KR20140037648A

KR20140037648A - Pharmaceutical composition and controlled release pharmaceutical formulation comprising carvedilol and tartaric acid

Info

Publication number: KR20140037648A
Application number: KR1020120104052A
Authority: KR
Inventors: 김용일; 정하영; 김경수; 정기우; 박재현; 우종수
Original assignee: 한미약품 주식회사
Priority date: 2012-09-19
Filing date: 2012-09-19
Publication date: 2014-03-27

Abstract

The present invention relates to a pharmaceutical composition comprising carvedilol and tartaric acid, and a controlled release pharmaceutical formulation. The controlled release pharmaceutical formulation of the present invention produced by using the pharmaceutical composition displays excellent carvedilol solubility and stability even in a high pH range; has an excellent bioavailability throughout the entire region of a gastro-intestinal tract; has a minimized drug absorption deviation; and is thereby capable of being usefully applied to a treatment of high blood pressure, congestive heart failure, and angina. [Reference numerals] (AA) Elution rate (%); (BB) Example 8; (CC) Example 9; (DD) Comparative example 12; (EE) Time (minute)

Description

PHARMACEUTICAL COMPOSITION AND CONTROLLED RELEASE PHARMACEUTICAL FORMULATION COMPRISING CARVEDILOL AND TARTARIC ACID}

The present invention relates to pharmaceutical compositions comprising carvedilol and tartaric acid, and controlled release pharmaceutical formulations prepared using the same.

Carvedilol (compound name: 1- (carbazol-4-yloxy-3-[[2- (o-methoxyphenoxy) ethyl] -amino] -2-propanol) represented by the following formula is hypertension It is used in the treatment of congestive heart failure and angina pectoris, and has a low bioavailability of typically 25 to 35% Cabedilol is currently available as an oral tablet prescribed as 12.5 to 25 mg twice daily.

Carvedilol is usually synthesized in free base form. Free base carvedilols include an α-hydroxyl secondary amine group (pKa = 7.8). Carvedilol exhibits low solubility in neutral or alkaline solvents under the influence of functional groups, for example, low solubility of 0.5 μg / ml or less in strong alkaline regions at pH 10.0 at room temperature and 26 μg / ml in buffered solutions at pH 6.8. The solubility in ml is shown. The solubility of carvedilol increases with decreasing pH and shows the highest solubility of 570 μg / ml in a buffer solution of pH 4.5-5.0. On the other hand, in the strongly acidic solution similar to the gastric juice of pH 1.2, the solubility is reduced to show a solubility of 180 μg / ml.

Release-controlled sustained release carvedilol formulations are oral formulations commonly prescribed in the United States marketed product (Coreg CR, GSK) at 32-64 mg once daily. In the case of controlled-release preparations, the maximum drug blood concentration is shown around 6-8 hours after administration, so the absorption rate in the high pH region of the small intestine as well as the low pH of the gastrointestinal tract greatly influences the bioavailability. Thus, efforts have been made to improve the low solubility of carvedilol in high pH environments.

US Pat. No. 7,268,156 discloses a pharmaceutical composition using carvedilol substituted in the form of phosphate to improve the solubility of carvedilol at high pH. Carvedilol phosphate has the effect of increasing the solubility of carvedilol because it releases phosphoric acid in solution to lower the pH of the surrounding microenvironment.

However, the acidifying agent used to improve the solubility of carvedilol causes a problem in coating efficiency, such as decreasing the proportion of the coating base as the amount used increases the film forming ability of the coating film and forming a cracked film. Therefore, there is a need for the development of a pharmaceutical formulation that can sufficiently increase the solubility of carvedilol even when a small amount of acidifying agent is used.

U.S. Patent Publication No. 2004/0220250 discloses a controlled release capsule formulation comprising a carvedilol core, but this formulation also has a slight level of solubility of carvedilol to expect sufficient pharmaceutical effect in the high pH range. Indicates. In addition, U.S. Patent Publication No. 2004/0019096 discloses a controlled release formulation of carvedilol containing an organic acid, but does not describe the role of the organic acid and the effect of the formulation. Even adversely affects.

