.

The method for producing a preparation according to the present invention comprises:

A first step of preparing a mixture by mixing a phamacartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable additive;

Rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof; Amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof; And a pharmaceutically acceptable additive to prepare a mixture; And

And a step of titrating the mixture prepared in the first step and the mixture prepared in the second step.

In embodiments of the present invention, the pharmaceutically acceptable additive in the second step comprises low-substituted hydroxypropylcellulose.

In embodiments of the present invention, the mixture prepared in the second step may contain from about 3% to about 50% by weight of low-substituted hydroxypropylcellulose based on the total weight of the mixture, May range from about 5% to about 40% by weight.

In embodiments of the present invention, said first step may comprise the step of preparing a granulate comprising a pimaserartan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof. Specifically, the step of preparing the granules may be performed by a wet granulation method or a dry granulation method, more specifically, by a wet granulation method.

The matters mentioned in the formulations of the present invention can be applied to the above-mentioned manufacturing methods as well, unless they are mutually contradictory.

The present invention relates to a pharmaceutical composition comprising a first layer comprising as an active ingredient, And

A second layer comprising amlodipine and rosuvastatin as an active ingredient,

Wherein the second layer comprises low-substituted hydroxypropylcellulose. ≪ Desc / Clms Page number 16 >

The present invention relates to a pharmaceutical composition comprising a first layer comprising as an active ingredient, And

A second layer comprising amlodipine and rosuvastatin as an active ingredient,

Wherein the second layer provides a therapeutically effective amount of a pharmaceutical composition comprising a low-substituted hydroxypropylcellulose to prevent or treat a cardiovascular disease.

The present invention relates to a pharmaceutical composition comprising a first layer comprising as an active ingredient, And

A second layer comprising amlodipine and rosuvastatin as an active ingredient,

The second layer provides a prophylactic or therapeutic use of a cardiovascular disease in a composition comprising low-substituted hydroxypropylcellulose.

The matters mentioned in the preparations of the present invention can be equally applied to pharmaceutical compositions, therapeutic methods and therapeutic uses, unless they are mutually contradictory.

The present invention relates to a unit dosage form containing all of pisartan, rosuvastatin and amlodipine as active ingredients, and although all three components are contained in one unit dosage form, all three components exhibit excellent dissolution rate and stability without interference The convenience of medicines can be remarkably improved.

Brief Description of the Drawings Figure 1 shows dissolution rates of pimarastine in tablets according to the examples and tablets according to the comparative examples.
Figure 2 shows dissolution rates of amlodipine in tablets according to the examples and tablets according to the comparative examples.
Figure 3 shows dissolution rates of rosuvastatin in tablets according to the examples and tablets according to the comparative examples.
1 to 3, the ordinate axis represents dissolution rate (%) and the abscissa axis represents minutes.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

The potassium permanganate trihydrate used in the above Examples and Comparative Examples was Bordeong Pharm Co., Ltd. and amlodipine besaline salt, Reddy, rosuvastatin calcium, MSN, meglumine, Merck, and crospovidone were purchased from ISP. NBD-021 (ShinEtsu) was purchased from low-substituted hydroxypropyl methylcellulose.

Example 1.

(1) Preparation of Granules Containing Pimasartan as Active Ingredient

(400 mg) The granules containing the pharmacological active ingredient as the ingredients and contents as shown in Table 1 were prepared as follows.

After mixing the potassium pivalate trihydrate, microcrystalline cellulose and croscarmellose sodium for about 10 minutes, the mixture was placed in a high speed mixer and mixed for about 3 minutes to obtain a mixture containing as an active ingredient pimasartan .

Separately, hydroxypropylcellulose was dissolved in 60 ml of purified water to prepare a binding solution.

The prepared binding solution was put into a high-speed stirrer and wet-granulated together with the mixture containing the above-mentioned pimarastane as an active ingredient, followed by sizing with a 20-mesh sieve and drying. After drying, croscarmellose sodium was added and mixed in a double cone mixer for about 5 minutes. Magnesium stearate was added to the mixture and the mixture was further mixed for about 5 minutes to prepare granules containing the pimaserartan as an active ingredient.

(2) Preparation of a mixture containing amlodipine and rosuvastatin as active ingredients

A mixture containing amlodipine and rosuvastatin as an active ingredient of Example 1 was prepared so as to have the same contents as in Table 1 per unit dosage form.

First, amlodipine besylate, rosuvastatin calcium, meglumine stabilizer, and colloidal silicon dioxide were added, mixed for about 5 minutes, and then placed in a 30 mesh sieve. The apple mixture, microcrystalline cellulose, low-substituted hydroxypropylcellulose and crospovidone were put into a double cone mixer and mixed for about 15 minutes. Magnesium stearate was added as a lubricant and further mixed for about 5 minutes to prepare a mixture containing amlodipine and rosuvastatin as an active ingredient.

(3) Tabletting

Granules containing pimasartan as an active ingredient, and amlodipine and a mixture containing rosuvastatin as an active ingredient were put into a punch die, respectively, and the mixture was compressed to prepare a two-layer tablet.

The hardness of the two-layer tablet 1 was set to 10 to 15 kp by using a multi-layer tablet press (picola double layer tablet machine). The thus obtained tablets were measured for the degree of scratching using a scratch meter (25 rpm, free fall of 100 times). The degree of fatigue was 0.1% or less and the strength of the tablets was good. Hardness was measured using VARIAN VK200.

Example 2.

A two-layer tablet was prepared in the same manner as in Example 1, except that the components and the contents per unit formulation were set to the components and contents described in Example 2 of Table 1.

Example 3.

A two-layer tablet was prepared in the same manner as in Example 1, except that the components and the contents per unit formulation were set to the components and contents described in Example 3 of Table 1.

Example 4.

