WO2023132699A1 - Carvedilol sustained release tablet with improved compliance through reduction of tablet size using ilet (innovation low excipient tablet) technology - Google Patents

Abstract

The present disclosure relates to a sustained-release tablet comprising carvedilol granules in which the carvedilol granules are contained in an amount of 33 to 53 wt% based on the total weight of the tablet, and to a method for preparing the same.

Description

CARVEDILOL SUSTAINED RELEASE TABLET WITH IMPROVED COMPLIANCE THROUGH REDUCTION OF TABLET SIZE USING ILET (INNOVATION LOW EXCIPIENT TABLET) TECHNOLOGY

The present disclosure relates to a sustained-release tablet comprising carvedilol granules and a method for preparing the same.

Carvedilol is "(±)-[3-(9H-carbazol-4- yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine (IUPAC name)", which is used for the treatment of hypertension and angina.

Carvedilol acts to dilate blood vessels through α1 and β blocking action, and is used as a third-generation β-blocker with indications for hypertension, angina pectoris, heart failure, and the like. Carvedilol is a drug that not only has excellent blood pressure lowering effect, but also does not have side effects such as edema, reflex tachycardia, dry cough, and the like that are common with other antihypertensive drugs, and was the first antihypertensive drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of congestive heart failure.

Carvedilol is available in two dosage forms: a tablet dosage form and a sustained-release capsule form, and the dosage regimen of carvedilol varies depending on the indication. Carvedilol tablets are administered at 3.125 mg to 50 mg once or twice a day, depending on the indication, and the sustained-release capsules are administered at 16 mg to 128 mg once a day, depending on the indication.

However, the conventionally used carvedilol capsules have disadvantages when taken in clinical practice, such as a case where the capsules are not being able to swallow but only water is swallowed since the capsules are lighter than water, a case where the capsules stick to the mouth, and the like, and thus separate medication guidance and caution are required.

In addition, the dosage regimen of carvedilol varies for each indication, and the initial amount and maintenance amount thereof are different even for the same indication, and as necessary, the dosage is decreased and increased. Thus, it is required to develop a sustained-release tablet capable of being administered in a low dose.

Currently, as carvedilol sustained-release tablets, Dilatrend SR tablet 8 mg^TM containing 8 mg carvedilol and Dilatrend SR tablet 16 mg^TM containing 16 mg carvedilol are commercially available. However, since they are low-content formulations, it is necessary to develop a sustained-release tablet containing carvedilol at a high content and being able to be administered once a day, while simultaneously having high medication compliance.

An object of the present disclosure is to provide a sustained-release tablet comprising carvedilol granules in which the carvedilol granules are contained in an amount of 33 to 53 wt% based on the total weight of the tablet, and a method for preparing the same.

In one general aspect, the present disclosure provides a sustained-release tablet comprising carvedilol granules in which the carvedilol granules are contained in an amount of 33 to 53 wt% based on the total weight of the tablet.

In the present disclosure, the carvedilol is (±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine and refers to a compound that has a vasodilatory action through β1, β2 and α1 blocking action, and exhibits excellent effects as a first-line drug for circulatory diseases such as hypertension, angina pectoris and heart failure.

In the sustained-release tablet of the present disclosure, carvedilol may be in the form of a free base or a salt, a solvate, or an anhydride.

In the present disclosure, the carvedilol granules comprise any granules containing carvedilol without limitation.

Preferably, the carvedilol granule may contain a primary coated granulate and a secondary coated granulate.

In addition, preferably, the carvedilol granule may contain the primary coated granulate, the secondary coated granulate, and/or a mixture thereof.

Preferably, a weight ratio of the primary coated granulate and the secondary coated granulate may be 1 : 1 to 1 : 10.

Further, preferably, a weight ratio of the primary coated granulate and the secondary coated granulate may be 1 : 2 to 1 : 6.

When the weight ratio of the primary coated granulate and the secondary coated granulate is out of the range of 1 : 2 to 1 : 6, there are problems in that it is not possible to exhibit a desired dissolution pattern as a once-a-day sustained-release tablet comprising carvedilol which is the object of the present invention, and biological equivalence is not achieved in the pharmacokinetic test with the reference drug (for example, the same dose of Dilatrend SR capsule). In addition, in particular, when the weight ratio of the primary coated granulate and the secondary coated granulate exceeds 1 : 6, there is a problem in that an initial dissolution rate of carvedilol is significantly lowered.

The primary coated granulate of the present disclosure may be a granulate coated with a drug layer comprising carvedilol, a solubilizer, and a coating agent on a surface of an inert core.

The inert core of the present disclosure may be one or more selected from monosaccharides, disaccharides, polysaccharides, celluloses, microcrystalline celluloses, cellulose derivatives, and mixtures thereof generally used as pharmaceutical excipients, and preferably the inert core of the present disclosure may be microcrystalline cellulose.

The solubilizer of the present disclosure is a substance that contributes to increasing the water solubility of carvedilol. For example, the solubilizer may be at least one selected from the group consisting of hard silicic anhydride, glyceryl monooleate, docusate sodium, lauryl dimethylamino acetate betaine, sodium lauryl sulfate, myristyl alcohol, benzalkonium chloride, vitamin E polyethylene glycol succinate, cetrimide, cetyl pyridinium chloride, sorbitan sesquioleate, sorbitan ester, sorbitan trioleate, phospholipid, cocamidopropyl betaine, cocamido DEA, tricaprylin, polysorbate, polyoxyl glyceride, polyethylene glycol monostearic acid, polyoxyethylene nonylphenyl ether, polyoxyethylene alkyl ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polyoxyethylene castor oil, polyoxyl 40 hydrogenated castor oil, propylene glycol dilaurate, propylene glycol monolaurate, tyloxapol, TEA-cocoyl glutamate, phosphoric acid, sodium dihydrogen phosphate, calcium phosphate, citric acid, sodium citrate, ascorbic acid, sodium hydrogen sulfite, hydrochloric acid, tartaric acid, fumaric acid, and a mixture thereof.

Preferably, the solubilizer contained in the primary coated granulate of the present disclosure may be a phosphoric acid.

