KR20170083484A - Pharmaceutical composition with improved dissolution rate comprising nebivolol - Google Patents

Abstract

A pharmaceutical composition for preventing or treating cardiovascular diseases comprising neviborol or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive is provided. the dissolution rate of nevivolol does not decrease even at a relatively low pH of 5 to 7 as well as at a low pH such as pH 1.2, and thus the dissolution rate can be greatly improved, so that an improved therapeutic effect can be expected. It is possible to reduce the manufacturing cost, and there is little variation in the dissolution rate according to the pH change. Therefore, the occurrence of variation in bioavailability due to pre- or post-meal administration can be minimized and a constant pharmacological action can be maintained. Or other active ingredients such as rosuvastatin calcium It is very useful for the preparation of pharmaceutical preparations.

Description

[0001] PHARMACEUTICAL COMPOSITION WITH IMPROVED DISSOLUTION RATE COMPRISING NEBIVOLOL [0002]

The present invention relates to a pharmaceutical composition with improved dissolution rate of nevvolol and a method for producing the same. More specifically, the present invention relates to a pharmaceutical composition having improved dissolution rate, comprising nebivolol or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive as an active ingredient.

Beta-blockers are used in the treatment of hypertension, angina pectoris, myocardial infarction, heart disease, migraine or essential tremor.

Among these beta-blockers, naviborol is a 2,2'-iminobiethanol derivative of the general formula (1), having a central symmetrical structure with four chiral centers.

[Chemical Formula 1]

Navibiovol is a beta -receptor blocking drug that is a mixture of D- and L-enantiomers, which has a high selectivity for the? 1-adrenergic receptor and has a vasodilating effect associated with the effect on the endotoxin nitrogen, . Navibiovol is believed to increase the concentration of nitric oxide through the L-arginine-nitric oxide pathway in the vascular endothelium and has been shown to improve endothelial dysfunction and vascular elasticity. In addition, naviborol is known to have desirable antioxidant properties for normal function of vascular endothelium, and thus is used as an effective antihypertensive agent having a desired effect on vascular endothelium and cardiovascular system. In addition, naviborol has been found to be beneficial in the treatment of cardiovascular diseases such as hypertension, congestive heart failure, atherosclerosis and endothelial dysfunction.

In general, the pharmaceutical composition is provided in the form of a solid preparation, i.e., a tablet, suitable for oral administration in consideration of convenience of administration, and in this case, the bioavailability is very important. An important factor affecting the bioavailability is the in vivo dissolution process of the drug, which can be confirmed by the dissolution rate through the dissolution test in the laboratory. However, naviborol has a drawback that it exhibits a very low dissolution rate at a relatively high pH.

As a conventional technique for improving the disadvantages of the navi boreh, there is a method of minimizing the navi boreol (Korean Patent No. 0361636). However, there is a limit in the dissolution rate of the minified navi boreol, There is a problem that a large variation in bioavailability occurs. In addition, in order to improve the dissolution rate, there is a method (European Patent Registration No. 0145067) in which the moistened neviborol is mixed with wetting agent (European Patent Registration No. 0145067), so that it has an equilibrium dissolution rate in the form of naviborol hydrochloride without using a wetting agent 896266) discloses the prior art that Korean Patent Laid-Open Publication No. 2011-0130872 discloses that a crystalline level of naviborol can be used together with starch to obtain an equivalent level of dissolution rate.

However, according to these prior arts, it is very troublesome to grind and sieve the raw material in order to make the navi boreh less, which leads to increase in manufacturing time and cost, which is not economical, and addition of the wetting agent also increases the manufacturing cost It can be a factor. In addition, there is a problem that the treatment effect is deteriorated when the variation of the bioavailability due to meals or after meals is large.

Furthermore, in all of these prior arts, only the dissolution rate at pH 1.2 to 4.0 was actually confirmed, but the dissolution rate in the aqueous solution was not confirmed. As a result of the preliminary tests conducted prior to the present invention, it was confirmed that these navi-borool preparations exhibited a low dissolution rate of less than 70% when tested in water. In the case of in vivo administration of a drug with a low dissolution rate of the drug, oral absorption and bioavailability of the drug may be lowered, which may result in lowering of the drug efficacy in the human body. Accordingly, there is a strong demand for the development of a naviborol formulation which can secure a sufficient dissolution rate in vivo without variation.

