CA3010857C

CA3010857C - Pharmaceutical composition comprising nebivolol with improved dissolution rate

Info

Publication number: CA3010857C
Application number: CA3010857A
Authority: CA
Inventors: Eul Won DHONG; Hong Gu Hu; Hae Yang KIM; Hye-Gyeong SHIN; Hyo-Jin Park; Sang-Geun Park
Original assignee: Elyson Pharm
Current assignee: Elyson Pharm
Priority date: 2016-01-08
Filing date: 2016-12-16
Publication date: 2020-09-15
Anticipated expiration: 2036-12-16
Also published as: CN108463250B; CN108463250A; AU2016385282B2; AU2016385282A2; MX2018008443A; KR102203229B1; KR20170083484A; AU2016385282A1; CA3010857A1; MY201954A

Abstract

The present invention relates to a pharmaceutical composition having an improved dissolution rate of nebivolol. A pharmaceutical composition, containing nebivolol or a pharmaceutically acceptable salt thereof, an alkalizing agent, and a pharmaceutically acceptable additive, for prevention or treatment of cardiovascular diseases, does not cause a decrease in the dissolution rate of nebivolol and can significantly improve the dissolution rate, not only at 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. In addition, the pharmaceutical composition can reduce the preparation cost since the micronization of nebivolol or the addition of a wetting agent is not required, and can minimize the occurrence of a deviation of bioavailability due to pre- or post-meal intake since there is little deviation of the dissolution rate due to the pH change, thereby maintaining a constant pharmaceutical action, and thus, the pharmaceutical composition is very useful in the preparation of a composite preparation containing a nebivolol preparation, or another active ingredient, such as rosuvastatin calcium.

Description

Description Title of Invention PHARMACEUTICAL COMPOSITION COMPRISING NEBIVOLOL
WITH IMPROVED DISSOLUTION RATE
Technical Field The present invention relates to a pharmaceutical composition having an improved dissolution rate of nebivolol and a method for preparing the same.
More io specifically, the present invention relates to a pharmaceutical composition with an improved dissolution rate, comprising nebivolol or a pharmaceutically acceptable salt thereof as an active ingredient, an alkalizing agent and a pharmaceutically acceptable additive.
Background Art A beta-blocker is used for the treatment of hypertension, angina pectoris, myocardial infarction, cardiac disorders, migraine or essential tremor, etc.
Nebivolol, a beta-blocker, which is a 2,2'-iminobisethanol derivative represented by the following Formula 1, has a centrosymmetric structure with four chiral centers.
[Formula 11 F

OH OH
Nebivolol, a mixture of D- and L-form enantiomers, is a 13¨receptor blocking agent, which is highly selective for 131 -adrenergic receptor, and has a vasodilation activity related to an effect on endothelial nitrogen oxide, which makes nebivolol different from other conventional 13-blockers. It is believed that nebivolol increases the concentration of nitrogen oxide via L-arginine-nitrogen oxide pathway in vascular endothelium, and it is found that nebivolol improves endothelial dysfunction and vascular elasticity. Furthermore, it is known that nebivolol has an antioxidant effect which is beneficial to vascular endothelial functionality, and therefore, nebivolol is used as an effective antihypertensive agent having a beneficial effect on vascular endothelium and cardiovascular system. It is also found that nebivolol is effective on cardiovascular disorders such as hypertension, congestive heart failure, arteriosclerosis and endothelial dysfunction, etc.
Generally, a pharmaceutical composition is provided as a solid formulation suitable for oral administration, i.e., tablets, etc., in consideration of convenient use, in which case bioavailability is significantly required. A critical factor affecting bioavailability is a dissolution process in vivo, which may be determined by a dissolution rate via a dissolution test in a laboratory. In this regard, nebivolol has a IS problem of a very low dissolution rate at a relatively high pH.
In order to solve the problem of nebivolol, KR Patent No. 0361636 discloses a method of micronizing nebivolol. However, micronized nebivolol still has a problem of a low dissolution rate, and also has a great deviation of bioavailability under fasting or fed condition. EP Patent No. 0145067 discloses a method of improving a dissolution rate of nebivolol by adding a wetting agent to micronized nebivolol. KR
Patent No. 896266 discloses a nebivolol hydrochloride form with improved dissolution rate without using a wetting agent, and KR Patent Publication No. 2011-0130872 discloses a pharmaceutical composition using crystalline form nebivolol with starch in order to improve a dissolution rate of nebivolol.
In the conventional methods, however, nebivolol should be milled and sieved to be micronized, which is very inconvenient and uneconomical due to increased process time and cost. Addition of a wetting agent also contributes to rise of manufacturing cost. In addition, a great deviation of bioavailability under fasting or fed condition