The coating agent of the present disclosure may be a water-soluble polymer that contributes to the formation of a coating film of the drug layer and dispersion of the drug as the water-soluble polymer. Preferably, the coating agent may be at least one selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and mixtures thereof as cellulose-based agents, or may be at least one selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, and mixtures thereof.

Preferably, the coating agent contained in the primary coated granulate of the present disclosure may be hydroxypropyl methylcellulose.

The primary coated granulate of the present disclosure may additionally include a pharmaceutical additive selected from the group consisting of a solubilization aid, an excipient, a binder, and any combination thereof.

The solubilization aid of the present disclosure may be, for example, at least one selected from the group consisting of hard silicic anhydride, glyceryl monooleate, docusate sodium, lauryl dimethylamino acetate betaine, sodium lauryl sulfate, myristyl alcohol, benzalkonium chloride, vitamin E polyethylene glycol succinate, cetrimide, cetyl pyridinium chloride, sorbitan sesquioleate, sorbitan ester, sorbitan trioleate, phospholipid, cocamidopropyl betaine, cocamido DEA, tricaprylin, polysorbate, polyoxyl glyceride, polyethylene glycol monostearic acid, polyoxyethylene nonylphenyl ether, polyoxyethylene alkyl ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polyoxyethylene castor oil, polyoxyl 40 hydrogenated castor oil, propylene glycol dilaurate, propylene glycol monolaurate, tyloxapol, TEA-cocoyl glutamate, phosphoric acid, sodium dihydrogen phosphate, calcium phosphate, citric acid, sodium citrate, ascorbic acid, sodium hydrogen sulfite, hydrochloric acid, tartaric acid, fumaric acid, and a mixture thereof.

Preferably, the solubilization aid contained in the primary coated granulate of the present disclosure may be polyoxyl 40 hydrogenated castor oil.

The excipient may be any disintegrant known in the art, for example, at least one disintegrant selected from the group consisting of sodium starch glycolate, pregelatinized starch, croscarboxymethyl cellulose sodium, crospovidone, and a mixture thereof.

Preferably, the excipient contained in the primary coated granulate of the present disclosure may be crospovidone.

The binder may be any binder known in the art, and for example, may be selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, povidone, copovidone, macrogol, and any combination thereof.

Preferably, the binder contained in the primary coated granulate of the present disclosure may be povidone.

The secondary coated granulate of the present disclosure may be a granulate coated with a sustained-release layer containing a sustained-release agent and a plasticizer on a surface of the primary coated granulate.

The sustained-release agent of the present disclosure is a release-controlling material for controlled release of a pharmacologically active substance, and may be at least one selected from methacrylic acid copolymers such as 2-dimethylaminoethyl methacrylate, methyl methacrylate, methacrylic acid, ethyl acrylate, butyl methacrylate, and a mixture thereof; and cellulose-based polymers dissolved at pH 5.5 to pH 7.4 such as cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, and a mixture thereof.

Preferably, the sustained-release agent of the present disclosure may be Eudragit L100-55 and Eudragit S100.

The plasticizer of the present disclosure may be at least one selected from dibutyl sebacate, dibutyl phthalate, diacetylated monoglyceride, diethyl phthalate, polyoxyl stearate 40, acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triacetin, polyethylene glycol, propylene glycol, triethyl citrate, glycerin fatty acid ester, polysorbate 80, and a mixture thereof.

Preferably, the plasticizer of the present disclosure may be triethyl citrate, glycerin fatty acid ester, and polysorbate 80.

The secondary coated granulate of the present disclosure may further contain a pharmaceutical additive selected from the group consisting of an excipient, a pH adjusting agent, and any combination thereof.

As the excipient, a solid fat component or a stabilizer may be used.

The solid fat component of the present disclosure is contained in the secondary coated granulate to induce continuous controlled release of the drug, and may be at least one selected from sorbitan fatty acid ester, sucrose fatty acid ester, fatty acid, fatty acid glycerol ester, fatty alcohol, fatty acid fatty alcohol ester, fatty acid propylene glycol, and a mixture thereof. Preferably, the fatty acid and fatty alcohol of the component may be selected from saturated fatty acid and saturated fatty alcohol. Specifically, the solid fat component of the present disclosure may be at least one selected from hydrogenated vegetable oil, hydrogenated castor oil, hydrogenated soybean oil, hydrogenated cottonseed oil, hydrogenated palm oil, glyceryl monostearic acid, glyceryl behenate, glyceryl palmitostearic acid, sorbitan monostearic acid, sorbitan monopalmitate, stearic acid, stearyl alcohol, sucrose lauric acid, sucrose stearic acid, and a mixture thereof.

Preferably, the solid fat component contained as an excipient in the secondary coated granulate of the present disclosure may be hydrogenated vegetable oil.

The stabilizer may be at least one selected from sodium gluconate, glutamic acid, glycerin, glycolic acid, dibutylhydroxytoluene, lactic acid, lecithin, D-mannitol, D-sorbitol, maleic acid, malic acid, meglumine, butylated hydroxyanisole, boric acid, white sugar, xanthan gum, magnesium oxide, succinic acid, disodium succinate, β-cyclodextrin, simethicone, citric acid, sodium citrate, ascorbic acid, sodium bisulfite, hydrochloric acid, lactose, liquid paraffin, silicon dioxide, phosphoric acid, sodium dihydrogen phosphate, calcium phosphate, L-phenylalanine, tartaric acid, talc, tocopherol, tocopherol acetate, glucose, poloxamer, fumaric acid, sodium pyrosulfite, sulfuric acid, and a mixture thereof.

Preferably, the stabilizer contained as an excipient in the secondary coated granulate of the present disclosure may be talc.

As the pH adjusting agent of the present disclosure, any conventionally used pharmaceutically acceptable pH adjusting agent may be used at random, and preferably, sodium hydroxide or aqueous ammonia may be used.

The sustained-release tablet of the present disclosure contains the carvedilol granules in an amount of 33 to 53 wt% based on the total weight of the tablet.

Further, preferably, the sustained-release tablet of the present disclosure may contain 38 to 48 wt% of the carvedilol granules based on the total weight of the tablet.

The sustained-release tablet of the present disclosure contains a high content of carvedilol granules in the tablet, thereby preventing the tablet from increasing in size and thus providing convenience of administration for ease of swallowing.

The carvedilol granule of the present disclosure may contain 64 mg of carvedilol.