Under these circumstances, the present inventors have made intensive efforts to prepare a nevibolol preparation that exhibits a stable and improved dissolution rate without any variation in in vivo pH. As a result, it has been found that when an alkalizing agent is added and formulated into a pharmaceutical composition, And has an excellent effect of improving the dissolution rate even in a water solution or a pH of 5 to 7, thereby completing the present invention.

In order to solve the above problems, it is an object of the present invention to provide a pharmaceutical composition of naviborol having improved dissolution rate and a method for producing the same.

As one embodiment for achieving the above object, the present invention provides a pharmaceutical composition for preventing or treating cardiovascular diseases, which comprises naviborol or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive do.

Herein, the pharmaceutically acceptable salt of naviborol is preferably naviborohydrochloride and may be included in an amount of 0.2 to 10 parts by weight based on 100 parts by weight of the total composition.

The alkalizing agent preferably exhibits a pH of 8 to 12 upon suspension or dissolution in water, and may be selected from the group consisting of magnesium oxide, magnesium carbonate and magnesium aluminum silicate. The alkalizing agent may be included in an amount of 0.02 to 10 parts by weight based on 100 parts by weight of the total composition.

The pharmaceutical composition according to another embodiment of the present invention may further comprise a component having a prophylactic or therapeutic activity for cardiovascular diseases, and these additional components may include hydrochlorothiazide, ramipril, enalapril, , Nisol dipine, amlodipine, losartan, fosartan, candesartan, telmisartan, valsartan, olmesartan, rosuvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, simvastatin and their pharmaceutically acceptable salts Acceptable salts thereof, and rosuvastatin calcium is particularly preferred.

A method of preparing a pharmaceutical composition for achieving another object of the present invention comprises:

a) mixing the naviborr or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive to prepare a mixture; And

b) molding said mixture,

Characterized in that an alkalizing agent is added in said step a) or b).

Hereinafter, the present invention will be described more specifically.

Neviporol having the following formula (I) as an active ingredient of the pharmaceutical composition according to the present invention is known as a beta-1 blocker having high selectivity and is useful for the management of hypertension.

[Chemical Formula 1]

In a composition according to the present invention, naviborol can be used in various forms, such as a free base of naviborol, or a pharmaceutically acceptable salt thereof, as long as equivalent pharmacological activity is maintained.

With respect to these pharmaceutically acceptable salts, navivorol has basicity and can be converted into its pharmaceutically acceptable acid addition salt form by treatment with an appropriate acid. Suitable acids include inorganic acids such as hydrohalic acids (e.g., hydrochloric, hydrobromic), sulfuric, nitric, phosphoric, and the like; (Z) -2-butenedioic acid, (E) -2 (2-hydroxypropanoic acid, Butanedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid , Toluene sulfonic acid, cyclohexane sulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, and the like. A preferred acid addition salt in the present invention is a hydrochloride salt.

The content of navivorol or a pharmaceutically acceptable salt thereof in the pharmaceutical composition can be controlled within a suitable range as required, preferably 0.2 to 10 parts by weight, more preferably 1 to 4 parts by weight, Weight portion. In one embodiment according to the present invention, about 100 parts by weight of the pharmaceutical composition, 1.5 to 3.6 parts by weight of naviborol is contained in hydrochloride form.

The pharmaceutical composition according to the present invention is characterized in that the neviborol or a pharmaceutically acceptable salt thereof is dissolved or dispersed in an aqueous medium such as an alkaline agent to prevent the problem that the dissolution rate is lowered at pH 5.0 to 7.0, And a control unit. Navi boreol is a weakly basic substance, and its solubility and dissolution rate decrease when pH is increased. Nevertheless, it has been found that the addition of the alkalizing agent according to the present invention significantly increases the dissolution rate of naviborol, which was first uncovered by the present invention in an unpredictable manner.