2 could decrease therapeutic effect.
Furthermore, in the conventional methods, only the dissolution rate of nebivolol at pH 1.2 to 4.0 was confirmed, and the dissolution rate in water was not verified.
According to the preliminary experiment performed previously to the present invention, it was confirmed that all the nebivolol preparations showed a low dissolution rate of 70% or less when tested in water. When the preparations with decreased dissolution rate of drug are administered, oral absorption and bioavailability of drug may decrease, which may lead to decreased efficacy of drug in a human body. Accordingly, there has been a compelling need for development of a nebivolol preparation ensuring a satisfactory dissolution rate without a deviation in vivo.
Under the circumstance, the present inventors have intensively studied for preparing a nebivolol preparation with a stable and enhanced dissolution rate without a deviation at the pH change in vivo and found that an alkalizing agent added to a pharmaceutical composition comprising nebivolol results in a significant enhancement of a dissolution rate even at pH 5 to 7 or in water as well as at a low pH to complete the present invention.
Disclosure of Invention Technical Problem An object of the present invention is to provide a pharmaceutical composition with an improved dissolution rate of nebivolol and a method for preparing the same.
Solution to Problem In accordance with one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating cardiovascular diseases, comprising nebivolol or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive.
In an embodiment, the pharmaceutically acceptable salt of nebivolol is

3 preferably a nebivolol hydrochloride, and may be comprised in an amount of 0.2 to 10 parts by weight based on 100 parts by weight of the composition.
The alkalizing agent is preferable to show a pH of 8 to 12 when suspended or dissolved in water, and may be selected from the group consisting of magnesium oxide, magnesium carbonate and magnesium aluminum silicate. Furthermore, the alkalizing agent may be comprised in an amount of 0.02 to 10 parts by weight based on 100 parts by weight of the composition.
In another embodiment, the pharmaceutical composition may further comprise an additional active ingredient for preventing or treating cardiovascular diseases. The additional active ingredient may be at least one selected from the group consisting of hydrochlorothiazide, ramipril, enalapril, lercanidipine, nisoldipine, amlodipine, losartan, eprosartan, candesartan, telmisartan, valsartan, olmesartan, rosuvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, simvastatin and pharmaceutically acceptable salts thereof, and rosuvastatin calcium is preferred.
In accordance with another aspect of the present invention, there is provided a method for preparing a pharmaceutical composition, which comprises the steps of:
a) mixing nebivolol or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive to form a mixture; and b) formulating the mixture, wherein an alkalizing agent is added in step a) or b).
Advantageous Effects of Invention The pharmaceutical composition of the present invention does not cause a decrease in the dissolution rate of nebivolol and can significantly improve the dissolution rate, 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.
Furthermore, the pharmaceutical composition may reduce the manufacturing cost since the micronization of nebivolol or the addition of a wetting agent is not required, and can