Accordingly, the present inventors have made diligent efforts to prepare a carvedilol controlled release pharmaceutical formulation that exhibits excellent carvedilol solubility even at high pH. As a result, tartaric acid is used as an acidifying agent or stabilizer having a high solubility improving effect and easy coating. The present invention has been completed by discovering that it is effective to use.

[Patent Document 1] US Patent No. 7,268,156

[Patent Document 2] US Patent Publication No. 2004/0220250

[Patent Document 3] US Patent Publication No. 2004/0019096

Accordingly, it is an object of the present invention to provide a carvedilol-containing pharmaceutical composition that exhibits good solubility and stability.

It is another object of the present invention to provide controlled release pharmaceutical preparations of carvedilol which have excellent bioavailability and minimized drug absorption deviation and ensure stability over the entire gastrointestinal tract.

Still another object of the present invention is to provide a method for preparing the controlled release pharmaceutical preparation of carvedilol.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising carvedilol and tartaric acid.

To achieve these and other objects,

1) solid preparations including carvedilol and tartaric acid; And

2) It provides a controlled release pharmaceutical formulation formed on the surface of the solid preparation comprising a coating layer comprising a release delayed release sustained release coating substrate.

According to another aspect of the present invention,

1) preparing a pellet by coating a solution containing carvedilol and tartaric acid on spherical beads; And

2) provides a method for preparing a controlled release pharmaceutical formulation comprising the step of coating the pellet obtained in step 1) with a release delayed sustained release coating substrate.

The oral pharmaceutical composition according to the present invention exhibits excellent carvedilol solubility and stability even in a high pH range, and the controlled release pharmaceutical formulation prepared using the same has excellent bioavailability and minimized drug absorption variation over the entire gastrointestinal tract. It can be usefully used for the treatment of hypertension, congestive heart failure and angina pectoris.

1 is a graph measuring the water solubility of carvedilol with pH change,
2 is a graph measuring the solubility of carvedilol using the pellets of Examples 1 to 4 and Comparative Examples 1 and 2,
3 is a graph measuring the amount of lead substance produced from carvedilol using the pellets of Comparative Examples 4, 6, 8, and 10,
Figure 4 is a graph measuring the dissolution rate of carvedilol with pH change using the controlled release pharmaceutical formulation of Examples 8 and 9, and Comparative Example 12.

The present invention provides a pharmaceutical composition comprising carvedilol and tartaric acid.

The pharmaceutical composition of the present invention comprises carvedilol as a pharmacologically active ingredient. The carvedilol is a non-selective beta-blocker / alpha-1 blocker and relaxes blood vessels and lowers blood pressure in patients with hypertension, congestive heart failure, and angina pectoris and has symptomatic relief.

Carvedilol used in the present invention may be in the free base state or a pharmaceutically acceptable salt, and carvedilol in the free base state is preferred.

Tartaric acid used in the present invention has two enantiomers of D and L forms, and racemic, D and L forms may be used, but L form is preferable.

Tartric acid in the pharmaceutical composition of the present invention improves the solubility of carvedilol and is used in an amount of 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent by weight of carvedilol.

The tartaric acid is present in direct contact with carvedilol, thereby reducing the microenvironment pH around the carvedilol upon in vivo exposure and thus increasing the water solubility of carvedilol to increase bioabsorption. In addition, tartaric acid in the present invention has the effect of increasing the solubility of carvedilol in a high pH environment of neutral to basic. When the tartaric acid is used in an amount of less than 1 equivalent part (for example, about 0.5 equivalent parts) to 1 equivalent part of carvedilol, the solubility of the desired level of carvedilol cannot be obtained, and more than 3 equivalent parts (for example When used in an amount of about 5 equivalents), the solubility increase level due to the increase of the acidifying agent is insignificant, which is uneconomical, and deteriorates the film forming ability of the coating film, thereby adversely affecting both coating efficiency and quality.