In a preferred embodiment of the present invention, the alkalizing agent may be selected to exhibit a pH of 8 to 12 upon suspension or dissolution in water, such as magnesium oxide, magnesium carbonate or magnesium aluminum silicate. In the present invention, by adding an alkalizing agent to neviborol or a pharmaceutically acceptable salt thereof, an excellent dissolution rate is exhibited not only at a low pH such as pH 1.2 but also at a pH of 5 to 7 such as a water solution, So that the high dissolution rate of the drug can be maintained despite the change. As a result, as a problem of conventional naviborol, a low dissolution rate at a relatively high pH and a rapid change in dissolution rate in the body can be solved.

In the composition of the present invention, the content of the alkalizing agent is preferably 0.02 to 10 parts by weight, more preferably 0.04 to 4 parts by weight based on 100 parts by weight of the total composition. If the content of the alkalizing agent is less than 0.02 parts by weight based on 100 parts by weight of the total composition, the effect of improving the dissolution rate is insufficient, and if it is more than 10 parts by weight, the dissolution rate may be lowered. In the examples according to the present invention, compositions (Examples 1 to 5) each containing magnesium carbonate, magnesium oxide and magnesium aluminum silicate as an alkalizing agent together with naviborol, and an alkalizing agent in a composite composition of naviborol and rosuvastatin (Examples 6 to 9) exhibited a significantly higher dissolution rate in the aqueous solution as compared with the formulation of the prescription (Comparative Example 1) similar to the marketed formulation containing no alkalizing agent and the preparations of Comparative Examples 2 and 3 Respectively.

In addition to the pharmacologically active ingredient and the alkalizing agent, the pharmaceutical composition according to the present invention may further include a pharmaceutically acceptable additive within the range not affecting the effect of the present invention. Specifically, these pharmaceutically acceptable additives may be at least one selected from the group consisting of fillers, binders, disintegrants, glidants, and lubricants.

Examples of excipients which can be used in the composition according to the present invention include microcrystalline cellulose, low substituted hydroxypropylcellulose, cellulose derivatives such as methylcellulose, starch such as potato starch and corn starch, lactose and fructose.

Examples of the binder include polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, methylcellulose, poloxamer, polyethylene oxide, polymethyl acrylate, Natural gums, synthetic gums, copovidone, and gelatin.

Examples of disintegrants include starch glycolic acid sodium, carboxymethylcellulose sodium, croscarmellose sodium, low-substituted hydroxypropylcellulose, pregelatinized starch, crospovidone, and the like.

Examples of the fluidizing agent include colloidal silicon dioxide, magnesium metasilicate aluminate, and the like.

Examples of lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, and glycerol palmitostearic acid.

In one preferred embodiment, the pharmaceutical composition of the present invention comprises, as a pharmaceutically acceptable additive, from 40 to 95 parts by weight of an excipient, from 1 to 10 parts by weight of a binder, from 1 to 10 parts by weight of a disintegrant, 0.1 to 2 parts by weight of the lubricant and 0.1 to 2 parts by weight of the lubricant.

The dosage form of the pharmaceutical composition with improved dissolution rate according to the present invention is not particularly limited and may be a dosage form suitable for various administration routes such as oral, parenteral (muscle, subcutaneous, intravenous, etc.) Do. Examples of the oral administration formulations include tablets, capsules, granules, troches, dispersants and suspending agents, and may be provided as solid oral formulations such as tablets or capsules, taking into account ease of administration . The composition according to the present invention can be used effectively because it does not cause a decrease in the dissolution rate regardless of the dosage form and has little variation with pH variation in the body.

The pharmaceutical composition according to the present invention can be produced by using an alkalizing agent such as magnesium carbonate, magnesium oxide and magnesium aluminum silicate without using a complicated and expensive process such as miniaturizing naviborol or containing wetting agent, , There is no decrease in the dissolution rate in the aqueous solution and an excellent dissolution rate of not less than 80% within 15 minutes after dissolution. Accordingly, since the composition of the present invention does not require the addition of micronization or wetting agent, the manufacturing cost can be reduced, and the dissolution rate of the composition varies little with pH change, so that occurrence of variation in bioavailability due to pre- or post- A certain pharmacological action and an improved therapeutic effect can be expected.