4 minimize the occurrence of a deviation of bioavailability under fasting or fed condition since there is little deviation of dissolution rate due to the pH change, thereby maintaining a constant pharmacological action, and therefore, the pharmaceutical composition is very useful in the preparation of a nebivolol preparation or a composite preparation containing an additional active ingredient, such as rosuvastatin calcium.
Brief Description of Drawings Fig. I is a graph showing a dissolution rate of nebivolol in water over time for the preparations of Examples 1 to 6 and Comparative Examples 1 to 3, measured i() according to paddle method.
Detailed Description Hereinafter, the present invention will be further explained.
Nebivolol, an active ingredient of the pharmaceutical composition according to the present invention, which is represented by the following Formula 1, is a highly selective p 1 -blocker and known to be efficacious in the control of hypertension.
[Formula 11 OH OH
In the composition according to the present invention, nebivolol may be used as various forms such as a free base or a pharmaceutically acceptable salt thereof, as long as an equivalent pharmacological activity of nebivolol is maintained.
As for the pharmaceutically acceptable salt, since nebivolol is basic, it may be treated with acid to be converted into a pharmaceutically acceptable acid addition salt thereof. Examples of a suitable acid include an inorganic acid such as a hydrohalogenic acid (e.g., hydrochloric acid, hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc.; or an organic acid such as acetic acid, propanoic acid,

5 hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z)-2-butenedioic acid, (E)-2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, etc. According to the present invention, a preferred acid addition salt is hydrochloride.
The amount of nebivolol or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may be adjusted in an acceptable range if needed, and preferably, 0.2 to 10 parts by weight, more preferably, 1 to 4 parts by weight based on 100 parts by weight of the composition. According to an embodiment of the present invention, the amount of nebivolol is 1.5 to 3.6 parts by weight, as nebivolol hydrochloride form, based on 100 parts by weight of the composition.
The pharmaceutical composition according to the present invention is characterized in that an alkalizing agent is comprised in the composition in order to solve the problem that the dissolution rate of nebivolol or a pharmaceutically acceptable salt thereof decreases at pH 5.0 to 7.0, e.g., in water, thereby resulting in reduced absorption and bioavailability. It is generally known that since nebivolol is weak base, its solubility and dissolution rate would reduce with the increase of pH.
Surprisingly, the present inventors found that the dissolution rate of nebivolol significantly increased with the addition of an alkalizing agent, which would be quite unexpected by those skilled in the art and confirmed for the first time by the present inventors.
In a preferred embodiment of the present invention, the alkalizing agent showing a pH of 8 to 12 when suspended or dissolved in water may be selected.
For example, magnesium oxide, magnesium carbonate or magnesium aluminum silicate is preferred. According to the present invention, an excellent dissolution rate of nebivolol may be obtained at a low pH such as pH 1.2 as well as at pH 5 to 7, e.g., in water, by the addition of an alkalizing agent to nebivolol or a pharmaceutically

6 acceptable salt thereof, thereby maintaining a high dissolution rate of drug even with the pH change when administered to a living body. Therefore, the problem of a low dissolution rate of nebivolol and the consequential sudden change in dissolution rate in vivo may be settled.
In the composition of the present invention, the amount of 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 composition. If the amount of alkalizing agent is less than 0.02 parts by weight based on 100 parts by weight of the composition, the effect on improvement of dissolution rate may be week, whereas an excessive amount over parts by weight based on 100 parts by weight of the composition may lead to a decreased dissolution rate of nebivolol. In the Examples of the present invention, compositions containing nebivolol with each of magnesium carbonate, magnesium oxide and magnesium aluminum silicate as an alkalizing agent (Examples 1 to 5) and composite preparations of nebivolol and rosuvastatin containing an alkalizing agent (Examples 6 to 9) were compared with a preparation similar to commercial product containing no alkalizing agent (Comparative Example 1) and preparations of Comparative Examples 2 and 3, and it was confirmed that the compositions of Examples showed significantly high dissolution rates of nebivolol in water.
The pharmaceutical composition according to the present invention further comprises a pharmaceutically acceptable additive, in addition to an active ingredient and an alkalizing agent, within a range having no influence on the effect of the present invention. Specifically, the pharmaceutically acceptable additive may be at least one selected from the group consisting of a filler, a binder, a disintegrant, a glidant and a lubricant.
Examples of the filler which may be used in the present composition include cellulose derivatives such as microcrystalline cellulose, low-substituted hydroxypropyl cellulose, methyl cellulose, etc., starches such as potato starch, corn starch, etc., lactose, fructose, etc.