The sustained-release tablet of the present disclosure has a dissolution rate of carvedilol of 20% or more and 30% or less at 15 minutes in the dissolution test with 900 mL of 0.1 mol/L HCl at 100 rpm according to Dissolution Test Method 2 of General Test Method of the Korean Pharmacopoeia.

The sustained-release tablet of the present disclosure contains a disintegrant and a binder.

The disintegrant may be any disintegrant used in the preparation of tablets. Preferably, the disintegrant may be at least any one selected from the group consisting of sodium starch glycolate, croscarmellose sodium, and low-substituted hydroxypropyl cellulose. More preferably, the disintegrant contained in the sustained-release tablet of the present disclosure may be a low-substituted hydroxypropyl cellulose.

The disintegrant of the present disclosure may be contained in 3 wt% or more based on the total weight of the sustained-release tablet. Preferably, the disintegrant in the sustained-release tablet of the present disclosure may be contained in 3 wt% to 10 wt% based on the total weight of tablet. When the disintegrant is contained in less than 3 wt%, there is no sufficient disintegration effect, or there is a concern that the initial drug release rate may slow due to a delay in disintegration. When the disintegrant is contained in an amount exceeding 10 wt%, a problem may occur in tableting.

In an experimental example, in the case of a sustained-release tablet (Example 3) containing 1.9 wt% of a disintegrant while containing 42.6 wt% of the carvedilol granules based on the total weight of the tablet, it could be confirmed that the disintegration time was 35 minutes, resulting in a delay in disintegration (Experimental Example 3).

The binder of the present disclosure may be any binder known in the art. Preferably, the binder may be at least one selected from the group consisting of polyvinylpyrrolidone, povidone and copovidone. More preferably, the binder contained in the sustained-release tablet of the present disclosure may be copovidone.

The binder of the present disclosure may be contained in 9 wt% or less based on the total weight of the sustained-release tablet. For example, in the sustained-release tablet of the present disclosure, the binder may not be contained, or may be contained in an amount greater than 0 and less than or equal to 9 wt% based on the total weight of the sustained-release tablet. When the binder is contained in an amount exceeding 9 wt%, aggregation of the granules may occur and the initial release may be lowered.

In an experimental example, in the case of a sustained-release tablet (Example 3) containing 10.2 wt% of a binder while containing 42.6 wt% of the carvedilol granules based on the total weight of the tablet, it could be confirmed that the dissolution rate of carvedilol was significantly low at about 7.1% at 15 minutes in the dissolution test with 900 mL of 0.1 mol/L HCl at 100 rpm according to Dissolution Test Method 2 of General Test Method of the Korean Pharmacopoeia (Experimental Example 4).

Preferably, the sustained-release tablet of the present disclosure may contain the disintegrant and the binder in a weight ratio of 1 : 1. Preferably, the sustained-release tablet of the present disclosure may contain low-substituted hydroxypropyl cellulose and copovidone in a weight ratio of 1 : 1.

The sustained-release tablet of the present disclosure contains the disintegrant in an amount of 3 wt% or more and the binder in an amount of 9 wt% or less based on the total weight of the sustained-release tablet, and thus it is possible to secure an optimal disintegration time of about 10 minutes and an excellent dissolution pattern without aggregation of granules and a decrease in initial release.

In some Experimental Examples, in the case of a sustained-release tablet (Example 4) containing 5 wt% of a disintegrant and 5 wt% of a binder, while containing 41.2 wt% of carvedilol granules based on of the total weight of the tablet, it could be confirmed that the disintegration time was 3-5 minutes, and the dissolution rate at 15 minutes in the dissolution test was about 23.9%, indicating excellent disintegration ability and dissolution pattern (Experimental Examples 6 and 7).

The sustained-release tablet of the present disclosure may have a total weight of 1000 mg or less. Preferably, the sustained-release tablet of the present disclosure may have a total weight of 900 mg or less. More preferably, the sustained-release tablet of the present disclosure may have a total weight of 800 to 900 mg.

The sustained-release tablet of the present disclosure has excellent convenience of administration because it contains a high content of carvedilol granules and the total weight of the tablet is small. Further, the sustained-release tablet of the present disclosure overcome the disadvantages of having to take several tablets in order to reach the desired dose, or having to take a capsule that are not easy to take as the capsule sticks to the mouth when taking.

The dissolution rate of carvedilol in the sustained-release tablet of the present disclosure is characterized by indicating the area under the plasma concentration-time curve (AUC) and the peak blood concentration (C_max) at equivalent or bioequivalent levels compared with Dilatrend SR Capsule^TM having the same active ingredient dose.

Here, whether the area under the plasma concentration-time curve (AUC) and the peak blood concentration (C_max) represent the bioequivalence level may be determined according to the pharmaceutical equivalence standard. For example, in the case where log transformation and statistical evaluation on the area under the plasma concentration-time curve (AUC) and the peak blood concentration (C_max) of the reference drug and the test drug are performed according to the bioequivalence test of the drug equivalence test standard of the Pharmaceutical Affairs Regulations, when both parameters in the 90% confidence intervals for the difference in log-transformed mean values between the test and reference drugs are within log 0.8 to log 1.25, the drug equivalence test is considered to be equivalent. Provided, as an exception for biological equivalence, the case that meets the following conditions is considered to be equivalent: 1) when the difference in log-transformed mean values between the reference and test drugs is between log 0.9 to log 1.11, and 2) when the comparative dissolution test is conducted according to the pharmaceutical equivalence test standard, all values are equivalent under all conditions prescribed.

In an experimental example, the sustained-release tablet of the present disclosure (Example 4) had AUC T/R of 0.88 and C_max T/R of 1.00 before meals; and AUC T/R of 0.91 and C_max T/R of 0.94 after meals, in which all four values showed equivalence (Experimental Example 8) when Dilatrend SR Capsule 64 mg^TM having the same active ingredient dose was used as a reference drug.

The sustained-release formulation of the present disclosure is characterized in that it is administered once a day with the dissolution rate and pharmacokinetic pattern as described above.

The sustained-release formulation of the present disclosure may further contain a pharmaceutically acceptable additive as necessary, and may be formulated by containing an additive such as a pharmaceutically acceptable excipient, lubricant, and coating agent, or the like, within the range that does not impair the effects of the present disclosure.