The pharmaceutical composition of the present invention can be prepared by a conventional preparation method in the form of a solid oral dosage form, for example, by direct compression, wet granulation or dry granulation . A preferred method of preparing a pharmaceutical composition according to the present invention comprises the steps of: a) preparing a mixture by mixing naviborr or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; And b) shaping the mixture, wherein an alkalizing agent is added in step a) or b).

Preferably, the mixing step may comprise mixing and compressing the active ingredient, including an effective amount of navivorol or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable additive to produce granules. More preferably, the granules can be prepared by the wet granulation method.

Preferably, the shaping step may include mixing and tabletting the remaining amount of pharmaceutically acceptable additives in the granules prepared from the mixture. In the preparation process according to the invention, the alkalizing agent may be granulated with the active ingredient and the additive in the mixing step, or mixed with the remaining amount of the pharmaceutically acceptable additives and the granules prepared in the mixing step in the molding step.

In a further embodiment, the manufacturing method may further comprise coating the molded pharmaceutical composition by known methods.

The pharmaceutical composition of the present invention may be used in combination with nevibolol or a pharmaceutically acceptable salt thereof for the prophylaxis or treatment of cardiovascular diseases such as hypertension, congestive heart failure, arteriosclerosis, metabolic dysfunction and endothelial dysfunction, May be included together. Examples of the component having a prophylactic or therapeutic activity for these cardiovascular diseases include hydrochlorothiazide, ramipril, enalapril, recondydipine, nisol dipine, amlodipine, losartan, frosaran, candesartan, telmisartan, But are not limited to, valsartan, olmesartan, rosuvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, simvastatin or pharmaceutically acceptable salts thereof. In a preferred embodiment, the additional active ingredient is rosuvastatin or a pharmaceutically acceptable salt thereof, more preferably rosuvastatin calcium.

The pharmaceutical composition of the present invention can improve the dissolution rate rather than lowering the dissolution rate of navivorous not only at a low pH such as pH 1.2 but also at a relatively high pH of 5 to 7 so that an improved therapeutic effect can be expected, It is possible to reduce the manufacturing cost since there is no need for microenvironment of the borehole or the addition of the wetting agent and since there is little variation in the dissolution rate according to the pH change, the occurrence of variation in bioavailability due to pre- or postmeal use can be minimized, , It is very useful for the preparation of complex preparations containing other active ingredients such as navibirol or rosuvastatin calcium.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graph showing the dissolution rate of water in the aqueous solution prepared in Examples 1 to 6 and Comparative Examples 1 to 3 by the paddle method. Fig.

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

Example  1 to 3

The granules were prepared according to the wet granulation method by mixing the neviborol hydrochloride and the additives according to the composition shown in Table 1 below, adding purified water dissolved in Tween 80. Thereafter, magnesium oxide, magnesium carbonate or magnesium aluminum silicate and the balance of the additive were respectively mixed as the alkalizing agent, colloidal silicon dioxide and magnesium stearate were mixed as a lubricant, and the mixture was discharged through a tableting machine (STP Machinery Co., Ltd., ZP198 Model) using a circular punch with a diameter of 8.6 mm.

Table 1 below shows the composition of the amount of raw materials per one drug.

Ingredients standard Example 1 Example 2 Example 3 Mg / Tab % Mg / Tab % Mg / Tab % Nebivolol HCl Wet granule 5.45 2.3 5.45 2.3 5.45 1.6 Latose monohydrate 168.99 70.6 170.49 71.3 185.35 53.0 Microcrystalline cellulose 46.00 19.2 46.00 19.2 80.00 22.9 Hypromellose 2910 4.60 1.9 4.60 1.9 12.00 3.4 Tween 80 0.46 0.2 0.46 0.2 - - Butylated hydroxyanisole - - - - - - Microcrystalline cellulose After mixing - - - - - - sodium starch glycolate 10.00 4.2 10.00 4.2 10.00 4.2 Croscarmeliose Na - - - - - - MgO 20 .. 0.8 0.50 0.2 0.10 0.04 Magnesium aluminum sillicate - - - - - - MgCO3 - - - - - - Rosuvastatin Ca - - - - - - Colloidal sillicon dioxide Contact mixture 0.50 0.20 0.50 0.2 0.50 0.2 Mg Stearate 1.20 0.5 1020 0.5 1.20 0.5 ethanol - - - - - - water 35.00 - 35.00 - 35.00 - Opadry 03B28796 - - - - - - Total wet granulation 225.50 - 227.00 - 227.40 - Sum 239.200 100.0 239.200 100.0 239.200 100.0