7 Examples of the binder include polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, poloxamer, polyethylene oxide, polymethylacrylate, natural gums, synthetic gums, copovidone, gelatin, etc.
Examples of the disintegrant include sodium starch glycolate, sodium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pre-gelatinized starch, crospovidone, etc.
Examples of the glidant include colloidal silicon dioxide, magnesium aluminum metasilicate, etc.
Examples of the lubricant include magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl palmitostearate, etc.
In a preferred embodiment, the pharmaceutical composition of the present invention may comprise, as pharmaceutically acceptable additives, 40 to 95 parts by weight of a filler, 1 to 10 parts by weight of a binder, 1 to 10 parts by weight of a disintegrant, 0.1 to 2 parts by weight of a glidant, 0.1 to 2 parts by weight of a lubricant based on 100 parts by weight of the composition.
The type of administration for the pharmaceutical composition with improved dissolution rate according to the present invention is not specifically limited, and may be any one suitable for various administration route such as oral, parenteral (i.e., intramuscular, subcutaneous, intravenous, etc.). Oral administration is especially preferred for the present composition. Examples of formulations for oral administration include tablets, capsules, granules, troches, emulsions, suspensions, etc.
Preferably, the present composition may be provided as a solid formulation for oral administration such as tablets or capsules in consideration of convenient use.
The composition according to the present invention may be effectively used since it has no decrease in the dissolution rate regardless of the administered formulations and also has little deviation of dissolution rate due to the pH change in vivo.
The composition according to the present invention uses an alkalizing agent

8 such as magnesium carbonate, magnesium oxide and magnesium aluminum silicate, and therefore, without going through a complicated and high-priced process such as micronization of nebivolol or addition of a wetting agent, it may ensure an excellent dissolution rate of 80% or higher within 15 minutes after starting dissolution with no decrease of dissolution rate in water, as confirmed in Experimental Example.
Accordingly, the composition according to the present invention may reduce the manufacturing cost since the micronization of nebivolol or the addition of a wetting agent is not required, and may minimize the occurrence of a deviation of bioavailability under fasting or fed condition since there is little deviation of the dissolution rate due to the pH change, thereby ensuring a constant pharmacological action and an improved therapeutic effect.
The pharmaceutical composition of the present invention may be prepared according to a conventional manufacturing process of a solid oral dosage form, for example, direct compression, wet granulation, dry granulation, etc. Preferred method Is for preparing a pharmaceutical composition according to the present invention comprises the steps of: a) mixing nebivolol or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive to form a mixture; and b) formulating the mixture, wherein an alkalizing agent is added in step a) or b).
Preferably, the mixing step may comprise the step of mixing an active ingredient comprising an effective amount of nebivolol or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive to form a mixture and compressing the mixture to form granules. More preferably, granules may be prepared by a wet granulation method.
Preferably, the formulating step may comprise the step of mixing the granules prepared from the mixture with the remains of a pharmaceutically acceptable additive and compressing into tablets. In the manufacturing method according to the present invention, an alkalizing agent may be mixed with an active ingredient and an additive to be granulated in the mixing step, or post-mixed with granules prepared in the mixing