The excipient is a substance added when the active ingredient is low or for the purpose of increasing the amount, and may be, for example, mannitol, cellulose, lactose, starch, microcrystalline cellulose, lactose hydrate, glucose, alginate, alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, a mixture thereof, and the like.

Preferably, silicified microcrystalline cellulose may be used for the sustained-release tablet of the present disclosure. The excipient may be contained in an amount of 10 to 67 wt%, preferably 36 to 65 wt%, and more preferably 45 to 55 wt% based on the total weight of the tablet.

The lubricant is added in order to smoothly perform the compression operation of the granules, and serves to improve the fluidity of pellets to increase the filling properties, to reduce friction, and to prevent adhesion of the granules.

As the lubricant, magnesium metasilicate aluminate, glyceryl behenate, calcium stearate, stearic acid, sodium fumarate stearate, silicon dioxide, or the like, may be used.

Preferably, magnesium metasilicate aluminate and glyceryl behenate may be used for the sustained-release tablet of the present disclosure.

The coating agent may contain hydroxypropyl methylcellulose, ethyl cellulose, polyvinyl acetate, polyethylene glycol, titanium dioxide, iron oxide, or the like, or Opadry^®.

Further, the present disclosure provides a method for preparing the sustained-release tablet as described above, comprising: preparing carvedilol granules; forming a mixture by mixing the carvedilol granules with an excipient, a binder, and a disintegrant; and adding a lubricant to the mixture and mixing the mixture, followed by tableting and coating.

In the step of preparing the carvedilol granules, for example, a primary coated granulate may be prepared, and secondary coating may be performed on the primary coated granulate to prepare a secondary coated granulate, and then the primary coated granulate and the secondary coated granulate may be mixed to prepare the carvedilol granules.

For the details of the method for preparing the sustained-release formulation, the description as to the sustained-release formulation of the present disclosure may be applied as it is. Specifically, the carvedilol granules, excipients, binders, disintegrants, and lubricants are the same as described above.

The method for preparing the sustained-release tablet according to the present disclosure may be performed by using any means and methods known in the art with respect to a method for preparing granules, a mixing method, a tableting method, and a coating method.

Since the sustained-release tablet of the present disclosure contains carvedilol granules in a high content, the tablet has a small size to achieve excellent convenience of administration. In addition, the sustained-release tablet of the present disclosure is a once-a-day sustained-release formulation that exhibits an appropriate disintegration rate and dissolution rate, in particular, exhibits bioequivalence with Dilatrend SR Capsule^TM, ensuring safety and effectiveness, and achieves excellent medication compliance that fundamentally improves the inconvenient dosing problem of conventional capsule formulations that stick to the mouth.

Hereinafter, the present disclosure will be described in detail through Examples and Experimental Examples. However, these Examples and Experimental Examples are merely illustrative of the present disclosure, and the scope of the present disclosure is not limited thereto.

Preparation Example 1: Preparation of carvedilol granules of Comparative Example 2 and Example 1

Preparation of primary coated granulates

According to the amounts shown in Table 1 below, hypromellose and povidone were added to ethanol and purified water and dissolved, then polyoxyl 40 hydrogenated castor oil and carvedilol were added, stirred, and dispersed. Then, phosphoric acid was added, and the mixture was stirred and left to stand to prepare a coating solution 1.

Ethanol and purified water were added with stirring, and crospovidone was added and dispersed to prepare a coating solution 2.

The coating solution 2 was added to the coating solution 1 and mixed with stirring.

Microcrystalline cellulose was put into a fluidized bed granule coating machine, and the mixed coating solution was sprayed, followed by primary coating and drying, to form primary coated granulates.

Classification	Purpose of mixing	Ingredient Name	Comparative Example 2		Example 1
			mg/T	%	mg/T	%
Primary coated granulate	Main ingredient	Carvedilol	16.00	26.4	64.00	26.4
	Solubilizer	Phosphoric acid	5.00	7.0	20.00	7.0
		(as phosphoric acid)	(4.25)		(17)
	solubilization aid	Polyoxyl 40 hydrogenated castor oil	1.50	2.5	6.00	2.5
	Coating agent	Hypromellose	10.00	16.5	40.00	16.5
	Excipient	Crospovidone	8.00	13.2	32.00	13.2
	Excipient	Microcrystalline cellulose	18.38	30.3	73.50	30.3
	Binder	Povidone	2.50	4.1	10.00	4.1
	Total		60.625	100.0	242.5	100.0

Preparation of secondary coated granulates

According to the amounts shown in Table 2 below, 75% of the primary coated granulates were subjected to secondary coating.

Ethanol, purified water, sodium hydroxide, aqueous ammonia, triethyl citrate, glycerin fatty acid ester, and polysorbate 80 were added and dissolved with stirring, and then Eudragit L100-55, Eudragit S100, and talc were added and dispersed with stirring to prepare a coating solution 3.

Ethanol, purified water, and hydrogenated vegetable oil were added and dispersed with stirring to prepare a coating solution 4, followed by stirring and dispersing with the coating solution 3.

The secondary coating was performed by spraying the mixed coating solution onto 75% of the primary coated granulates, followed by drying to obtain secondary coated granulates.

Classification	Purpose of mixing	Ingredient Name	Comparative Example 2		Example 1
			mg/T	%	mg/T	%
Secondary coated granulate	Main ingredient	Primary coated granulate	45.47	64.1	181.875	64.1
	Excipient	Hydrogenated vegetable oil	5.20	7.3	20.8	7.3
	Excipient	Talc	3.61	5.1	14.434	5.1
	Sustained-release agent	Eudragit L100-55	8.00	11.3	32.00	11.3
	Sustained-release agent	Eudragit S100	4.00	5.6	16.00	5.6
	Plasticizer	Triethyl citrate	3.90	5.5	15.6	5.5
	Plasticizer	Glycerin fatty acid ester	0.39	0.6	1.56	0.6
	Plasticizer	Polysorbate 80	0.13	0.2	0.52	0.2
	pH adjusting agent	Sodium hydroxide	0.09	0.1	0.34	0.1
	pH adjusting agent	Aqueous ammonia	0.11	0.2	0.45	0.2
	Total		70.89	100.0	283.579	100.0

Post-mix

The primary coated granulates, secondary coated granulates, and talc were put into a double cone mixer according to the amounts in Table 3 below, and mixed at 15 rpm for 20 minutes, to thereby prepare carvedilol granules to be used in the preparation of tablets of Comparative Example 2 and Example 1, respectively.