According to one embodiment of the invention, when preparing a pharmaceutical composition comprising tartaric acid in an amount of 1.5 to 2 equivalents relative to 1 equivalent by weight of carvedilol, the solubility of carvedilol of up to 584.5 μg / ml in a buffer of pH6.8 The solubility is increased by about 20 times as compared with the case without containing tartaric acid.

The pharmaceutical composition of the present invention may further increase the solubility of carvedilol by further including the surfactant described below, and in the present invention, it is preferable to use a polyoxyethylene polyoxypropylene block copolymer.

1) polyoxyethylene sorbitan fatty acid esters: esters of mono or trilauryl, palmityl, stearyl or oleyl (polysorbate, trade name: Tween, Uniquema);

2) sorbitan fatty acid esters: sorbitan monolauryl, sorbitan monopalmityl, sorbitan monostearyl (trade name: Span, Uniquema);

3) polyoxyethylene polyoxypropylene block copolymer (trade name: Poloxamer, BASF);

4) Reaction products of natural or hydrogenated vegetable oils with ethylene glycol: polyoxyethylene glycolated natural or hydrogenated castor oil (trade names: HCO-50, NiKKOL; Cremophor RH40, BASF);

5) polyoxyethylene fatty acid esters: polyoxyethylene stearic acid ester (trade name: Myrj, Uniquema);

6) dioctylsulfosuccinate sodium or lauryl sulfate sodium; And

7) Mixtures of mono, di and triesters of glycerol, mono and diesters or free polyethylene glycols of polyethylene glycol (trade names Gelucire, Gattefosse).

The surfactant may be used in an amount of 0.05 to 0.5 parts by weight based on 1 part by weight of carvedilol.

In addition to the above components, the pharmaceutical composition of the present invention may further include disintegrants, diluents, stabilizers, binders, lubricants, and the like, which are commonly used as pharmaceutically acceptable excipients.

The disintegrant may be selected from the group consisting of crospovidone, sodium starch glyconate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, alginic acid or its sodium salt, and mixtures thereof, but is not limited thereto. It is not.

The diluent may be selected from the group consisting of microcrystalline cellulose, lactose, ruddy press, mannitol, calcium dihydrogenphosphate, starch, low-substituted hydroxypropylcellulose, and mixtures thereof, but is not limited thereto.

The stabilizer may include an antioxidant, an acidifying agent or a basicizing agent, but is not limited thereto.

The binder may be selected from the group consisting of silicate derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, copovidone, macrogol, light silicic anhydride, synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate; Phosphates such as calcium hydrogen phosphate; Carbonates such as calcium carbonate; And mixtures thereof, but are not limited thereto.

The lubricant may be selected from the group consisting of stearic acid, metal salts of stearic acid such as calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, high melting point wax, glyceryl fatty acid esters, And mixtures thereof. However, the present invention is not limited thereto.

The pharmaceutical compositions of the present invention may be formulated in solid oral preparations, for example pellets, capsules, tablets, powders, syrups, granules, for example, in the form of capsules filled with pellets.

The present invention also provides a controlled release pharmaceutical formulation prepared using the pharmaceutical composition.

Specifically, the present invention is a solid preparation comprising 1) carvedilol and tartaric acid; And 2) a coating layer formed on the surface of the solid preparation and including a release delayed sustained release coating substrate.

The amount of tartaric acid usable in the formulations of the invention is as mentioned above in connection with the pharmaceutical composition.

The release delayed sustained release coating substrate may be used in an amount of 0.05 to 0.5 parts by weight based on 1 part by weight of the solid preparation (eg, pellet) before coating. When the content of the delayed-release sustained release coating substrate is less than 0.05 parts by weight, it is difficult to obtain a release control effect. When the content of the delayed-release sustained-release coating substrate is greater than 0.5 parts by weight, the weight of the coated formulation is so large that the size of the capsule becomes too large in future processes, especially when filling the capsule. Disadvantages can arise.