9 step and the remains of a pharmaceutically acceptable additive in the formulating step.
In a further embodiment, the manufacturing method may further comprise the step of coating the formulated pharmaceutical composition by a conventional method.
The pharmaceutical composition of the present invention may further comprise an additional active ingredient for preventing or treating cardiovascular diseases such as hypertension, congestive heart failure, arteriosclerosis, metabolic disorder, endothelial dysfunction, etc. in addition to nebivolol or a pharmaceutically acceptable salt thereof.
Examples of the additional active ingredient for preventing or treating cardiovascular diseases include, but not limited to, hydrochlorothiazide, ramipril, enalapril, lo lercanidipine, nisoldipine, amlodipine, losartan, eprosartan, candesartan, telmisartan, valsartan, olmesartan, rosuvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, simvastatin or pharmaceutically acceptable salts thereof. In a preferred embodiment, the further active ingredient is rosuvastatin or a pharmaceutically acceptable salt thereof, more preferably, rosuvastatin calcium.
Mode for the Invention Hereinafter, the present invention is explained in detail by Examples. The following Examples are intended to further illustrate the present invention without limiting its scope.
Examples 1 to 3 In accordance with the composition as described in Table 1, nebivolol hydrochloride was mixed with additives, and purified water with Tween 80 dissolved therein was added thereto. The mixture was used to prepare granules according to a wet granulation method. Subsequently, magnesium oxide, magnesium carbonate or magnesium aluminum silicate, as an alkalizing agent, and the remains of additives were post-mixed with the granules, and colloidal silicon dioxide and magnesium stearate, as a lubricant, were added thereto. The resultant was compressed into tablets (239.2 mg/tablet) using a tablet press (STP Machinery Co., Ltd., ZP198 Model) with a round punch having a diameter of 8.6 mm.
Table 1 below shows the amount of component per tablet.
[Table 1]
Components Process Example 1 Example 2 Example 3 mg/Tab % mg/Tab % mg/Tab %
Nebivolol HC1 Wet granulation 5.45 2.3 5.45 2.3 5.45 1.6 Lactose monohydrate 168.99 70.6 170.49 71.3 185.35 53.0 Microcrystalline cellulose 46.00 19.2 46.00 19.2 80.0 22.9 Hypromellose 2910 4.60 1.9 4.60 1.9 12.0 3.4 Tween 80 0.46 0.2 0.46 0.2 -Butylated hydroxyanisole Microcrystalline cellulose Post-mixing Sodium starch glycolate 10.00 4.2 10.00 4.2 10.00 4.2 Croscarmellose Na Magnesium oxide 20.00 0.8 0.50 0.2 0.10 0.04 Magnesium aluminum silicate Magnesium carbonate Rosuvastatin Ca Colloidal silicon dioxide Lubricant 0.50 0.2 0.50 0.2 0.50 0.2 Magnesium stearate mixing 1.20 0.5 1020 0.5 1.20 0.5 Ethanol Water 35.00 35.00 35.00 Opadry 03B28796 Subtotal for wet granules 225.50 227.00 227.40 Total 239.20 100.0 239.20 100.0 239.20 100.0 Examples 4 and 5 In accordance with the composition as described in Table 2, nebivolol hydrochloride was mixed with additives, and purified water was added thereto.
The mixture was used to prepare granules according to a wet granulation method.
Subsequently, magnesium oxide, magnesium carbonate or magnesium aluminum silicate, as an alkalizing agent, and the remains of additives were post-mixed with the granules, and colloidal silicon dioxide and magnesium stearate, as a lubricant, were added thereto. The resultant was compressed into tablets (350.0 mg/tablet) using a tablet press (STP Machinery Co., Ltd., ZP198 Model) with a round punch having a diameter of 10 mm.
Examples 6 and 7 In accordance with the composition as described in Table 2, nebivolol hydrochloride was mixed with additives, and a mixture of purified water and ethanol with BHA and Tween 80 dissolved therein was added thereto. The mixture was used to prepare granules according to a wet granulation method. Subsequently, rosuvastatin calcium, magnesium aluminum silicate, as an alkalizing agent, and the remains of additives were post-mixed with the granules, and colloidal silicon dioxide and magnesium stearate, as a lubricant, were added thereto. The resultant was compressed into tablets (350.0 mg/tablet: Example 6; 147.0 mg/tablet: Example 7) using a tablet press (STP Machinery Co., Ltd., ZP198 Model) with a round punch having a diameter Of 10 MM or 7.5 mrn.
The tablets thus obtained were coated by spray coating with Opadry 03B28796 (Colorcon, Inc.) dissolved in 80% ethanol and water to produce film-coated tablets.
Table 2 below shows the amount of component per tablet.
[Table 2]
Components Process Example 4 Example 5 Example 6 Example 7 mg/Tab % mg/Tab % mg/Tab % mg/Tab %
