KR20150120008A - Pharmaceutical combinations for oral use containing bisoprolol and rosuvastatin - Google Patents

Abstract

The present invention relates to an orally administered composite formulation containing bisoprolol and rosuvastatin and a producing method thereof. an orally administered composite formulation of the present invention has effects on preventing and treating hypertension, angina and hypercholesterinemia, has excellent storage stability that the reduction in stability of the formulation is improved by a mutual reaction between two active ingredients, thereby improving drug administration convenience of the patient and being useful in the treatment of hypertension, angina, and hypercholesterolemia.

Description

[0001] PHARMACEUTICAL COMBINATIONS FOR ORAL USE CONTAINING BISOPROLOL AND ROSUVASTATIN [0002]

The present invention relates to oral pharmaceutical combination preparations for the prevention or treatment of cardiovascular diseases including non-soaprolol and nicotinamide inhibitor HMG-CoA reductase inhibitor.

Beta-blockers inhibit the beta-receptors distributed in the tissues, thereby decreasing the contractility of the myocardium and decreasing the heart rate by decreasing the pulse rate. As a result, the blood pressure-lowering agent is used as a medicine for the prevention of cardiovascular diseases including hypertension, angina, arrhythmia and myocardial infarction It has been used for a long time in symptom improvement and treatment.

Representative drugs for beta-blockers include bisoprolol, Nebivolol, Carvedilol, Propranolol and Atenolol.

The non-soprolol of the formula can be prepared by reacting (α-1 - [[α- (2-isopropoxyethoxy) -p-tolyl] oxy] -3- (isopropylamino) -2- It is used in the treatment and symptomatic relief of hypertension, angina pectoris and chronic heart failure with [α- (2-isopropoxyethoxy) -p-tolyl] oxy] -3- (isopropylamino) -2- propanol. Because of the high selectivity for the distributed beta 1 receptors, there are few side effects such as bronchoconstriction, peripheral blood flow disorders, and the risk of developing diabetes, which can occur due to the use of other beta blockers.

On the other hand, the HMG-CoA reductase inhibitor inhibits the enzymes involved in the conversion step from HMG-CoA to mevalonate, which is a rate-determining step during cholesterol biosynthesis in hepatocytes, As a drug that inhibits the biosynthesis of total cholesterol and LDL by lowering the effect is shown.

Rosuvastatin was synthesized from bis [(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) aminopyrimidin- Dihydroxyhept-6-enoic acid (bis [(E) -7- [4- (4- fluorophenyl) -6-isopropyl- 2- [methyl (methylsulfonyl) amino] pyrimidin- 5-yl] (3R, 5S) -3,5-dihydroxyhept-6-enoic acid] as a representative HMG CoA reductase inhibitor or a blood lipid lowering agent called "statin" ≪ / RTI > and atherosclerosis.

It is well known that increased risk of cardiovascular disease in hyperlipidemic patients and increase in coronary artery disease in hypertensive patients (Arterioscler Thromb Vasc Biol. 2003; 23: 885-891), combined with HMG-CoA reductase inhibitor and hypertension treatment It has been reported clinically that administration of the agent is effective in the treatment of cardiovascular disease (Am J Cardiol 2004; 93: 603-606).

The combination administration of a therapeutic agent for hypertension and an HMG-CoA reductase inhibitor as a single preparation includes, for example, amlodipine besylate, an angiotensin receptor blocker (ARB), and atorvastatin I have a combination medicine.

However, there is no commercial development of a combined preparation comprising a single formulation of a beta blocker and an HMG-CoA reductase inhibitor.

There are various difficulties in implementing a combination preparation of a beta blocker and an HMG-CoA reductase inhibitor, especially a combination preparation containing a representative HMG-CoA reductase inhibitor rosuvastatin.

In formulating the two active ingredients into a single preparation, the physicochemical properties of the two active ingredients, the internal / external ( In vivo / in The effect on bioavailability and stability due to the in vitro interaction should be considered important.

Rosubastatin is a biologic class II or III drug, and its bioavailability can be very easily affected by a change in dissolution rate depending on the degree of ionization of the drug liberated at a specific pH. According to Martin et al., The absorption of suvastatin in the body decreases by about 50% when the pH of the body changes due to an alkalizing agent (Martin PD et al., "The effect of a combination antacid preparation containing aluminum hydroxide and magnesium hydroxide on rosuvastatin pharmacokinetics" Curr Med Res., 2008, Vol. 24, No. 4, 1231-1235). Furthermore, rosuvastatin is a substance that is easily decomposed or oxidized when exposed to specific physico-chemical conditions (acid, moisture and light), and it is not easy to secure long-term stability of the drug.

British Patent No. 2262229 discloses a stabilized pharmaceutical formulation of a specific 7-substituted-3,5-dihydroxy-6-heptanoate salt of an HMG-CoA reductase inhibitor at a pH of 8 or above, Lt; / RTI > Rosubastatin is degraded by acids to produce lactone, which is a degradation product, and it is difficult to ensure stability.

The properties of rosuvastatin as described above are a major impediment to the development of a combination preparation with other ingredients. Although formulations or compositions with stability of rosuvastatin single formulation can not guarantee the stability of the formulation in combination with other drug components, they may not meet the required bioavailability.

On the other hand, in the case of non-soaprolol, there is a problem that stability is lowered by moisture and light.

Korean Patent No. 10-1302243 discloses a pharmaceutical composition which is excellent in storage stability and contains calcium dihydrogenphosphate as rosuvastatin or a pharmaceutically acceptable salt thereof and a stabilizer, , There is a limitation in solving the problem that the instability of the preparation is increased due to the interaction of rosuvastatin and nonsofrolrol, or the absorption of the drug is decreased in the body.

Korean Patent Laid-Open No. 10-2011-0063563 discloses a composition containing amlodipine and non-soaprolol packaged in a moisture-proof package. This patent discloses the use of N - (2 - {[4- (2-chlorophenyl) -3- (ethoxycarbonyl) -5- (methoxycarbonyl) -6 -Methyl-1,4-dihydro-2-pyridinyl] -methoxy} -ethyl) -asparic acid is formed. However, since the above-mentioned patent relates to a combination preparation of amlodipine other than rosuvastatin, when lactosubstatin is exposed to an acidic drug such as nonsofrolol, lactone, which is an acid-decomposed product, is produced, No suggestions are made on the problem.