In controlled release pharmaceutical formulations of the present invention, coating with a release delayed sustained release coating substrate delays the release of the drug until the pharmaceutical formulation of the present invention reaches a high pH region resulting in minimized drug absorption deviations in the gastrointestinal tract. .

Release delayed sustained release coating substrates usable in the present invention include polyvinylpyrrolidone (PVP), water insoluble polymers or hydrophobic compounds.

The water-insoluble polymers are water-insoluble polymethacrylate copolymer [for example, poly (ethyl acrylate-methyl methacrylate) copolymer (e.g., Eudragit ^® NE30D), a poly (ethyl acrylate-methyl Methacrylate-trimethylaminoethylmethacrylate chloride) copolymers (eg Eudragit ^® RSPO) and the like, phthalic acid hydroxypropylmethylcellulose (HPMCP), polyvinylacetate (eg Colicoat ^® SR 30D), ethylcellulose, cellulose esters, cellulose ethers, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, and mixtures thereof, preferably Poly (ethylacrylate-methylmethacrylate) copolymer, poly (Ethylacrylate-methylmethacrylate-trimethylaminoethylmethacrylate chloride) copolymer, phthalic acid hydroxypropylmethylcellulose, polyvinylacetate, ethylcellulose, cellulose acetate, and mixtures thereof, More preferably, it may be selected from the group consisting of poly (ethyl acrylate-methyl methacrylate) copolymer, phthalic acid hydroxypropyl methyl cellulose, ethyl cellulose, cellulose acetate and mixtures thereof.

The hydrophobic compound may be selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances and mixtures thereof.

The fatty acids and fatty acid esters may be selected from the group consisting of glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate, stearic acid and mixtures thereof; The fatty acid alcohols may be selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and mixtures thereof; The waxes may be selected from the group consisting of carnauba wax, beeswax, microcrystalline wax, and mixtures thereof; The inorganic material may be selected from the group consisting of talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, bum, and mixtures thereof.

Hydrophobic compound in the present invention is preferably selected from the group consisting of glyceryl palmitostearate, glyceryl behenate, stearic acid, cetyl alcohol, carnauba wax, and mixtures thereof, more preferably glyceryl behe Nate, stearic acid, carnauba wax, and mixtures thereof.

The most preferred release delayed sustained release coating substrate in the present invention may be selected from the group consisting of phthalic acid hydroxypropylmethyl cellulose, ethyl cellulose, poly (ethylacrylate-methyl methacrylate) copolymer, cellulose acetate and mixtures thereof. .

According to the present invention, a controlled release pharmaceutical formulation, for example, a pellet formulation coated with a release delayed-release sustained-release coating substrate, includes: 1) preparing pellets by coating a solution containing carvedilol and tartaric acid on spherical beads; And 2) coating the pellets obtained in step 1) with a release delayed sustained release coating substrate.

In this case, the spherical beads may have an appropriate size, preferably 50 μm to 700 μm particle diameter, and may be composed of components such as microcrystalline cellulose, spheronized sugar molecules or mannitol, and microcrystalline cellulose is preferable.

In addition, in the manufacturing method, the coating is performed according to the fluidized bed coating method, and the method may be performed using a conventional method used for coating a drug in the art, and bottom spray method is preferable.

The controlled release pharmaceutical formulation according to the present invention exhibits excellent carvedilol solubility and stability even at high pH, and thus has excellent bioavailability and minimized drug absorption deviations over the entire gastrointestinal tract, thereby treating hypertension, congestive heart failure and angina. It can be usefully used.