Classification	Purpose of mixing	Ingredient Name	Comparative Example 2		Example 1
			mg/T	%	mg/T	%
Post-mix	Main ingredient	Primary coated granulate	15.16	17.3	60.63	17.3
	Main ingredient	Secondary coated granulate	70.89	80.7	283.58	80.7
	Lubricant	Talc	1.75	2.0	7.00	2.0
	Total		87.80	100.0	351.20	100.0

Comparative Example 1

Comparative Example 1 is Dilatrend SR Capsule 64 mg^TM commercially available in Korea.

Comparative Example 2 and Example 1: Preparation of carvedilol sustained-release tablet

Each of the carvedilol granules prepared in Preparation Example 1, silicified microcrystalline cellulose, and crospovidone were put into a bin mixer according to the amounts in Table 4 below, and mixed at 6 rpm for 60 minutes. Then, magnesium metasilicate aluminate and glyceryl behenate were added according to the amounts in Table 4 and mixed at 6 rpm for 60 minutes, followed by tableting and coating with opadry beige to prepare tablets of Comparative Example 2 and Example 1.

Purpose of mixing	Ingredient Name	Comparative Example 2		Example 1
		mg/T	%	mg/T	%
Main ingredient	Carvedilol granule	87.80	22.0	351.20	22.0
	as carvedilol	16.00	-	64.00	-
Excipient	Silicified microcrystalline cellulose	285.80	71.5	1,143.20	71.5
Disintegrant	Crospovidone	20.00	5.0	80.00	5.0
Lubricant	Magnesium metasilicate aluminate	4.00	1.0	16.00	1.0
Lubricant	Glyceryl behenate	2.40	0.6	9.60	0.6
Total (tablet)		400.00	100.0	1,600.00	100.0
Coating agent	Opadry beige	12.00	-	48.00	-
Total (Coating)		412.00	-	1,648.00	-

Experimental Example 1: Disintegration test of Comparative Example 2 and Example 1

The disintegration test for the tablets of Comparative Example 2 and Example 1 was performed according to the disintegration test method of General Test Method of the Korean Pharmacopoeia.

The results are shown as follows.

Classification	Comparative Example 2	Example 1
Disintegration time (min)	5 min	5 min

Compared with Comparative Example 2, Example 1 is a tablet in which all weights of the main component, excipient, disintegrant, lubricant, and coating agent contained therein were increased by 4 times as the same as the ratio of the main component. It was shown that Example 1 containing 64 mg as carvedilol and 22 wt% of carvedilol granules disintegrated over 5 minutes as in Comparative Example 2, thereby confirming that the disintegration was well achieved.

Experimental Example 2: Dissolution test of Comparative Examples 1, 2 and Example 1

A dissolution test was performed on the capsule of Comparative Example 1, the tablet of Comparative Example 2, and the tablet of Example 1. The dissolution test was performed at 100 rpm with 0.1 mol/L HCl 900 mL, according to Dissolution Test Method 2 of General Test Method of the Korean Pharmacopoeia.

<Dissolution test analysis conditions>

- Detector: Ultraviolet spectrometer (measurement wavelength: 285 nm)

- Column: Inertsil ODS-4 (4.6*150 nm, 5 μm) or column equivalent thereto

- Injection volume: 50 μl

- Flow rate: 1.5 ml/min

- Column temperature: constant temperature around 35℃

- Sample temperature: constant temperature around 25℃

- Mobile phase: a mixed solution of pH 2.0 solution and methanol (30 : 70)

The analysis results are shown in Table 6.

Dissolution rate (%)

Time (hr)

0.083

0.17

0.25

0.5

0.75

1

1.5

2

3

5

6

8

10

12

18

24

Comparative Example 1

13.8±0.6

23.1±1.1

24.9±0.9

25.6±0.9

25.9±0.7

27.2±0.9

36.9±1.0

42.0±0.5

46.9±0.6

54.6±0.6

57.7±0.6

63.3±0.6

67.3±0.6

70.3±0.7

76.3±0.7

80.6±0.7

Comparative Example 2

22.5±0.2

26.8±0.8

27.1±0.8

27.9±1.0

29.4±1.0

32.3±1.3

41.4±1.5

45.7±1.6

49.9±0.8

56.5±2.1

59.4±2.1

64.2±2.4

68.2±2.4

70.9±2.7

77.5±3.1

83.0±3.1

Example 1

22.1±1.0

27.4±0.3

27.7±0.3

28.6±0.4

30.4±0.4

35.8±0.7

44.1±0.9

47.1±0.9

51.6±1.0

58.8±1.3

61.7±1.2

66.9±1.5

70.8±1.6

73.7±1.4

79.9±1.9

84.7±2.0

According to the dissolution rate results in Table 6, the tablets of Comparative Example 1 (Dilatrend SR Capsule 64 mg^TM), Comparative Example 2, and Example 1 showed similar dissolution rates, confirming that the carvedilol drug release behaviors were similar to each other. In particular, it was confirmed that compared to Comparative Example 2, Example 1 exhibited an excellent dissolution pattern even though the weight of each of the main component, excipient, disintegrant, lubricant, and coating agent in the tablet was increased by 4 times as the same as the ratio of the active ingredient. However, since the tablet of Example 1 contained 22 wt% of carvedilol granules, which was low, based on the total weight of the tablet, the total weight of the tablet was 1,648 mg, and the tablet size was large, which caused a problem in that medication compliance was lowered.

Examples 2 and 3: Carvedilol sustained-release tablet

The sustained-release tablet of Example 1 had excellent disintegration time and dissolution pattern, but had lowered medication compliance due to the large tablet size. Thus, in order to reduce the tablet size, Examples 2 and 3 of sustained-release tablets having a reduced size by increasing the content of carvedilol granules were prepared as follows.