International Publication WO 01/074394 discloses a composition containing a beta-blocker and an HMG-CoA reductase inhibitor, but specifically discloses only metoprolol without specific disclosure of non-soaprolol, As a simple composite composition, there is no technical suggestion for improvement of stability.

Korean Patent Publication No. 10-2011-0117758 discloses a pharmaceutical composition comprising a prior-release compartment containing a beta adrenergic blocker as a pharmacologically active ingredient and a delayed-release compartment containing an HMG-CoA reductase inhibitor as a pharmacologically active ingredient Lt; / RTI > However, in addition to describing neviverol as a beta adrenergic blocker, it does not mention any problems such as the stability caused by the complex of the two active ingredients or the absorption rate in the body.

Korean Patent Laid-Open No. 10-2013-0111335 discloses a pharmaceutical composition comprising olmesartan medoxomil and rosuvastatin or a salt thereof. The pharmaceutical compositions disclosed in this patent are formulated in a separate compartment formulations of olmesartan methoxycin and rosuvastatin or its salts to solve the problem of absorption inhibition due to drug interaction.

As such, it is obvious to those skilled in the art that, in the case of a drug having an interaction, it is generally known to disinfect unwanted interactions by separating components by applying methods such as granulation, capsules, and multi-layered tablets. However, applying separate granulation, multi-layered tablets, etc., to separate the active components requires special machines and processes. Therefore, there is a high demand for the development of a combination preparation which is simple formulation and stable.

British Patent No. 2,262,229 Korean Patent No. 10-1302243 Korean Patent Publication No. 10-2011-0063563 International Publication No. WO 01/074394 Korean Patent Publication No. 10-2013-0111335

Accordingly, the inventors of the present invention have found that by including an alkalizing agent to improve the stability of rosuvastatin when reacted with an acidic substance, it is possible to improve or prevent the drug reaction due to the interaction between non-soaprolol and rosuvastatin, It is possible to provide a combined preparation of a single formulation having optimized storage stability of non-soprolol and rosuvastatin, which are unstable to acid and moisture, and have completed the present invention.

Accordingly, it is an object of the present invention to provide a stable, single-dosage oral pharmaceutical combination comprising non-soaprolol and rosuvastatin as a combined preparation for oral administration for prevention or treatment of cardiovascular diseases.

It is another object of the present invention to provide a method for producing the pharmaceutical composition for oral use of the single dosage form.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, non-soaprolol or a pharmaceutically acceptable salt thereof, a hygroscopic excipient and an alkalizing agent, Or a pharmaceutical composition for oral < RTI ID = 0.0 > pharmaceutical < / RTI >

The present invention also provides a method of preparing the pharmaceutical composition for oral use of the single formulation.

The oral pharmaceutical combination preparation comprising non-soaprolol and rosuvastatin according to the present invention exhibits the same level of bioavailability as the conventional non-soaprolol or single formulation containing rosuvastatin, Can be used for the prevention or treatment of cardiovascular diseases such as hypertension, angina pectoris and hypercholesterolemia, and it is possible to provide a stabilized pharmaceutical combination for oral use without problems of instability due to acid or moisture, .

In addition, the present invention has an effect of providing a manufacturing method that can be formulated into a combined preparation without the need for a special pharmaceutical process, even with general formulation techniques alone. The pharmaceutical combination preparation according to the present invention can be produced by simple mixing of ingredients without the need for complicated methods such as granulating the respective active ingredients independently or separating the layers for the purpose of blocking the interaction of rosuvastatin with non- The present invention provides a method which can be produced by a simple manufacturing method.

Hereinafter, the present invention will be described in detail.

In one aspect, the present invention provides a pharmaceutical composition comprising a single agent for the prevention or treatment of cardiovascular diseases, including non-soprolol or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, hygroscopic excipients and an alkalizing agent The present invention provides an oral pharmaceutical combination preparation of the present invention.

Pharmaceutically acceptable salts of non-soapsolol in the above pharmaceutical combination preparations include, for example, fumarate, hydrochloride, methanesulfonate, and the like, preferably hemopumaric acid nonsofrolol.

Pharmaceutically acceptable salts of rosuvastatin in such pharmaceutical combination preparations include, for example, calcium salts, sodium salts, manganese salts, copper salts and iron salts and the like, preferably rosuvastatin calcium salts.

In the present invention, 1.4 to 3% by weight of the non-isoproylol or pharmaceutically acceptable salt thereof and, in terms of the total weight of the pharmaceutical combination preparation of the present invention, rosuvastatin or a pharmaceutically acceptable salt thereof is 3 to 12 wt% %, But the present invention is not limited thereto.

In the pharmaceutical combination preparation of the present invention, in order to improve the storage stability of water-unstable nonsofrolrol or a pharmaceutically acceptable salt thereof, it is preferable to use a pre-classified, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate and carboxymethylcellulose Hygroscopic excipients such as calcium can be used, but are not limited thereto.

Croscarmellose sodium, crospovidone, sodium starch glycolate, and carboxymethylcellulose, which correspond to the quick-disintegrating agent, are capable of wetting moisture in a short period of time, but they are not suitable because they may significantly affect the disintegration and dissolution profile of the preparation in excessive use , The microcrystalline cellulose has a relatively low moisture wetting rate and a relatively low moisture content with time.

The above-mentioned pre-sort is most preferable because it has an exponential increase in moisture content with time in the water environment and can be used in an excess amount as an excipient. Therefore, the hygroscopic excipient is most preferably a pre-classified, but not limited thereto. More specifically, the preculture may be one or more starches selected from the group consisting of corn starch, potato starch or pregelatinized starch.

The content of the above-mentioned pre-classified is suitably selected by those skilled in the art, but it is preferable that the pre-classified is contained in the range of 0.0001 to 200 parts by weight based on 1 part by weight of non-soaprolol or its pharmaceutically acceptable salt. If the content of the total fraction is less than 0.0001 based on 1 part by weight of non-soaprolol or its pharmaceutically acceptable salt, a desired stabilization effect can not be expected. If the total content of the former is 200 parts by weight or more, the total weight of the preparation becomes ineffective, And the dissolution profile.