Nebivolol HC1 Wet 5.45 1.6 5.45 1.6 5.45 1.5 5.45 3.6 Lactose monohydrate granulation 185.35 53.0 189.35 54.1 162.32 44.8 68.33 45.0 Microcrystalline 80.00 22.9 80.00 22.9 80.00 22.1 33.70 22.2 cellulose 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 0.03 0.0 0.02 0.0 hydroxyanisole Microcrystalline Post- 40.00 11.4 40.00 11.4 42.00 11.6 17.70 11.6 cellulose mixing Sodium starch glycolate 15.00 4.3 15.00 4.1 6.30 4.1 Croscarmellose Na 15.00 4.3 Magnesium oxide Magnesium aluminum 7.00 2.0 7.00 1.9 3.00 2.0 silicate Magnesium carbonate - 3.00 0.9 Rosuvastatin Ca - _____________________________ 20.80 5.7 5.20 3.4 Colloidal silicon Lubricant 1.70 0.5 1.70 0.5 1.70 0.5 0.70 0.5 dioxide mixing Magnesium stearate 3.50 , 1.0 3.50 1.0 3.50 1.0 1.50 1.0 Ethanol 3.00 2.00 __ Water 45.00 45.00 41.00 18.00 Opadry 031128796 12.0 3.3 5.0 3.3 Subtotal for wet granules 282.80 286.80 260.00 112.60 , Total 350.00 100.0 350.00 100.0 362.00 , 100.0 -- 152.00 -- 100.0 Examples 8 and 9 In accordance with the composition as described in Table 3, nebivolol hydrochloride was mixed with additives, and a mixture of purified water and ethanol with Tween 80 dissolved therein was added thereto. The mixture was used to prepare granules according to a wet granulation method. Subsequently, rosuvastatin calcium, magnesium carbonate, as an alkalizing agent, and the remains of additives were post-mixed with the granules, and colloidal silicon dioxide and magnesium stearate, as a lubricant, were added thereto. The resultant was compressed into tablets (350.0 mg/tablet) using a tablet press (STP Machinery Co., Ltd., ZP198 Model) with a round punch having a diameter of 10 mm.
The tablets thus obtained were coated by spray coating with Opadry 031;680010 (Colorcon, Inc.) dissolved in 80% ethanol to produce film-coated tablets.
[Table 3]
Components Process Example 8 Example 9 mg/Tab % mg/Tab %
Nebivolc11-1C1 Wet granulation 5.45 1.5 5.45 1.5 I.actose monohydrate 162.35 44.8 162.35 44.8 Mierocrystalline 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 Post-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 silicon dioxide Lubricant 1.70 0.5 1.70 0.5 Magnesium stearate mixing 3.50 1.0 3.50 1.0 Opadry 03B28796 12.00 3.3 12.00 3.3 Total 362.00 100.0 362.00 100.0 Comparative Examples 1 to 3 In accordance with the composition as described in Table 4, ncbivolol hydrochloride was mixed with additives, and purified water with Tween 80 dissolved therein (Comparative Examples l and 2) or purified water (Comparative Example 3) was added thereto. The mixture was used to prepare granules according to a wet granulation method. Subsequently, the remains of additives were post-mixed with the granules, and colloidal silicon dioxide and magnesium stearate, as a lubricant, were added thereto. The resultant was compressed into tablets (239.2 mg/tablet:
lo Comparative Example 1 similar to a commercial product; 350.0 mg/tablet:
Comparative Examples 2 and 3) using a tablet press (STP Machinery Co., Ltd., ZP198 Model) with a round punch having a diameter of 8.6 mm or 10.0 mm.
[Table 4]
Components Process Comparative Comparative Comparative Example 1 Example 2 Example 3 mg/Tab % mg/Tab % mg/Tab %
Nebivolol HCI Wet granulation 5.45 2.3 5.45 1.6 5.45 1.6 Lactose 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 Post-mixing 23.00 9.6 40.00 11.4 Sodium starch glycolate - 15.00 4.3 Croscarmellose Na 16.10 6.7 15.00 4.3 Magnesium oxide Magnesium aluminum silicate Magnesium carbonate Rosuvastatin Ca Colloidal silicon dioxide Lubricant 0.69 0.3 1.70 0.5 1.70 0.5 Magnesium stearate mixing 1.15 0.5 3.50 1.0 3.50 1.0 Ethanol Water 35.00 35.00 35.00 Opadry 03B28796 Subtotal for wet granules 198.26 289.80 329.80 Total 239.20 100.0 350.00 100.0 350.00 100.0 Experimental Example: Dissolution test in water Tablets prepared in Examples 1 to 6, 8 and 9 and Comparative Examples 1 to 3 were subjected to a drug dissolution test to determine the dissolution rate of nebivolol.
Dissolution test was performed at 50 rpm according to paddle method using water as a dissolution medium. 5 mL of each test solution taken at 5, 10, 15, 30, 45, 90 and 120 minutes after starting the test was filtered through a membrane filter and analyzed using HPLC under the following condition to calculate dissolution rate against the standard solution. Table 5 and Fig. 1 show the results.
- Analytical conditions of HPLC -Detector: UV 225 nm Column: Xbridge C18, 4.6 x 150 mm, 5 pm Mobile phase: buffer/methanol (40/60) (Buffer: 3.4 g of tetrabutyl ammonium hydrogen sulfate dissolved in 1L of water) Flow rate: 1.0 mL/min Injection volume: 20 pL
[Table 5]
Samples 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 confirmed in Table 5 and Fig. 1, all of the nebivolol preparations and the composite preparations comprising nebivolol and rosuvastatin according to the present invention showed excellent dissolution rates of 83% to 93% within 15 minutes after starting the test, while the tablets of Comparative Examples 1 to 3 prepared without adding alkalizing agents showed very low dissolution rates even at 2 hours after starting the test.
Furthermore, it was confirmed that the composite preparations of nebivolol and rosuvastatin using magnesium carbonate as an alkalizing agent (Examples 8 and 9) as well as those using magnesium aluminum silicate (Examples 6 and 7) showed dissolution rates of 80% or higher at 15 minutes after starting the test.
The above results demonstrates that nebivolol preparations as well as composite preparations comprising nebivolol and an additional active ingredient for preventing or treating cardiovascular diseases may have the effect of improving dissolution rate of nebivolol in water of relatively high pH, regardless of the type of alkalizing agent.