The carvedilol granules of Example 1 prepared in Preparation Example 1, silicified microcrystalline cellulose, copovidone, and crospovidone, were put into a bin mixer according to amounts in Table 7 below, and mixed at 6 rpm for 60 minutes. Then, magnesium metasilicate aluminate and glyceryl behenate were added according to the amounts in Table 7, and mixed at 6 rpm for 60 minutes, followed by tableting and coating with opadry beige to prepare tablets of Examples 2 and 3.

Purpose of mixing	Ingredient Name	Example 2		Example 3
		mg/T	%	mg/T	%
Main ingredient	Carvedilol granule	351.20	28.8	351.20	42.6
	(as carvedilol)	64.00	-	64.00	-
Excipient	Silicified microcrystalline cellulose	700.00	57.3	360.00	43.6
Binder	Copovidone	125.00	10.2	84.00	10.2
Disintegrant	Crospovidone	24.00	2.0	16.00	1.9
Lubricant	Magnesium metasilicate aluminate	8.40	0.7	5.3	0.6
Lubricant	Glyceryl behenate	12.40	1.0	8.5	1.0
Total (tablet)		1221.00	100.0	825.00	100.0
Coating agent	Opadry beige	36.00	-	25.00	-
Total (Coating)		1257.00	-	850.00	-

Experimental Example 3: Disintegration test of Examples 2 and 3

The disintegration test for the tablets of Examples 2 and 3 was performed according to the disintegration test method of General Test Method of the Korean Pharmacopoeia.

The results are shown as follows.

Classification	Example 2	Example 3
Disintegration time (min)	10 min	35 min
Tableting pressure (kgf)	920	1,140

Example 3, which had a smaller weight compared to Example 2, had a higher content ratio of carvedilol granules in one tablet, thereby the binding force was weakened, and thus it was shown that a higher tableting pressure was required to secure hardness suitable for the friability standard (0.5% or less).

It could be confirmed that the tablet of Example 2 containing 28.8 wt% of carvedilol granules disintegrated well over 10 minutes, whereas the tablet of Example 3 containing carvedilol granules in a high content of 42.6 wt% disintegrated over 35 minutes, resulting in a delay in disintegration.

Experimental Example 4: Dissolution test of Comparative Example 1 and Examples 1 to 3

A dissolution test was performed on the capsule of Comparative Example 1 and the tablets of Examples 1 to 3. The dissolution test was performed at 100 rpm, with 0.1 mol/L HCl 900 mL, according to Dissolution Test Method 2 of General Test Method of the Korean Pharmacopoeia.

<Dissolution test analysis conditions>

- Detector: Ultraviolet spectrometer (measurement wavelength: 285 nm)

- Column: Inertsil ODS-4 (4.6*150 nm, 5 μm) or column equivalent thereto

- Injection volume: 50 μl

- Flow rate: 1.5 ml/min

- Column temperature: constant temperature around 35℃

- Sample temperature: constant temperature around 25℃

- Mobile phase: a mixed solution of pH 2.0 solution and methanol (30 : 70)

The analysis results are shown in Table 9.

Dissolution rate (%)

Time (hr)

0.083

0.17

0.25

0.5

0.75

1

1.5

2

3

5

6

8

10

12

18

24

Comparative Example 1

13.8±0.6

23.1±1.1

24.9±0.9

25.6±0.9

25.9±0.7

27.2±0.9

36.9±1.0

42.0±0.5

46.9±0.6

54.6±0.6

57.7±0.6

63.3±0.6

67.3±0.6

70.3±0.7

76.3±0.7

80.6±0.7

Example 1

22.1±1.0

27.4±0.3

27.7±0.3

28.6±0.4

30.4±0.4

35.8±0.7

44.1±0.9

47.1±0.9

51.6±1.0

58.8±1.3

61.7±1.2

66.9±1.5

70.8±1.6

73.7±1.4

79.9±1.9

84.7±2.0

Example 2

8.4±00.5

20.3±1.0

26.5±0.7

27.4±0.6

28.6±0.8

31.5±1.0

40.3±1.0

44.5±1.0

48.1±1.0

53.6±1.0

55.8±0.9

60.0±1.0

63.5±1.0

65.9±0.0

71.3±1.1

75.6±1.1

Example 3

1.9±0.2

4.4±0.5

7.1±1.0

17.7±3.5

28.3±0.7

31.0±0.6

38.7±1.1

44.2±0.7

48.4±0.6

54.3±0.6

56.7±0.7

61.3±0.6

64.9±0.8

64.5±0.8

73.2±1.1

77.8±1.1

According to the dissolution rate results in Table 9, it could be confirmed that Comparative Example 1 (Dilatrend SR Capsule 64 mg^TM) and the tablet of Example 2 containing 28.8 wt% of carvedilol granules showed a similar dissolution pattern, but the tablet of Example 3 containing 42.6 wt% of carvedilol granules showed a significant drop in initial drug dissolution. In particular, at 15 minutes of the dissolution test, Example 2 showed a dissolution rate of 20 to 30 wt%, but the tablet of Example 3 showed a dissolution rate of 7.1 wt%, confirming that the initial dissolution was lowered.

Meanwhile, since the tablet of Example 2 contained the carvedilol granules at an amount of 28.8 wt%, which was still relatively low, based on the total weight of the tablet, the total weight of the tablet was 1,257 mg, and the tablet size was large, which caused a problem in that medication compliance was lowered.

Experimental Example 5: Pharmacokinetic (PK) test of Examples 2 and 3

The pharmacokinetic (PK) test was performed on the tablets of Examples 2 and 3 employing the capsule of Comparative Example 1 as a reference drug, and the results are shown in Table 10 below.

Classification			Example 2	Example 3
PK	Before meals	AUC T/R	-	0.98(equivalent)
		Cmax T/R	-	0.69 (non-equivalent)
	After meals	AUC T/R	0.99(equivalent)	0.99(equivalent)
		Cmax T/R	0.95(equivalent)	1.06(equivalent)

As could be seen in Table 10 above, the tablet of Example 3 containing 42.6 wt% of carvedilol granules had a C_max T/R of 0.69 before meals, which showed non-equivalence, in a bioequivalence test employing Comparative Example 1 (Dilatrend SR Capsule 64 mg^TM) as a reference drug.