By the following examples will be described the present invention in more detail. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Example 1 to 4 and Comparative Example 1 to 10: containing acidifying agent Carvedilol Pellet Produce

Carvedilol acetone-water mixed solution (acetone :) containing an acidulant (tinic acid, citric acid, fumaric acid, alginic acid or erythorbic acid), polyvinylpyrrolidone (PVP, BASF) and talc according to the components and compositions shown in Table 1 below. After producing water = 2: 1), it was coated with a bottom spray method on the Cellet Microcrystalline Cellulose Spheres (PHARMATRANS SANAQ) using a Fluid Bed Container (Fluid Bed Container, NQ-160, Dalton). . The prepared pellets were sieved through a 25 mesh sieve and dried at 60 ° C. for 2 hours to prepare carvedilol pellets.

Components and Content of Carvedilol Pellets (Usage Unit: mg) Carvedilol Acidic agent PVP Talc Acidifier / Carvedilol Equivalence Ratio Tartaric acid Citric acid Fumaric acid Alginic acid Erythorbic acid Comparative Example 1 64 11.8 48 8 0.5 Example 1 64 23.6 48 8 One Example 2 64 35.4 48 8 1.5 Example 3 64 47.2 48 8 2 Example 4 64 70.8 48 8 3 Comparative Example 2 64 118.0 48 8 5 Comparative Example 3 64 33.1 48 8 One Comparative Example 4 64 49.7 48 8 1.5 Comparative Example 5 64 18.3 48 8 One Comparative Example 6 64 27.5 48 8 1.5 Comparative Example 7 64 23.6 48 8 Polymer Comparative Example 8 64 35.4 48 8 Polymer Comparative Example 9 64 27.7 48 8 One Comparative Example 10 64 55.4 48 8 1.5

Comparative Example 11: does not contain acidifying agents Carvedilol Pellet Produce

Carvedilol pellets were prepared in the same manner as in Example 1, except that the ingredients and compositions shown in Table 2 were used and no acidifying agent was added.

Components and Content of Carvedilol Pellets (Usage Unit: mg) Carvedilol PVP Talc Acidifying Agent / Carvedilol
Equivalence ratio Comparative Example 11 64 48 8 0

Examples 5 to 7: Preparation of Pellets Including Carvedilol and Surfactant

The ingredients and compositions shown in Table 3 below were used, except that Labrasol (GATTEFOSSE), Polysorbate 80 (CRODA OLEOCHEMICALS LBERICA) or hardened castor oil (BASF) was added as a surfactant. Carvedilol pellets were prepared in the same manner as in Example 2.

Components and Content of Carvedilol Pellets (Usage Unit: mg) Carvedilol Tartaric acid Surfactants PVP Talc Acidifying Agent / Carvedilol
Equivalence ratio Labrasol Polysorbate 80 Hardening
Castor Oil Example 5 64 35.4 6 48 8 1.5 Example 6 64 35.4 6 48 8 1.5 Example 7 64 35.4 6 48 8 1.5

Example 8 and 9, and Comparative Example 12: emission delay coated Carvedilol Pellet Produce

Using the pellets prepared in Examples 2 and 5, and Comparative Example 11 as a core (core pellets), the release delayed coating was carried out with a release delayed release sustained release coating substrate using the ingredients and contents as shown in Table 4 below. At this time, sodium hydroxide, aqueous ammonia, triethyl citrate and talc were added to methacrylic acid copolymer Type 1 and Type 2 (Evonik) as poly (ethyl acrylate-methyl methacrylate) copolymer for smooth coating. A coating solution was prepared, and a mixed solution of water and ethanol was used as a solvent, and generally coated with a fluidized bed coater used for coating the pellet, to prepare a release delay coated carvedilol pellet.