The pharmaceutical combination preparation according to the present invention may further comprise an alkalizing agent.

The alkaline agent improves the problem that the stability of rosuvastatin is reduced when reacting with an acidic substance. As the alkalizing agent used in the combination preparation of the present invention, a pharmaceutically acceptable alkalizing agent commonly used in the pharmaceutical industry can be used. Examples of such an alkalizing agent include magnesium oxide, magnesium aluminum silicate, potassium dihydrogenphosphate, potassium citrate, potassium citrate hydrate and anhydrous calcium dihydrogenphosphate, preferably anhydrous calcium dihydrogenphosphate.

It is preferable that the alkalizing agent is contained in the preparation so that the pH can be maintained at 6.5 or more and 10 or less in the aqueous dispersion state of 5% of rosuvastatin or a pharmaceutically acceptable salt thereof.

The content of the alkalizing agent may be appropriately selected by those skilled in the art and may be 0.00001 to 200 parts by weight, preferably 0.00002 to 100 parts by weight, based on 1 part by weight of rosuvastatin or a pharmaceutically acceptable salt thereof . If the content of the alkalizing agent is less than 0.00001 based on 1 part by weight of rosuvastatin or a pharmaceutically acceptable salt thereof, the stabilizing effect of the drug can not be expected. If the amount of the alkalizing agent is excessively used, the amount of the alkalizing agent exceeds the daily allowable amount of the alkalizing agent This can cause safety problems.

The pharmaceutical combination preparation according to the present invention may further contain pharmaceutically acceptable diluents, binders, disintegrants, and lubricants, which are commonly used in the pharmaceutical industry.

The diluent may be any diluent commonly used in the pharmaceutical industry, and examples thereof include lactose, microcrystalline cellulose, mannitol, colloidal silicon dioxide and the like, and microcrystalline cellulose may be preferably used. The content of the diluent can be appropriately selected by the skilled person and can be appropriately adopted, for example, in the range of 0.0001 to 200 parts by weight per 1 part by weight of the rosuvastatin and non-sofrorol mixture as the active ingredient.

The binder may be any of those conventionally used in the pharmaceutical industry, and examples thereof include starch, microcrystalline cellulose, colloidal silicon dioxide, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone copolymer, hydroxypropylmethylcellulose , Hydroxypropylcellulose, gelatin, or a mixture thereof, but are not limited thereto. Preferably, hydroxypropylmethylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone copolymers can be used. The content of the binder can be appropriately selected by a person skilled in the art and can be suitably adopted, for example, in the range of 0.0001 to 200 parts by weight per 1 part by weight of the rosuvastatin and non-sofrorol mixture as the active ingredient.

Disintegrants may be any disintegrants commonly used in the pharmaceutical industry and include, for example, starches such as corn starch, potato starch, pregelatinized starch, sodium starch glycolate and the like, microcrystalline cellulose, hydroxypropylcellulose or Cellulose such as carboxymethyl cellulose, cross-linked cellulose such as croscarmellose sodium, cross-linked polymer such as crosslinked polyvinyl pyrrolidone, anisotropic agent such as sodium bicarbonate and citric acid, or a mixture thereof may be used. It is not. Preferably, crospovidone may be used. The content of the disintegrant can be appropriately selected by a person skilled in the art and can be appropriately adopted, for example, within the range of 0.0001 to 200 parts by weight per 1 part by weight of the rosuvastatin and the nonsofrolol mixture as the active ingredient.

The lubricant may be any lubricant commonly used in the pharmaceutical industry and may be any lubricant such as stearic acid, magnesium stearate, calcium stearate, sodium benzoate, sodium stearyl fumarate, glyceryl monolate, glyceryl monostearate, Glyceryl behenate, glyceryl palmitostearate, zinc stearate, paraffins and the like can be used, but are not limited thereto. Preferably, magnesium stearate may be used. The content of the lubricant may be suitably selected by those skilled in the art and may be suitably selected within the range of, for example, 0.0001 to 100 parts by weight based on 1 part by weight of the rosuvastatin and the nonsofrolol mixture as the active ingredient.

The cardiovascular diseases described in the present invention are selected from the group consisting of hypertension, angina pectoris and hypercholesterolemia, but are not limited thereto.

In another aspect, the present invention also provides a method for preparing the pharmaceutical composition for oral administration of the single formulation.

The single oral pharmaceutical combination preparation of the present invention can be prepared by standard techniques and manufacturing methods generally known in the pharmaceutical industry.

In one embodiment, the pharmaceutical combination preparations of the present invention may be formulated as a pharmaceutical composition comprising, for example, rosuvastatin or a pharmaceutically acceptable salt thereof, nonsofrolol or a pharmaceutically acceptable salt thereof, an alkalizing agent, a hygroscopic excipient, After one or more binders, one or more disintegrants or other additional excipients are mixed together, the lubricant may be added to the mixture to continue mixing until a homogeneous mixture is obtained, and the mixture may be compressed into tablets to form a single tablet .

In another embodiment, the pharmaceutical combination of the present invention may be prepared using a wet granulation method. For example, rosuvastatin or a pharmaceutically acceptable salt thereof, non-soaprolol or a pharmaceutically acceptable salt thereof, an alkalizing agent, hygroscopic excipient, at least one diluent, at least one disintegrant, and other additional excipients are mixed together And granulated with a small amount of a binding liquid. The granules are dried to formulate, the excipients, disintegrant and the residue of the glidant are added to the milled granules, and the resulting mixture is compressed into tablets after mixing. The dry mixing and wet granulation methods, including the order of addition of the ingredients and their mixture before compression into tablets, can be modified according to principles known in the pharmaceutical arts.