A two-layer tablet was prepared in the same manner as in Example 1, except that the components and the contents per unit formulation were set to the components and contents described in Example 4 of Table 1. [

Comparative Example  One

(1) granules containing an active ingredient of pimarate

Granules containing the pimasartan of Comparative Example 1 as an active ingredient were prepared so as to have the components and contents as shown in the following Table 2 per unit dosage form (400 mg).

After mixing the potassium pivalate trihydrate, microcrystalline cellulose and croscarmellose sodium for about 10 minutes, the mixture was placed in a high speed mixer and mixed for about 3 minutes to obtain a mixture containing as an active ingredient pimasartan .

Separately, hydroxypropylcellulose was dissolved in 60 ml of purified water to prepare a binding solution.

The prepared binding solution was put into a high-speed stirrer and wet-granulated together with the mixture containing the pimasartan, followed by sizing with a 20-mesh sieve and drying. After drying, croscarmellose sodium was added and mixed in a double cone mixer for about 5 minutes. Magnesium stearate was added to the mixture and the mixture was further mixed for about 5 minutes to prepare granules containing the pimaserartan as an active ingredient.

(2) Preparation of a mixture containing amlodipine and rosuvastatin as active ingredients

A mixture containing amlodipine and rosuvastatin of Comparative Example 1 was prepared so as to have the components and contents shown in Table 2 per unit dosage form.

Amlodipine besylate, rosuvastatin calcium, meglumine as a stabilizer, and colloidal silicon dioxide were mixed and mixed for about 5 minutes to prepare a mixture. The mixture was placed in a 30 mesh sieve and was then applicated. The apple mixture, mannitol and crospovidone were placed in a double cone mixer and mixed for about 15 minutes. Magnesium stearate was added as a lubricant and further mixed for about 5 minutes to prepare a mixture containing amphodipine and rosuvastatin as an active ingredient.

(3) Tabletting

Granules containing pimasartan as an active ingredient, and amlodipine and a mixture containing rosuvastatin as an active ingredient were put into a punch die, respectively, and the mixture was compressed to prepare a two-layer tablet.

 The hardness of the tableted two-layered tablet 1 was made to be 10 to 15 kp using a double-layer tableting machine (Piccola double layer tablet machine). The thus obtained tablets were measured for the degree of scratching using a scratch meter (25 rpm, free fall of 100 times). The degree of fatigue was 0.1% or less and the strength of the tablets was good. Hardness was measured using VARIAN VK200.

Comparative Example 2

A two-layer tablet was prepared in the same manner as in Comparative Example 1, except that the ingredients and the contents contained in the unit dosage form were the same as those described in Comparative Example 2 in Table 2, except that lactose was used instead of mannitol.

Comparative Example 3

A two-layer tablet was prepared in the same manner as in Comparative Example 1, except that the components and the contents contained in the unit dosage form were the same as those described in Comparative Example 3 in Table 2, except that microcrystalline cellulose was used instead of mannitol .

[Experimental Example] The dissolution rate of each component in the tablets of Examples and Comparative Examples

The dissolution test was carried out by using each of Examples 1 to 4, Comparative Examples 1 to 3, and commercially available reference materials such as cannabinoids, novasque tablets and crestor tablets. The dissolution test method is shown in Table 3. The dissolution test results are shown in Figs. 1 to 3 and show the average dissolution rate.

According to the dissolution test method of the Korean Pharmacopoeia (the paddle method), a combination preparation containing the pimazartan, amlodipine and rosuvastatin prepared in Examples and Comparative Examples as the active ingredient under the same conditions as those shown in Table 3 A dissolution test was performed. In order to compare the dissolution rate with the combination preparation of the present invention, the combination product of Borysung Pharmaceutical Co., Ltd., Bournung Pharma Co., Ltd., 60 mg of Porphyromycin, 10 mg of Pyridyl Norbasc, a single product of amlodipine, and 20 mg of Crestor, AstraZeneca, Lt; / RTI > under the same conditions.

1 to 3, elution of pimazartan, amlodipine and rosuvastatin from the tablets of Examples 1 to 4 was carried out by dissolving 60 mg of cannabine, a single preparation of each component, Novast and Crestone, And there was almost no difference in dissolution rate for each formulation.

Thus, it can be seen that the tablets of the present invention exhibit excellent dissolution of about the same degree as the single agent without interference between the components, despite the form of the combined preparation.

On the other hand, the tablets according to the comparative examples had a significantly lower dissolution rate of the active ingredient contained in the tablet than the single agent.

From these results, it can be seen that the combined preparation of the unit dosage form according to the present invention exhibits an excellent dissolution pattern without interference between the three kinds of active ingredients having different action mechanisms, and the convenience of medication can be remarkably improved.

From the above description, it will be understood by those of ordinary skill in the art to which the present invention pertains that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all aspects and are not intended to limit the invention. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.

Claims (7)

A first layer comprising a pimassarthan, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof; And
A second layer 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, ≪ / RTI &
Said first layer comprising croscarmellose sodium,
Wherein the second layer is selected from the group consisting of calcium phosphate anhydrous, calcium phosphate monobasic, calcium ginseng,
At least one selected from the group consisting of calcium phosphate, tribasic aluminum phosphate and meglumine, and Low Substituted Hydroxypropylcellulose,
A formulation that is a two-layer tablet. The formulation of claim 1, wherein the second layer comprises from 3% to 50% by weight of low substituted hydroxypropyl cellulose based on the weight of the second layer. delete delete The preparation according to claim 1, wherein the second layer further comprises at least one selected from the group consisting of microcrystalline cellulose, mannitol, and lactose. The method of claim 1, wherein the second layer
Rosuvastatin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof; And
Wherein the amlodipine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a hydrate or solvate thereof is mixed. delete

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