Composition and content of release delay-coated carvedilol pellets in dosage units: mg Example 8 Example 9 Comparative Example 12 Core Pellets (Pellets of Example 2) 205 Core pellets (pellets of Example 5) 205 Core pellets (pellets of Comparative Example 11) 205 Methacrylic acid copolymer Type 1 26 26 26 Methacrylic acid copolymer Type 2 26 26 26 Triethyl citrate 15.6 15.6 15.6 ammonia 0.5 0.5 0.5 Sodium hydroxide 0.3 0.3 0.3 Talc 17.4 17.4 17.4 ethanol 550 550 550 Purified water 330 330 330

Test Example 1: Solubility Test of Carvedilol

500 mg of carvedilol was placed in a 10 mL flask, filled with pH 1.2 buffer, pH 4.0 buffer, distilled water, or pH 6.8 artificial intestinal fluid (USP) to the mark, stirred and mixed for 24 hours, and filtered through a 0.45 μm filter. This was analyzed by HPLC to measure the respective solubility (PPM (μg / ml)), and the measurement results are shown in Table 5 and Figure 1 (analysis method: BP (British Pharmacopoeia) see the 'Carvedilol' section).

Solubility of Carvedilol (μg / ml) pH 1.2 buffer 180.9 pH 4.0 buffer 570.0 Distilled water 86.6 pH 6.8 artificial intestinal fluid 26.0

From the results of Table 5 and FIG. 1, carvedilol was hardly soluble in distilled water and artificial intestinal fluid at pH 6.8 because it is very poorly soluble in neutral to basic solutions. On the other hand, the solubility increased in the acidic region, showing the highest solubility around pH 4.0.

Test Example 2 Comparison of Solubility of Carvedilol with Acidifying Agents

Take the pellets prepared in Examples 1 to 7, and Comparative Examples 1 to 11 to the equivalent amount of carvedilol 100mg to measure the solubility (μg / ml) in a pH 6.8 buffer in the same manner as in Test Example 1 and the results are shown in Table 6 And shown in FIG. 2.

Acidic agent Acidifier / Carvedilol Equivalence Ratio pH 6.8 buffer solubility Comparative Example 1 Tartaric acid 0.5 99.6 Example 1 Tartaric acid One 328.3 Example 2 Tartaric acid 1.5 401.5 Example 3 Tartaric acid 2 427.9 Example 4 Tartaric acid 3 430.1 Comparative Example 2 Tartaric acid 5 429.6 Comparative Example 3 Citric acid One 183.7 Comparative Example 4 Citric acid 1.5 227.9 Comparative Example 5 Fumaric acid One 29.6 Comparative Example 6 Fumaric acid 1.5 34.5 Comparative Example 7 Alginic acid Polymer 32.1 Comparative Example 8 Alginic acid Polymer 29.4 Comparative Example 9 Erythorbic acid One 88.9 Comparative Example 10 Erythorbic acid 1.5 124.6 Comparative Example 11 - 0 29.1 Example 5 Tartaric acid 1.5 584.5 Example 6 Tartaric acid 1.5 469.3 Example 7 Tartaric acid 1.5 479.8

From the results of Table 6 and FIG. 2, the carvedilol pellets of Examples 1 to 7 using tartaric acid showed an excellent solubility increase effect compared to the carvedilol pellets of the comparative examples using other acidifying agents. In addition, it can be seen that the solubility increase efficiency compared to the amount of tartaric acid used was shown in the result of using 1 to 3 equivalent parts.

In addition, the pellets used in combination with the surfactant shows a remarkably good carvedilol solubility, so that the pharmaceutical composition of the present invention is expected to exhibit improved in vivo absorption.

On the other hand, the solubility of the pellets of Comparative Example 2 containing tartaric acid in an amount of 5 equivalent parts was similar to those of Examples 3 and 4, but it was found that the coating was not properly formed when the pellets of Comparative Example 2 were not formed properly. Could.

Test Example 3: Stability Test

In order to evaluate the stability of the pharmaceutical composition of the present invention, the pellets prepared in Example 2 and Comparative Examples 4, 6, 8, and 10 were stored for 1 week and 2 weeks at 0 ° C of 0% moisture, and then, each sample. The sample was taken so that 25 mg of equivalent as carvedilol.