In another embodiment, the combination prepared by the wet granulation method can be prepared by separating and granulating each active ingredient of rosuvastatin or a pharmaceutically acceptable salt thereof and nonsofrolol or a pharmaceutically acceptable salt thereof have. For example, rosuvastatin or a pharmaceutically acceptable salt thereof is mixed with an alkalizing agent, a hygroscopic excipient, and at least one diluent, granulated with a small amount of a binding solution, dried and sized to prepare granule 1 . In the same manner, non-soaprolol or a pharmaceutically acceptable salt thereof is mixed with an alkalizing agent, hygroscopic excipient, and at least one diluent, granulated with a small amount of a binding liquid, dried and sized to prepare a granule 2. The prepared granule 1 and the granule 2 are mixed together with a predetermined disintegrant and a lubricant and compressed into tablets.

In another embodiment, the composition of the composite preparation prepared by the wet granulation method of the present invention can be prepared by post-mixing the remaining active ingredients in granules containing one active ingredient. For example, rosuvastatin or a pharmaceutically acceptable salt thereof or nonsofrolol or a pharmaceutically acceptable salt thereof is mixed with an alkalizing agent, a hygroscopic excipient, and one or more diluents, and granulated with a small amount of a binding liquid Followed by drying and sizing to prepare Granule 1. The remaining active ingredient is added to the granulate with anhydrous calcium dihydrogenphosphate, pregelatinized starch, one or more diluents and mixed, and the mixture is filtered with a lubricant and compressed into tablets.

In another embodiment, the combined preparation produced via wet granulation comprises separately isolating, granulating and granulating each active ingredient of rosuvastatin or a pharmaceutically acceptable salt thereof and nonsofrolol, or a pharmaceutically acceptable salt thereof, . For example, rosuvastatin or a pharmaceutically acceptable salt thereof is mixed with an alkalizing agent, hygroscopic excipient, disintegrant, at least one diluent, granulated with a small amount of a binding solution, dried and sized to prepare granule 1 do. In the same manner, non-soaprolol or a pharmaceutically acceptable salt thereof is mixed with an alkalizing agent, hygroscopic excipient, disintegrant, and at least one diluent, granulated with a small amount of a binding liquid, dried and sized to prepare granular material 2 do. A lubricant is added to each of the granulated material 1 and the granulated material 2, followed by mixing, followed by tableting in a two-layer tablet machine.

The single tablet of the present invention may be coated, and the tablet coating may be applied by spraying with an aqueous film coating. Coating agents may include, for example, hydroxypropylmethylcellulose, triacetin, titanium dioxide and ferric oxide, and the coating may be present in an amount of 0.5 to 10 wt%, preferably 2 to 5 wt%, based on the total weight of the tablet composition %. ≪ / RTI >

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples. However, the scope of the present invention is not limited by the following examples.

[ Example ]

Test Example  1: Evaluation of interactions between active ingredients

In order to confirm the instability due to the interaction between the active ingredients, a simple chemical stability test was carried out.

As shown in the following Table 1, 200 mg of hemisulfatinic acid isophilol powder, 200 mg of rosuvastatin calcium salt powder, 100 mg of hemisuccinic acid nonaspoprolol, and 100 mg of rosuvastatin calcium salt were mixed and pelletized with 1 ton of a pellet Were stored in HDPE plastic containers and stored for 4 weeks under harsh conditions (60 ± 2 ° C., 80 ± 5% RH). The content (%) of the substances was confirmed by HPLC and the results are shown in Table 1 below.

The content of the test substance was confirmed by HPLC analysis as follows.

Column: ODS-2, 4.6 * 250, 5 [mu] m, C18

Detector: Absorbance intensity detector (hemifumaric acid nonsofrolol: 225 nm, rosuvastatin calcium salt: 242 nm)

Mobile phase A: 20 mM KH ₂ PO ₄ : ACN (9: 1, v / v)

Mobile phase B: H ₂ O: ACN (1: 9, v / v)

Flow rate: 1 mL / min

Column temperature: 35 ° C

Analysis time: 10 minutes

Results of stability test between active ingredients Sample Test commencement 2 parking 4 parking Hemifumaric acid non-isoprolauro total flexible substance N.D. 0.09% 0.06% Rosuvastatin calcium salt total flexible substance 0.25% 0.39% 0.44% 1: 1 mixed pellets Hemifumaric acid non-isoprolauro total flexible substance N.D. 0.03% 0.34% Rosuvastatin calcium salt total flexible substance 0.17% 3.35% 12.08%

As a result, it was confirmed that the total flexibility of non-soaprolol and rosuvastatin calcium salt was largely formed due to the mutual reactivity of the two active ingredients in the mixture of nonsofrolol and rosuvastatin calcium salt.

Test Example  2: Evaluation of interaction between active ingredient and excipient

Each of the excipients listed in the following Table 2 was mixed with rosuvastatin calcium salt at a ratio of 1: 1 (w / w) with 1: 1 (w / w) hemisulfamic acid nonsofrolol or each of the excipients listed in Table 3 below, The mixed powders were stored in HDPE plastic containers and stored for 4 weeks under harsh conditions (60 ± 2 ° C., 80 ± 5% RH). The content (%) of the substances was confirmed by HPLC and the results are shown in Tables 2 and 3 Respectively.

Results of the simple stability test for evaluating the interaction between non-isopropylol and excipients Excipient Hemifumaric acid bisoprolol
Total flexible material Test commencement 4 parking Raw material powder N.D. 1.50% Lactose baggage N.D. 3.66% Pregelatinized starch N.D. 0.38% D-mannitol N.D. 2.49% Microcrystalline cellulose N.D. 0.85% Crospovidone N.D. 1.94% Starch glycolate sodium N.D. 0.83% Croscarmellose sodium N.D. 0.30% Carboxymethylcellulose N.D. 0.50%

As shown in Table 2, the total amount of the suppositories of hemifumarate isoprodolol was significantly increased in the 4-week severe condition, especially in the case of lactose hydrate and D-mannitol. On the other hand, in the case of pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, and carboxymethylcellulose, the amount of total flux of hemipungalic acid isophrolol was suitable to the standard value, The total number of flexible materials was the lowest.

Results of the simplified stability test to evaluate the interaction of rosuvastatin with excipients Excipient Rosuvastatin calcium salt
Total flexible material Test commencement 4 parking Raw material powder 0.25% 0.55% Magnesium oxide 0.31% 0.30% Anhydrous calcium dihydrogen phosphate 0.31% 0.73% Potassium dihydrogen phosphate 0.22% 0.28% Potassium citrate hydrate 0.22% 0.33%

As shown in Table 3 above, the amount of rosuvastatin calcium salt did not satisfy the standard, regardless of the type of excipients used.