Example 4: Carvedilol sustained-release tablet

The carvedilol granules of Example 1 prepared in Preparation Example 1, silicified microcrystalline cellulose, copovidone, and low-substituted hydroxypropyl cellulose were put into a bin mixer according to amounts in Table 11 below, and mixed at 6 rpm for 60 minutes. Then, magnesium metasilicate aluminate and glyceryl behenate were added according to the amounts in Table 11, and mixed at 6 rpm for 60 minutes, followed by tableting and coating with opadry beige to prepare Example 4.

Purpose of mixing	Ingredient Name	Example 4
		mg/T	%
Main ingredient	Carvedilol granule	351.20	41.2
	(as carvedilol)	64.00	-
Excipient	Silicified microcrystalline cellulose	401.00	47.1
Binder	Copovidone	43.00	5.0
Disintegrant	Low-substituted hydroxypropyl cellulose	43.00	5.0
Lubricant	Magnesium metasilicate aluminate	5.30	0.6
Lubricant	Glyceryl behenate	8.50	1.0
Total (tablet)		852.00	100.0
Coating agent	Opadry beige	26.00
Total (Coating)		878.00

Experimental Example 6: Disintegration test of Examples 3 and 4

The disintegration test for the tablets of Examples 3 and 4 was performed according to the disintegration test method of General Test Mtehod of the Korean Pharmacopoeia.

The results are shown as follows.

Classification	Example 3	Example 4
Disintegration time (min)	35 min	3-5 min
Tableting pressure (kgf)	1,140	950

By using the low-substituted hydroxypropyl cellulose as a fibrous disintegrant, it was possible to maintain the binding force and increase the disintegration force. Even though the amount of binder was reduced, the tableting pressure was lowered and the disintegration time was accelerated. Thus, it could be confirmed that the tablet of Example 3 containing 42.6 wt% of carvedilol granules, 10.2 wt% of binder, and 1.9 wt% of disintegrant had a disintegration time of 35 minutes, resulting in a delay in disintegration, whereas the tablet of Example 4 containing carvedilol granules in a high content of 41.2 wt%, 5 wt% of binder, and 5 wt% of disintegrant showed good disintegration with a disintegration time of 3-5 minutes.

Experimental Example 7: Dissolution test of Comparative Example 1 and Examples 3 and 4

A dissolution test was performed on the capsule of Comparative Example 1 and the tablets of Examples 3 and 4. The dissolution test was performed at 100 rpm, with 0.1 mol/L HCl 900 mL, according to Dissolution Test Method 2 of General Test Method of the Korean Pharmacopoeia.

<Dissolution test analysis conditions>

- Detector: Ultraviolet spectrometer (measurement wavelength: 285 nm)

- Column: Inertsil ODS-4 (4.6*150 nm, 5 μm) or column equivalent thereto

- Injection volume: 50 μl

- Flow rate: 1.5 ml/min

- Column temperature: constant temperature around 35℃

- Sample temperature: constant temperature around 25℃

- Mobile phase: a mixed solution of pH 2.0 solution and methanol (30 : 70)

The analysis results are shown in Table 13.

Dissolution rate (%)

Time (hr)

0.083

0.17

0.25

0.5

0.75

1

1.5

2

3

5

6

8

10

12

18

24

Comparative Example 1

13.8±0.6

23.1±1.1

24.9±0.9

25.6±0.9

25.9±0.7

27.2±0.9

36.9±1.0

42.0±0.5

46.9±0.6

54.6±0.6

57.7±0.6

63.3±0.6

67.3±0.6

70.3±0.7

76.3±0.7

80.6±0.7

Example 3

1.9±0.2

4.4±0.5

7.1±1.0

17.7±3.5

28.3±0.7

31.0±0.6

38.7±1.1

44.2±0.7

48.4±0.6

54.3±0.6

56.7±0.7

61.3±0.6

64.9±0.8

64.5±0.8

73.2±1.1

77.8±1.1

Example 4

5.1±10.1

14.9±2.5

23.9±1.7

28.1±0.8

32.7±0.9

38.0±0.7

43.3±1.1

46.1±1.2

50.1±1.3

57.1±1.4

59.8±1.4

64.1±1.6

67.1±1.5

69.4±1.6

74.4±1.8

78.4±1.8

According to the dissolution rate results in Table 13, it could be confirmed that the tablet of Example 3 showed significantly lowered initial drug dissolution, and in particular, the dissolution rate was 7.1% at 15 minutes of the dissolution test. On the other hand, it could be shown that the tablet of Example 4 exhibited good initial dissolution since the dissolution rate at 15 minutes of the dissolution test was 23.9%, confirming that it could be usefully utilized as a once-a-day sustained-release formulation showing an overall similar dissolution pattern to Comparative Example 1.

Experimental Example 8: Pharmacokinetic (PK) test of Examples 3 and 4

A pharmacokinetic (PK) test was performed on the tablets of Examples 3 and 4 employing the capsule of Comparative Example 1 as a reference drug, and the results are shown in Table 14 below.

Classification			Example 3	Example 4
PK	Before meals	AUC T/R	0.98(equivalent)	0.88(equivalent)
		Cmax T/R	0.69 (non-equivalent)	1.00(equivalent)
	After meals	AUC T/R	0.99(equivalent)	0.91(equivalent)
		Cmax T/R	1.06(equivalent)	0.94(equivalent)

As could be seen in Table 14 above, in a bioequivalence test employing Comparative Example 1 (Dilatrend SR Capsule 64 mg^TM) as a reference drug, the tablet of Example 3 had a C_max T/R of 0.69 before meals, which showed non-equivalence, but the tablet of Example 4 showed equivalence in all of the AUC T/R and C_max T/R values before and after meals.

Examples 5 to 7: Preparation of carvedilol sustained-release tablet

Carvedilol granules were prepared in the same manner as in Preparation Example 1, except that the primary coated granulates and the secondary coated granulates in the tablets were contained in the weight ratios as shown in Table 15 below, and carvedilol sustained-release tablets of Examples 5 to 7 were prepared in the same manner as in Example 1 in amounts shown in Table 16 below.