Example  4 and 5

The granules were prepared according to the wet granulation method by mixing purified water with Nevivorol hydrochloride and the additives according to the composition shown in Table 2 below. Thereafter, magnesium oxide, magnesium carbonate or magnesium aluminum silicate and the balance of the additive were each mixed as an alkalizing agent, and then colloidal silicon dioxide and magnesium stearate were mixed as a lubricant, and the mixture was discharged through a tableting machine (STP Machinery Co., Ltd., ZP198 Model) using a circular punch with a diameter of 10 mm.

Example  6 and 7

After mixing the neviborol hydrochloride and the additives according to the composition shown in Table 2 below, a solution in which BHA and Tween 80 were dissolved in purified water and ethanol mixed solution was added to prepare granules according to the wet granulation method. Then, colloidal silicon dioxide and magnesium stearate were mixed as a lubricant, and a tablet machine (STP Machinery Co., Ltd., ZP198 Model) was mixed with magnesium stearate as a lubricant, (Example 6) and 147.0 mg (Example 7), respectively, using a circular punch having a diameter of 10 mm and a diameter of 7.5 mm.

Opa-dry 03B28796 (manufactured by Colorcon Co.) was dissolved in 80% ethanol and water, and the obtained tablets were spray coated to prepare film-coated tablets.

Table 2 below shows the constitution of the amount of raw material drug per tablet.

Ingredients standard Example 4 Example 5 Example 6 Example 7 Mg / Tab % Mg / Tab % Mg / Tab % Mg / Tab % Nebivolol HCl Wet granule 5.45 1.6 5.45 1.6 5.45 1.5 5.45 3.6 Latose monohydrate 185.35 53.0 189.35 54.1 162.32 44.8 68.33 45.0 Microcrystalline cellulose 80.00 22.9 80.00 22.9 80.00 22.1 33.70 22.2 Hypromellose 2910 12.00 3.4 12.00 3.4 12.00 3.3 5.00 3.3 Tween 80 - - - - 0.20 0.06 0.10 0.07 Butylated hydroxyanisole - - - - 0.03 0.0 0.02 0.0 Microcrystalline cellulose After mixing 40.00 11.4 40.00 11.4 42.00 11.6 17.70 11.6 sodium starch glycolate 15.00 4.3 - - 15.00 4.1 6.30 4.1 Croscarmeliose Na - - 15.00 4.3 - - - - MgO - - - - - - Magnesium aluminum sillicate 7.00 2.0 - - 7.00 1.9 3.00 2.0 MgCO3 - - 3.00 0.9 - - - Rosuvastatin Ca - - - 20.80 5.7 5.20 3.4 Colloidal sillicon dioxide Contact mixture 1.70 0.5 1.70 0.5 1.70 0.5 0.70 0.5 Mg Stearate 3.50 10. 3.50 1.0 3.50 10. 1.50 1.0 ethanol - - - - 3.00 - 2.00 - water 45.00 - 45.00 - 41.00 - 18.00 - Opadry 03B28796 - - - - 12.0 3.3 5.0 3.3 Total wet granulation 282.80 - 286.80 - 260.00 - 112.60 Sum 350,000 100.0 350,000 100.0 350,000 100.0 350,000 100.0

Example  8 and 9

After mixing Nevivorol hydrochloride and additives according to the composition shown in Table 3 below, Tween 80 was added with a solution of purified water and ethanol mixed solution to prepare granules according to the wet granulation method. Thereafter, suvastatin calcium and an additive of magnesium carbonate as an alkalizing agent were mixed in the balance, colloidal silicon dioxide and magnesium stearate were mixed as a lubricant, and the mixture was kneaded in a tablet machine (STP Machinery Co., Ltd., ZP198 Model) Using a circular punch with a diameter of 10 mm, the tablet was compressed to 350.0 mg per tablet.