Example  1 - 4: Preparation of a single tablet 1

A single tablet of the pharmaceutical combination according to the present invention was prepared as follows.

(1) granule manufacture

As an alkalizing agent, magnesium oxide, anhydrous calcium dihydrogenphosphate, potassium dihydrogenphosphate and potassium citrate hydrate were added to a mixture of hemifumaric acid nonsofrolol, rosuvastatin calcium salt, pregelatinized starch, microcrystalline cellulose, Mixed with hydroxypropylmethylcellulose, granulated with a small amount of purified water, and then dried at 60 DEG C for 2 hours. The obtained granules were set at 35 mesh.

(2) After mixing  And Tableting

The granules prepared in (1) above were mixed together with sodium croscarmellose sodium and magnesium stearate and then tableted to prepare 170 mg of white tablets per unit tablet.

Raw material amount table Constituent Example 1 Example 2 Example 3 Example 4 Hemifumaric acid bisoprolol 5.0 mg 5.0 mg 5.0 mg 5.0 mg Rosuvastatin calcium 10.4 mg 10.4 mg 10.4 mg 10.4 mg Magnesium oxide 15.4 mg - - - Anhydrous calcium dihydrogen phosphate - 15.4 mg - - Potassium dihydrogen phosphate - - 15.4 mg - Potassium citrate hydrate - - - 15.4 mg Pregelatinized starch 63.0 mg 63.0 mg 63.0 mg 63.0 mg Microcrystalline cellulose 62.7 mg 62.7 mg 62.7 mg 62.7 mg Hydroxypropylmethylcellulose 6 cp 7.5 mg 7.5 mg 7.5 mg 7.5 mg Croscarmellose sodium 4.5 mg 4.5 mg 4.5 mg 4.5 mg Magnesium stearate 1.5 mg 1.5 mg 1.5 mg 1.5 mg Gross weight 170.0 mg 170.0 mg 170.0 mg 170 mg

(3) Stability test of preparation

The content (%) of the total flexible substances in the tablets of Example 1-4 prepared in (2) above was confirmed by the following method.

The prepared tablets were stored in an HDPE container for 2 weeks under the conditions of acceleration (40 ° C, 75% RH). 10 tablets of each tablet were taken and pulverized into fine powder. One part by weight of the tablet was taken in a 10 mL brown capacity flask, and a 70% (v / v) acetonitrile solution was added thereto, followed by ultrasonic treatment for 30 minutes After fitting the markings, they were filtered to give a sample solution.

HPLC analysis was carried out under chromatographic conditions as shown in Table 5 below.

Chromatographic method conditions column ODS-2, 4.6 * 250, 5 [mu] m, C18 Detector Absorbance photometric detector
- Hemifumaric acid bisoprolol: 225 nm
- rosuvastatin calcium: 242 nm) Mobile phase Mobile phase A: 20 mM KH ₂ PO ₄ : ACN (9: 1, v / v)
Mobile phase B: H ₂ O: ACN (1: 9, v / v) Flow rate 1 mL / min Column temperature 35 ℃ Analysis time 10 minutes

The stability test results are shown in Table 6 below.

Content of Total Flexible Substance Example Hemifumaric acid bisoprolol
Total flexible material Rosuvastatin calcium
Total flexible material Test commencement 2 parking Test commencement 2 parking Example 1 0.13% 0.36% 0.16% 0.15% Example 2 0.10% 0.13% 0.85% 9.88% Example 3 0.13% 0.16% 0.23% 0.82% Example 4 0.26% 0.32% 0.46% 3.94%

As shown in Table 6, hemisulfuric acid non-isopropyl alcohol was suitable for the amount of generated soft matter regardless of the type of alkalizing agent. The stabilizing effect of rosuvastatin calcium was shown in the order of magnesium oxide, potassium dihydrogenphosphate, potassium citrate hydrate, and anhydrous calcium dihydrogenphosphate, and it was confirmed that the stabilization effect was the most stabilized in Example 1 including magnesium oxide as an alkalizing agent.

(4) Depending on the type and amount of alkalizing agent pH  change

5 mg of hemifumaric acid isoprodol and 10 mg of rosuvastatin calcium salt were dissolved and dispersed in 200 mL of purified water, and the pH change of the dispersion was measured by adding an alkalizing agent to the dispersion. The results are shown in Table 7 below.

PH change according to kind and amount of alkalizing agent Alkalizing agent 0 mg 10 mg 30 mg 50 mg Magnesium oxide 5.58 10.48 10.69 10.82 Anhydrous calcium dihydrogen phosphate 5.58 6.05 6.67 6.97 Potassium dihydrogen phosphate 5.58 7.01 7.66 7.95 Potassium citrate hydrate 5.58 6.31 6.71 6.97

As a result, the pH-increasing effect of the dispersion was shown in the order of magnesium oxide, potassium dihydrogenphosphate, potassium citrate hydrate, and anhydrous calcium dihydrogenphosphate, which was the stabilization result of rosuvastatin in Examples 1, 2, 3 and 4 .

Based on the stability results of Examples 1, 2, 3 and 4 and the pH evaluation results according to the kinds and amounts of the alkalizing agents, stabilization of rosuvastatin calcium salt in the combined preparation of non-soaprolol and rosuvastatin It is preferable that the amount of the alkalizing agent capable of maintaining the pH of the dispersion at about 7 when the suvastatin calcium salt is dispersed at 5% in the aqueous solution is contained in the preparation.

Example  5-7: Preparation of a single tablet 2

A single tablet of the pharmaceutical composition according to the present invention was prepared as follows.

(1) granule manufacture

Granulated with a small amount of purified water, and then dried at 60 ° C for 2 hours. The granules were mixed with hemifumaric acid non-isoflavone hemisulfate, rosuvastatin calcium salt, magnesium oxide, pregelatinized starch, microcrystalline cellulose and hydroxypropylmethylcellulose, Respectively. The obtained granules were set at 35 mesh.