Claims

THE EMBODIMENTS OF THE INVENTION FOR WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition for preventing or treating cardiovascular diseases, comprising nebivolol or a pharmaceutically acceptable salt thereof, an alkalizing agent, and a pharmaceutically acceptable additive, wherein the alkalizing agent is at least one selected from the group consisting of magnesium oxide, magnesium carbonate and magnesium aluminum silicate.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of nebivolol is a nebivolol hydrochloride.

3. The pharmaceutical composition of claim 1, wherein the nebivolol or a 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 composition.

4. The pharmaceutical composition of 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 composition.

5. The pharmaceutical composition of any one of claims 1 to 4, further comprising an additional active ingredient for preventing or treating cardiovascular diseases.

6. The pharmaceutical composition of claim 5, wherein the additional active ingredient for preventing or treating cardiovascular diseases is at least one selected from the group consisting of hydrochlorothiazide, ramipril, enalapril, lercanidipine, nisoldipine, amlodipine, losartan, eprosartan, candesartan, telmisartan, valsartan, olmesartan, rosuvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, simvastatin and pharmaceutically acceptable salts thereof.

7. The pharmaceutical composition of claim 6, wherein the additional active ingredient for preventing or treating cardiovascular diseases is rosuvastatin calcium.

8. A
method for preparing the pharmaceutical composition of claim 1, which comprises the steps of:
a) mixing nebivolol or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive to form a mixture; and b) formulating the mixture, wherein the alkalizing agent is added in step a) or b) and is at least one selected from the group consisting of magnesium oxide, magnesium carbonate and magnesium aluminum silicate.