The sample was placed in a 100 mL flask, filled with methanol to the mark, stirred and mixed for 10 minutes, filtered through a 0.45 μm filter and analyzed by HPLC. The ratio of the main component to the unknown analogs A and B of carvedilol was calculated and the results are shown in Table 7 and FIG. 3 (analytical method: see the 'Carvedilol' section of BP).

Acidic agent Acidifier / Carvedilol Equivalence Ratio Unknown Lead A
(Relative time 1.30) Unknown Flexible Substance B
(Relative time 5.33) 1 week 2 weeks 1 week 2 weeks Example 2 Tartaric acid 1.5 0.00 0.02 0.00 0.01 Comparative Example 4 Citric acid 1.5 1.25 2.85 0.88 1.55 Comparative Example 6 Fumaric acid 1.5 0.17 0.34 0.06 0.18 Comparative Example 8 Alginic acid Polymer 0.75 1.22 0.13 0.44 Comparative Example 10 Erythorbic acid 1.5 0.39 1.13 0.15 0.59

From the results of Table 7 and Fig. 3, the carvedilol stability of the carvedilol pellets of Example 2 using tartaric acid was compared to Comparative Examples 2, 4, 6, 8 and citric acid and other organic acids (fumaric acid, alginic acid or erythorbic acid). It was found to be superior to the carvedilol pellets of Comparative Example 10. In FIG. 3, the pellets of Example 2 are hardly produced because no soft material is generated.

That is, since tartaric acid has the highest solubility effect and shows excellent stability, it is possible to obtain improved in vivo absorption rate of carvedilol by using the formulation including the same, and to secure stability, which is a problem of citric acid and other organic acids. You can expect

Test Example 4 Dissolution Test

The dissolution test was performed on the carvedilol pellets prepared in Examples 8 and 9 and Comparative Example 12 by applying USP No. 2 method (paddle method, rotational speed of paddle: 50 rpm).

The dissolution test method was designed considering the gastrointestinal retention time of 1 to 2 hours, and the test was performed for 2 hours in 700 ml of 0.1N HCl, and then adjusted to pH equivalent to artificial intestinal fluid (pH 6.8, USP) by adding 300 ml of phosphate buffer. The dissolution test was then continued (see elution of the "delayed release dosage form" of USP (US Pharmacopoeia)). The dissolution test results are shown in Table 8 and FIG. 4.

Example 8 Example 9 Comparative Example 12 Time (minutes) Average Standard Deviation Average Standard Deviation Average Standard Deviation 0 0.0 0.0 0.0 0.0 0.0 0.0 30 1.2 0.2 1.7 0.1 0.2 0.1 60 4.8 0.9 5.2 0.7 1.6 0.3 120 11.3 2.7 13.4 2.5 4.5 1.9 150 43.2 5.6 49.8 7.7 5.1 1.2 180 49.4 6.7 59.7 7.3 5.7 1.6 240 56.8 8.5 71.6 6.8 6.1 2.1 360 62.1 10.1 79.5 9.4 6.6 3.4 480 63.8 6.4 85.4 8.1 7.8 4.5

From the results of Table 8 and Figure 4, the formulation of Comparative Example 12 without the acidifier in the pH 6.8 region where the absorption time is delayed by the sustained release coating is very low carvedilol dissolution rate, while the implementation containing tartaric acid as the acidifier The formulation of Example 8 can observe a dramatic increase in carvedilol dissolution rate.

In addition, the formulation of Example 9 including the acidifying agent and the labrasol as a surfactant was able to obtain a high dissolution rate of 80% or more. That is, the formulations of Examples 8 and 9, which have increased solubility in the pH 6.8 region in the sustained release formulation, can expect high bioabsorption rate and relatively small absorption deviation of carvedilol, and thus are expected to exhibit high physiological activity. It is thought that it may be usefully used for the treatment of congestive heart failure and angina pectoris.

Claims

A pharmaceutical composition comprising carvedilol and tartaric acid.

The method of claim 1,
The pharmaceutical composition, characterized in that the tartaric acid is included in an amount of 1 to 3 equivalents based on 1 equivalent by weight of carvedilol.