(2) After mixing  And Tableting

The granules prepared in the above (1) were mixed together with croscarmellose sodium and magnesium stearate and then tableted to prepare 170 mg of white tablets per unit tablet, as shown in Table 8 below.

Constituent Example 5 Example 6 Example 7 Hemifumaric acid bisoprolol 5.0 mg 5.0 mg 5.0 mg Rosuvastatin calcium salt 10.4 mg 10.4 mg 10.4 mg Magnesium oxide 15.4 mg 15.4 mg 15.4 mg Pregelatinized starch 0.0 mg 61.2 mg 121.2 mg Microcrystalline cellulose 121.2 mg 60.0 mg 0.0 mg Hydroxypropylmethylcellulose 6 cp 12.0 mg 12.0 mg 12.0 mg Croscarmellose sodium 4.5 mg 4.5 mg 4.5 mg Magnesium stearate 1.5 mg 1.5 mg 1.5 mg Gross weight 170.0 mg 170.0 mg 170.0 mg

(3) Stability test of preparation

With respect to the tablets of Example 5-7 prepared above, the content (%) of total flexible substances was confirmed by the following method.

The prepared tablets were stored in an HDPE container for 2 weeks under the conditions of acceleration (40 ° C, 75% RH). The total content of the flexible materials was measured according to the method of measuring the content of the flexible materials in Examples 1-4. The stability test results are shown in Table 9 below.

Content of Total Flexible Substance Example Hemifumaric acid bisoprolol
Total flexible material Rosuvastatin calcium salt
Total flexible material Test commencement 2 parking Test commencement 2 parking Example 5 0.20% 0.44% 0.15% 0.15% Example 6 0.13% 0.31% 0.16% 0.13% Example 7 0.17% 0.16% 0.18% 0.14%

As shown in Table 9, hemifumaric acid non-isoproylol had a level of the total amount of the generated flexible substances with respect to both the starch starch and the microcrystalline cellulose. However, it was confirmed that as the content of pregelatinized starch increased, the degree of instability improvement with respect to moisture increased.

Example  8-11: Single tablet preparation 3

According to the stability results of Examples 1-4 and 5-7, an alkalizing agent which greatly improved the instability of hemisulfuric acid nonsofrolrol and rosuvastatin calcium salt was selected, and in order to evaluate stability of the preparation according to the manufacturing process Single tablets of Examples 8, 9, 10, and 11 were prepared using the following preparations with the following ingredients and compositions.

(One) In the straight line process  Following Single formulation  Produce

As shown in Table 10 below, hemisulfuric acid isoprodol, rosuvastatin calcium, magnesium oxide, calcium dihydrogenphosphate anhydrous, pregelatinized starch, microcrystalline cellulose, crospovidone, croscarmellose sodium and hydroxypropylcellulose Mixed together, and magnesium stearate was added thereto, mixed and then tableted to prepare 200 mg each of white tablets per unit tablet.

Raw material amount table Manufacture process Constituent Example 8 Straight Hemifumaric acid bisoprolol 5.0 mg Rosuvastatin calcium salt 10.4 mg Magnesium oxide 18.2 mg Anhydrous calcium dihydrogen phosphate 50.0 mg Pregelatinized starch 65.3 mg Microcrystalline cellulose 35.6 mg Crospovidone 5.0 mg Croscarmellose sodium 5.0 mg Hydroxypropylcellulose 4.0 mg Magnesium stearate 1.5 mg Gross weight 200.0 mg

(2) According to a single granulation process Single formulation  Produce

As shown in Table 11, hemifumaric acid non-isoprodol, rosuvastatin calcium, magnesium oxide, calcium dihydrogenphosphate anhydrous, pregelatinized starch, microcrystalline cellulose, crospovidone, croscarmellose sodium and hydroxypropyl cellulose were mixed together After the addition, a small amount of purified water was added to granulate, followed by drying at 60 ° C for 2 hours.

The obtained granules were set at 30 mesh. Magnesium stearate was added to the thus-prepared mixture, and the mixture was tabletted to prepare 200 mg of white tablets per unit tablet.

Raw material amount table Manufacture process Constituent Example 9 Granule Hemifumaric acid bisoprolol 5.0 mg Rosuvastatin calcium salt 10.4 mg Magnesium oxide 18.2 mg Anhydrous calcium dihydrogen phosphate 50.0 mg Pregelatinized starch 65.3 mg Microcrystalline cellulose 35.6 mg Crospovidone 5.0 mg Croscarmellose sodium 5.0 mg Hydroxypropylcellulose 4.0 mg After mixing Magnesium stearate 1.5 mg Gross weight 200.0 mg

(3) According to the separation granulation process Single formulation  Produce

As shown in the following Table 12, the single tablets of the present invention were prepared using ingredients and compositions according to the following production methods.

(3-1) Hemifumaric acid Nonsofrolol  Granule manufacture

Hemifumaric acid bisoprolol, calcium dihydrogenphosphate, pregelatinized starch, microcrystalline cellulose, croscarmellose sodium and hydroxypropylcellulose were mixed together and granulated by adding a small amount of purified water, followed by drying at 60 DEG C for 2 hours Respectively. The obtained granules were set at 35 mesh.

(3-2) Rosuvastatin  Manufacture of calcium salt granules

Magnesium oxide as the alkalizing agent was mixed with rosuvastatin calcium salt, pregelatinized starch, microcrystalline cellulose, crospovidone and hydroxypropylcellulose according to the examples in Table 12 below, granulated by adding a small amount of purified water, And dried at 60 DEG C for 2 hours. The obtained granules were set at 35 mesh.

(3-3) After mixing  And Tableting

The granules prepared in the above (3-1) and (3-2) were mixed and magnesium stearate was added thereto and mixed to prepare 200 mg of white tablets per unit tablet.