Opadried 03F680010 (manufactured by Colorcon) was dissolved in 80% ethanol, and the obtained tablets were spray coated to prepare film-coated tablets.

Ingredients fair Example 8 Example 9 Mg / Tab % Mg / Tab % Nebivolol HCl Wet granule 5.45 1.5 5.45 1.5 Latose monohydrate 162.35 44.8 162.35 44.8 Microcrystalline cellulose 80.00 22.1 80.00 22.1 Hypromellose 2910 12.00 3.3 12.00 3.3 Tween 80 0.20 0.06 0.20 0.06 Microcrystalline cellulose After mixing 48.00 13.3 63.60 17.6 sodium starch glycolate 15.00 4.1 15.00 4.1 Magnesium carbonate 1.00 0.3 1.00 0.3 Rosuvastatin Ca 20.80 5.7 5.20 1.4 Colloidal sillicon dioxide Contact mixture 1.70 0.5 1.70 0.5 Mg Stearate 3.50 1.0 3.50 1.0 Opadry 03B28796 12.0 3.3 12.0 3.3 Sum 362.0 100.0 362.0 100.0

Comparative Example  1 to 3

Granules were prepared according to the wet granulation method by adding purified water (Comparative Examples 1 and 2) or purified water (Comparative Example 3) in which Tween 80 was dissolved after mixing Neviborol hydrochloride and additives according to the composition shown in Table 4 below. Thereafter, the colloidal silicon dioxide and magnesium stearate were mixed as a lubricant, and a circular punch having diameters of 8.6 mm and 10.0 mm was used in a tablet machine (STP Machinery Co., Ltd., ZP198 Model) To give 239.2 mg (one comparable to a formulation similar to a commercial formulation) and 350.0 mg (Comparative Examples 2 and 3), respectively.

Ingredients standard Comparative Example 1 Comparative Example 2 Comparative Example 3 Mg / Tab % Mg / Tab % Mg / Tab % Nebivolol HCl Wet granule 5.45 2.3 5.45 1.6 5.45 1.6 Latose monohydrate 141.75 59.3 191.89 54.8 192.35 55.0 Microcrystalline cellulose 46.00 19.2 80.00 22.9 120.00 34.03 Hypromellose 2910 4.60 1.9 12.00 3.4 12.00 3.4 Tween 80 0.46 0.2 0.46 0.1 - - Butylated hydroxyanisole - - - - - - Microcrystalline cellulose After mixing 23.00 9.6 40.00 11.4 - - sodium starch glycolate - - 15.00 4.3 - - Croscarmeliose Na 16.10 6.7 - - 15.00 4.3 MgO - - - - - Magnesium aluminum sillicate - - - - - - MgCO3 - - - - - - Rosuvastatin Ca - - - - - - Colloidal sillicon dioxide Contact mixture 0.69 0.3 1.70 0.5 1.70 0.5 Mg Stearate 1.15 0.5 3.50 1.0 3.50 1.0 ethanol - - - - - - water 35.00 - 35.00 - 35.00 - Opadry 03B28796 - - - - - - Total wet granulation 198.26 - 289.80 - 329.80 - Sum 239.200 100.0 350,000 100.0 350,000 100.0

Test Example : In water  Dissolution test

In order to confirm the dissolution rates of the tablets prepared in Examples 1 to 6, 8 and 9 and Comparative Examples 1 to 3, a dissolution test was carried out for each.

The elution test was carried out by paddle method at 50 rpm and 5 mL of each sample taken at 5, 10, 15, 30, 45, 90, and 120 minutes were filtered with a membrane filter and analyzed by HPLC under the following conditions The dissolution rate relative to the standard solution was calculated. The results are shown in Table 5 and Fig.