The method of claim 1,
Pharmaceutical composition, characterized in that the carvedilol is in the free base state.

The method of claim 1,
The pharmaceutical composition is polyoxyethylene sorbitan fatty acid esters; Sorbitan fatty acid esters; Polyoxyethylene polyoxypropylene block copolymers; Reaction products of natural or hydrogenated vegetable oils with ethylene glycol; Polyoxyethylene fatty acid esters; Dioctylsulfosuccinate sodium or lauryl sulfate sodium; Mixtures of mono, di and triesters of glycerol, mono and diesters or free polyethylene glycols of polyethylene glycol; And a surfactant selected from the group consisting of a mixture thereof.

5. The method of claim 4,
The surfactant is a pharmaceutical composition, characterized in that contained in an amount of 0.05 to 0.5 parts by weight based on 1 part by weight of carvedilol.

1) solid preparations including carvedilol and tartaric acid; And
2) a coating layer formed on the surface of the solid preparation and including a release delayed sustained release coating substrate
A controlled release pharmaceutical formulation comprising a.

The method according to claim 6,
The tartaric acid is characterized in that the amount of 1 to 3 equivalents based on 1 equivalent by weight of carvedilol, controlled release pharmaceutical formulation.

The method according to claim 6,
The controlled release pharmaceutical formulation, characterized in that the carvedilol is in the free base state.

The method according to claim 6,
The solid preparation is polyoxyethylene sorbitan fatty acid ester; Sorbitan fatty acid esters; Polyoxyethylene polyoxypropylene block copolymers; Reaction products of natural or hydrogenated vegetable oils with ethylene glycol; Polyoxyethylene fatty acid esters; Dioctylsulfosuccinate sodium or lauryl sulfate sodium; Mixtures of mono, di and triesters of glycerol, mono and diesters or free polyethylene glycols of polyethylene glycol; And a surfactant selected from the group consisting of a mixture thereof.

The method of claim 9,
The surfactant is controlled, characterized in that it is included in an amount of 0.05 to 0.5 parts by weight based on 1 part by weight of carvedilol.

The method according to claim 6,
The release delayed sustained release coating substrate is polyvinylpyrrolidone (PVP), water-insoluble polymethacrylate copolymer, phthalic acid hydroxypropylmethyl cellulose (HPMCP), polyvinylacetate, ethyl cellulose, cellulose ester, cellulose ether, Water insoluble polymers selected from the group consisting of cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate and mixtures thereof; Fatty acids and fatty acid esters selected from the group consisting of glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate, stearic acid and mixtures thereof; Fatty acid alcohols selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and mixtures thereof; Waxes selected from the group consisting of carnauba wax, beeswax, microcrystalline wax and mixtures thereof; Inorganic materials selected from the group consisting of talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, bum and mixtures thereof; And mixtures thereof, controlled release pharmaceutical formulations.

The method of claim 11,
The release delayed sustained release coating substrate is selected from the group consisting of phthalic acid hydroxypropyl methyl cellulose, ethyl cellulose, poly (ethyl acrylate-methyl methacrylate) copolymer, cellulose acetate and mixtures thereof, Controlled release pharmaceutical preparations.

The method according to claim 6,
The release delayed sustained release coating base material, characterized in that used in an amount of 0.05 to 0.5 parts by weight based on 1 part by weight of the solid preparation, controlled release pharmaceutical formulation.

The method according to claim 6,
Release-controlled pharmaceutical formulation, characterized in that the solid preparation is in the form of pellets.

1) preparing a pellet by coating a solution containing carvedilol and tartaric acid on spherical beads; And
2) coating the pellet obtained in step 1) with a release delayed sustained release coating substrate, a method for preparing a controlled release pharmaceutical formulation.

The method of claim 15,
The tartaric acid is characterized in that it is contained in an amount of 1 to 3 equivalents based on 1 equivalent by weight of carvedilol.