Raw material amount table Manufacture process Constituent Example 10 Granule 1 Hemifumaric acid bisoprolol 5.00 mg Anhydrous calcium dihydrogen phosphate 50.00 mg Pregelatinized starch 50.00 mg Microcrystalline cellulose 9.80 mg Croscarmellose sodium 5.00 mg Hydroxypropylcellulose 2.00 mg Granule 2 Rosuvastatin calcium salt 10.40 mg Magnesium oxide 18.20 mg Pregelatinized starch 15.30 mg Microcrystalline cellulose 25.80 mg Crospovidone 5.00 mg Hydroxypropylcellulose 2.00 mg After mixing Magnesium stearate 1.50 mg Gross weight 200.00 mg

(4) After mixing  Process dependent Single formulation  Produce

As shown in the following Table 13, the single tablets of the present invention were prepared using the ingredients and composition as follows.

(4-1) Hemifumaric acid Nonsofrolol  Granule manufacture

Hemifumaric acid bisoprolol, anhydrous calcium dihydrogenphosphate, pregelatinized starch, microcrystalline cellulose, croscarmellose sodium and hydroxypropylcellulose were mixed together, granulated by adding a small amount of purified water, and then granulated at 60 ° C for 2 hours Lt; / RTI > The obtained granules were set at 35 mesh.

(4-2) After mixing  And Tableting

Magnesium oxide as an alkalizing agent was mixed with rosuvastatin calcium salt, pregelatinized starch, microcrystalline cellulose and crospovidone according to the examples in the following Table 13, magnesium stearate was added and mixed, and then 200 mg Of white tablets.

Raw material amount table Manufacture process Constituent Example 11 Granule 1 Hemifumaric acid bisoprolol 5.00 mg Anhydrous calcium dihydrogen phosphate 50.00 mg Pregelatinized starch 50.00 mg Microcrystalline cellulose 9.80 mg Croscarmellose sodium 5.00 mg Hydroxypropylcellulose 2.00 mg After mixing Rosuvastatin calcium salt 10.40 mg Magnesium oxide 18.20 mg Pregelatinized starch 15.30 mg Microcrystalline cellulose 25.80 mg Crospovidone 5.00 mg Hydroxypropylcellulose 2.00 mg Magnesium stearate 1.50 mg Gross weight 200.00 mg

(5) Stability test of preparation

The contents (%) of the total flexible substances were confirmed by the following method for the tablets of Examples 8, 9, 10 and 11 thus prepared.

The tablets prepared in the above examples were stored in an HDPE container for 4 weeks under the conditions of acceleration (40 DEG C, 75% RH). The content of the total flexible material was measured according to the method of measuring the content of the flexible material in Example 1 above. The stability test results are shown in Table 14 below.

Stability test results Example Hemifumaric acid bisoprolol
Total flexible material Rosuvastatin calcium salt
Total flexible material Test commencement 2 parking 4 parking Test commencement 2 parking 4 parking Example 8 0.18% 0.28% 0.42% 0.10% 0.09% 0.14% Example 9 0.20% 0.30% 0.43% 0.15% 0.11% 0.13% Example 10 0.06% 0.29% 0.54% 0.13% 0.17% 0.14% Example 11 0.24% 0.36% 0.46% 0.15% 0.11% 0.16%

As a result, the total amount of the suppositories of hemisuccinyl hemipurnalic acid and rosuvastatin calcium in the formulation did not show any difference depending on the manufacturing process. This means that the excellent stability of the preparation can be ensured even in a simple mixing process in the combination of non-soaprolol and rosuvastatin, which are inferior in stability due to mutual interaction.

Example  12-13: Single tablet preparation 4

According to the stability results of Examples 1-4 and 5-7, alkalizing agents which greatly improved instability of hemisulfuric acid nonsofrolrol and rosuvastatin calcium salts were selected, respectively, and pharmacokinetic effects and stabilization To evaluate the effects, a single tablet of the present invention was prepared using ingredients and compositions as shown in Table 15 below using the following production methods.

(One) Hemifumaric acid Nonsofrolol  Granule manufacture

Hemifumaric acid bisoprolol, anhydrous calcium dihydrogenphosphate, pregelatinized starch, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium and hydroxypropylcellulose are mixed together and granulated by adding a small amount of purified water, And dried at 60 DEG C for 2 hours. The obtained granules were set at 35 mesh.

(2) Rosuvastatin  Manufacture of calcium salt granules

Magnesium oxide or anhydrous calcium dihydrogenphosphate as an alkalizing agent was mixed with rosuvastatin calcium salt, pregelatinized starch, microcrystalline cellulose, crospovidone and hydroxypropylcellulose according to the examples in Table 15, and a small amount of purified water was added Granulated, and then dried at 60 DEG C for 2 hours. The obtained granules were set at 35 mesh.

(3) After mixing  And Tableting

The granules prepared in the above (1) and (2) were mixed and magnesium stearate was added thereto and mixed to prepare 200 mg of white tablets per unit tablet.

Raw material amount table Constituent Example 12 Example 13 Granule 1 Hemifumaric acid bisoprolol 5.00 mg 5.00 mg Anhydrous calcium dihydrogen phosphate 50.00 mg 50.00 mg Pregelatinized starch 40.00 mg 40.00 mg Microcrystalline cellulose 17.80 mg 17.80 mg Colloidal silicon dioxide 2.00 mg 2.00 mg Croscarmellose sodium 5.00 mg 5.00 mg Hydroxypropylcellulose 2.00 mg 2.00 mg Granule 2 Rosuvastatin calcium salt 10.40 mg 10.40 mg Magnesium oxide 18.20 mg - Anhydrous calcium dihydrogen phosphate - 18.20 mg Pregelatinized starch 15.30 mg 15.30 mg Microcrystalline cellulose 25.80 mg 25.80 mg Crospovidone 5.00 mg 5.00 mg Hydroxypropylcellulose 2.00 mg 2.00 mg After mixing Magnesium stearate 1.50 mg 1.50 mg Gross weight 200.00 mg 200.00 mg

(4) Beagles  Pharmacokinetic study

As tablets and comparative examples of Examples 12 and 13, 5 mg tablets of control drug Concord and 10 mg tablets of Crestor 10 mg were administered orally to each of six beagle dogs one at a time, followed by administration of cephalic vein (0 hour) and 2 ml of blood at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours after administration.

The collected blood was centrifuged to separate the plasma and stored in the freezer until analysis. After a sufficient 7-day withdrawal period, cross-testing was conducted in the same manner. The drug concentrations in plasma were analyzed by LC-MS / MS.