- HPLC analysis conditions -

Detector: UV 225 nm

Column: Xbridge C18, 4.6 x 150 mm, 5 탆

Mobile phase: Buffer / methanol (40/60)

(Buffer: solution obtained by dissolving 3.4 g of tetrabutylammonium hydrogen sulfate in 1 L of water)

Flow rate: 1.0 mL / min

Injection volume: 20 μl

Specimen name 0 5 10 15 30 45 60 90 120 Example 1 0.0 68.4 85.9 87.1 90.7 91.1 91.5 91.7 92.4 Example 2 0.0 64.7 78.7 86.0 87.2 88.7 90.0 91.5 93.3 Example 3 0.0 68.1 75.8 84.2 84.8 85.4 86.0 86.6 87.1 Example 4 0.0 71.8 83.7 85.8 92.3 92.6 93.0 93.3 93.7 Example 5 0.0 74.2 81.9 84.4 87.8 88.4 90.0 91.8 93.0 Example 6 0.0 80.6 91.3 93.0 95.6 96.9 97.6 98.0 98.3 Example 8 0.0 68.3 88.8 91.9 93.8 - - - - Example 9 0.0 68.0 78.8 83.5 87.8 - - - - Comparative Example 1 0.0 0.0 1.9 2.4 4.9 7.4 10.2 13.7 15.7 Comparative Example 2 0.0 56.6 57.0 55.4 55.5 55.9 54.7 54.6 54.54 Comparative Example 3 0.0 53.1 50.7 44.1 34.1 26.8 21.5 13.2 11.5

As can be seen in Table 5 and Fig. 1, both the combination tablet of naviborol according to the present invention and the combined preparation of naviborol and rosuvastatin exhibited excellent dissolution rate of not less than 83% and not more than 93% On the other hand, the tablets of Comparative Examples 1 to 3 prepared without addition of the alkalizing agent exhibited a very low dissolution rate even after 2 hours from the initiation of elution.

Also, in the case of the combination preparation of naviborol and rosuvastatin (Examples 8 and 9) using magnesium carbonate as the alkalizing agent, the same procedure as in the case of using magnesium aluminum silicate as the alkalizing agent (Examples 6 and 7) It was confirmed that the dissolution rate of naviborol was 80% or more.

The above results show that even in the case of a combination preparation containing a component having a preventive or therapeutic activity for cardiovascular diseases as well as a naviborol single preparation, the dissolution rate is improved in a relatively high pH aqueous solution regardless of the type of the alkalizing agent It is possible to prove that it is possible.

Claims (10)

A pharmaceutical composition for the prevention or treatment of cardiovascular diseases, comprising navivorol or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive. 2. The composition of claim 1, wherein the pharmaceutically acceptable salt of navivorol is navivorohydrochloride. The composition of claim 1, wherein the alkalizing agent exhibits a pH of from 8 to 12 upon suspension or dissolution in water. The composition according to claim 3, wherein the alkalizing agent is at least one selected from the group consisting of magnesium oxide, magnesium carbonate and magnesium aluminum silicate. 2. The composition of claim 1 wherein the nevvorol or pharmaceutically acceptable salt thereof is included in an amount of 0.2 to 10 parts by weight based on 100 parts by weight of the total composition. The composition according to claim 1, wherein the alkalizing agent is included in an amount of 0.02 to 10 parts by weight based on 100 parts by weight of the total composition. The composition according to any one of claims 1 to 6, further comprising a component having a prophylactic or therapeutic activity for cardiovascular diseases. The composition according to claim 7, wherein the component having a prophylactic or therapeutic activity for cardiovascular diseases is selected from the group consisting of hydrochlorothiazide, ramipril, enalapril, recarnidipine, nisol dipine, amlodipine, losartan, furansartan, candesartan, Wherein the composition is at least one selected from the group consisting of telmisartan, valsartan, olmesartan, rosuvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, simvastatin and pharmaceutically acceptable salts thereof. 9. The composition according to claim 8, wherein the component having a prophylactic or therapeutic activity of cardiovascular disease is rosuvastatin calcium. a) mixing the naviborr or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive to prepare a mixture; And
b) molding said mixture,
Characterized in that an alkalizing agent is added in step a) or b)
A method for preparing a pharmaceutical composition according to claim 1.

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