LC / MS / MS was used for the analysis of rosuvastatin and arsenic propol in plasma, and atorvastatin and propranolol were used as internal standards in the evaluation of pharmacokinetic absorption.

LC conditions were a column - Imtakt Cadenza CW-C18 (2.0 x 75 mm, 3 m m); Mobile phase - ACN: 0.1% formic acid = 150: 100; Flow rate - 0.25 ml / min; Dose - 10 μL; Sample temperature - 4 캜; And the column temperature was 35 ° C. MS conditions were ionization method - Electrospray ionization (ESI) in positive ionmode; M + H] + 559.3 → 440.3, propranolol [M + H] + 326.1 → 116.3, atorvastatin [M + H] + 482.2 → 258.2, arsenic chloride [ H] +260.0 - > 116.2.

Both rosuvastatin and arsenic propol were calculated by _Cmax and AUCt using WinNonlin version 5.2, a pharmacokinetic analysis program. The logarithmically transformed comparison items (AUCt, _Cmax ) Respectively.

Pharmacokinetic tests on the tablets of Examples 12 and 13 were conducted to examine the effect of drug absorption on alkalizing agents. The results are shown in Table 16 below.

Pharmacokinetic data on the concordant and crestor tablets as two-component complex single-tablet and control preparations of Examples 12 and 13 in beagle dogs Example Hemifumaric acid bisoprolol
Pharmacokinetic parameters Rosuvastatin calcium salt
Pharmacokinetic parameters t _max
(h) C _max
(ng / mL) AUC _last
(ng · hr / mL) t _1/2 t _max
(h) C _max (ng / mL) AUC _last (ng? R / mL) t _1/2 Example 12 1.33 ± 0.39 104.07 ± 13.79 903.26 + - 182.05 5.12 + - 0.72 2.08 ± 0.82 10.43 + - 4.99 71.97 ± 28.30 11.59 + - 8.82 Example 13 1.63 + - 0.61 98.29 ± 11.73 803.66 + - 113.83 5.12 + - 0.72 2.35 ± 1.52 19.03 + - 7.35 96.69 + - 39.15 7.39 ± 2.90 Concorde 1.54 + - 0.45 96.77 ± 12.41 857.58 ± 174.32 5.13 + - 0.71 - - - - Crestor tablets - - - - 1.65 ± 0.92 15.93 + - 6.79 93.57 ± 39.08 5.83 ± 3.40

As shown in Table 16 above, the pharmacokinetic parameters C _max , AUC _last of hemifumaric acid were similar in both of the single tablets of Examples 12 and 13. However, in the case of rosuvastatin, the tablet of Example 12 containing magnesium oxide as the alkalizing agent had lower values of C _max and AUC _last due to the pH change of magnesium oxide, and as an alkalizing agent, anhydrous calcium phosphate , The pharmacokinetic parameters of rosuvastatin were similar to the control formulation.

(5) Stability test of preparation

For the tablets of Example 13, the content (%) of total flexible substances was confirmed by the following method.

The tablets prepared in the above examples were stored in an HDPE container for 4 weeks under the conditions of acceleration (40 DEG C, 75% RH). The content of the total flexible material was measured according to the method of measuring the content of the flexible material in Example 1 above. The stability test results are shown in Table 17 below.

Example Hemifumaric acid bisoprolol
Total flexible material Rosuvastatin calcium salt
Total flexible material Test commencement 2 parking 4 parking Test commencement 2 parking 4 parking Example 13 N.D. N.D. 0.36% 0.19% 0.72% 0.95% Concorde 0.24% 1.32% 1.83% - - - Crestor tablets - - - 0.34% 1.56% 1.97%

As a result, the tablets according to Example 13 were superior to 5 mg of Concord tablets and 10 mg of Crestor tablets, which are the control agents in the production of the suppository.

Claims (15)

Or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, a hygroscopic excipient and an alkalizing agent for the prevention or treatment of cardiovascular diseases. The method according to claim 1,
Wherein the pharmaceutically acceptable salt of non-isoproylol is non-soaprolol hemifumarate. The method according to claim 1,
Wherein the pharmaceutically acceptable salt of rosuvastatin is rosuvastatin calcium salt. The method according to claim 1,
Characterized in that 1.4 to 3% by weight of the non-isoproylol or pharmaceutically acceptable salt thereof and 3 to 12% by weight of rosuvastatin or a pharmaceutically acceptable salt thereof are contained, based on the total weight of the pharmaceutical combination preparation Or a pharmaceutically acceptable salt thereof. The method according to claim 1,
Wherein the hygroscopic excipient is a pre-classified fraction. 6. The method of claim 5,
Wherein said preculture is selected from the group consisting of corn starch, potato starch and pregelatinized starch. The method according to claim 6,
Wherein the preclassified starch is pregelatinized starch. 6. The method of claim 5,
Characterized in that said preculture is contained in an amount of 0.00001 to 200 parts by weight per part by weight of non-soaprolol or a pharmaceutically acceptable salt thereof. The method according to claim 1,
Wherein the alkalizing agent is selected from the group consisting of magnesium oxide, calcium dihydrogenphosphate, potassium dihydrogenphosphate and potassium citrate hydrate. 10. The method of claim 9,
Wherein the alkalizing agent is anhydrous calcium dihydrogen phosphate. The method according to claim 1,
Wherein the alkalizing agent is contained so that the pH of the rosuvastatin or a pharmaceutically acceptable salt thereof can be maintained in a range of from 6.5 to 10 in an aqueous dispersion state of 5%. The method according to claim 1,
Wherein the alkalizing agent is contained in an amount of 0.00001 to 200 parts by weight based on 1 part by weight of rosuvastatin or a pharmaceutically acceptable salt thereof. The method according to claim 1,
A pharmaceutical composition for oral administration, which further comprises a pharmaceutically acceptable diluent, a binder, a disintegrant, and a lubricant. The method according to claim 1,
Wherein the cardiovascular disease is selected from the group consisting of hypertension, angina, and hypercholesterolemia. The method according to claim 1,
Wherein the combined preparation is a single formulation.