Nos.		Primary coated granulate	Secondary coated granulate	Talc	Total
Example 5	Amount (mg)	60.63	283.58	7.00	351.20
	Content ratio (%)	17	81	2	100%
Example 6	Amount (mg)	36.37	321.39	7.00	364.76
	Content ratio (%)	10	88	2	100%
Example 7	Amount (mg)	0	378.11	7.00	385.11
	Content ratio (%)	0	98	2	100%

Purpose of mixing	Ingredient Name	Example 5		Example 6		Example 7
		mg/T	%	mg/T	%	mg/T	%
Main ingredient	Carvedilol granule	351.20	52.89	357.76	51.11	378.11	54.02
	(as carvedilol)	64.00	-	64.00	-	64.00	-
Excipient	Silicified microcrystalline cellulose	268.70	40.47	289.04	41.29	268.70	38.39
Lubricant	Magnesium metasilicate aluminate	7.00	1.05	7.00	1.00	7.00	1.00
Disintegrant	Crospovidone	32.90	4.95	35.00	5.00	35.00	5.00
Lubricant	Glyceryl behenate	4.20	0.63	4.20	0.60	4.20	0.60
Lubricant	Talc			7.00	1.00	7.00	1.00
Total (tablet)		664.00	100.00	700.00	100.00	700.00	100.00
Coating agent	Opadry white	20.00		21.00		21.00
Total (Coating)		684.00		721.00		721.00

Experimental Example 9: Dissolution test of Examples 5 to 7

Dissolution tests for the tablets of Examples 5 to 7 were performed using the same analysis conditions as those described in Experimental Example 4 (reference drug: Dilatrend SR Capsule 64 mg^TM).

Dissolution rate (%) per hour (hr)

0.083

0.17

0.25

0.5

0.75

1

1.5

2

3

5

6

8

10

12

18

24

Reference drug

13.8±0.6

23.1±1.1

24.9±0.9

25.6±0.9

25.9±0.7

27.2±0.9

36.9±1.0

42.0±0.5

46.9±0.6

54.6±0.6

57.7±0.6

63.3±0.6

67.3±0.6

70.3±0.7

76.3±0.7

80.6±0.7

Example 5

25.9±0.8

27.9±0.7

28±0.6

30.2±0.5

34.1±0.7

38.9±0.7

46.2±0.6

49.4±0.5

53.9±0.5

61.1±0.3

64.4±0.3

69.9±0.2

73.3±0.4

76.3±0.3

82.4±0.1

87.6±0.6

Example 6

14.9±0.2

16.8±0.3

17.9±0.4

26.8±0.5

36±0.5

40.2±0.6

44.4±0.8

47.2±0.7

52.2±0.5

61.7±0.8

65.6±0.9

72.3±0.8

76.8±1

80.1±1.1

88.2±0.9

94.4±1.2

Example 7

0.5±0.1

1±0.1

2.2±0.1

12.8±0.4

24.5±0.6

30±0.5

35.2±0.6

38.6±0.6

44.8±0.8

55.5±1

60.1±0.9

67.4±1

72.5±1.3

76.6±1.1

85.9±1.5

92.9±1.5

According to the dissolution rate results in Table 17, it could be confirmed that the tablets of Examples 6 and 7 showed lowered initial drug dissolution, in particular, the dissolution rates of about 17.9% and about 2.2% at 15 minutes of the dissolution test, respectively. On the other hand, it could be shown that the tablet of Example 5 exhibited good initial dissolution since the dissolution rate at 15 minutes of the dissolution test was about 28%, and had a similar dissolution pattern to the reference drug, confirming that it could be usefully utilized as a once-a-day sustained-release formulation.

Examples 8 to 11: Preparation of carvedilol sustained-release tablet

Carvedilol sustained-release tablets of Examples 8 to 11 were prepared in the same manner as in Example 1 in amounts shown in Tables 18 and 19 below.

Purpose of mixing	Ingredient Name	Example 8		Example 9		Example 10
		mg/T	%	mg/T	%	mg/T	%
Main ingredient	Carvedilol granule	351.20	42.57	351.20	42.57	351.20	42.57
	(as carvedilol)	64.00	-	64.00	-	64.00	-
Excipient	Silicified microcrystalline cellulose	376.00	45.58	376.00	45.58	360.00	43.64
Lubricant	Magnesium metasilicate aluminate	5.30	0.64	5.30	0.64	5.30	0.64
Disintegrant	Crospovidone	42.00	5.09	-	-	16.00	1.94
Binder	Copovidone	42.00	5.09	84.00	10.18	84.00	10.18
Lubricant	Glyceryl behenate	8.50	1.03	8.50	1.03	8.50	1.03
Total (tablet)		825.00	100.00	825.00	100.00	825.00	100.00
Coating agent	Opadry white	25.00		25.00		25.00
Total (Coating)		850.00		850.00		850.00

Purpose of mixing	Ingredient Name	Example 11
		mg/T	%
Main ingredient	Carvedilol granule	351.20	41.22
	(as carvedilol)	64.00	-
Excipient	Silicified microcrystalline cellulose	360.00	42.25
Lubricant	Magnesium metasilicate aluminate	5.30	0.62
Disintegrant	Crospovidone	43.00	5.05
Binder	Copovidone	84.00	9.86
Binder	L-HPC
Lubricant	Glyceryl behenate	8.50	1.00
Total (tablet)		852.00	100.00
Coating agent	Opadry white	26.00
Total (Coating)		878.00

Experimental Example 10: Disintegration and tableting pressure tests of Examples 4, 8 to 11

The disintegration test for the tablets of Examples 4, 8 to 11 was performed according to the disintegration test method of General Test method of the Korean Pharmacopoeia.

The results are shown as follows.

Classification	Example 4	Example 8	Example 9	Example 10	Example 11
Disintegration time (min)	3-5	10	40-50	30-35	20-25
Tableting pressure (kgf)	950	1200	970	920	920

As could be confirmed in Table 20, the tablets of Examples 9-11 containing the binder in an amount exceeding 9 wt% based on the total weight of the tablet showed a significant delay in disintegration time. On the other hand, it could be confirmed that the tablets of Examples 4 and 8 containing 3% or more of the disintegrant and 9% or less of the binder based on the total weight of the tablet exhibited a desirable disintegration time of 3-5 minutes and 10 minutes.

Claims (21)

1. A sustained-release tablet comprising carvedilol granules in which the carvedilol granules are contained in an amount of 33 to 53 wt% based on the total weight of the tablet.
2. The sustained-release tablet of claim 1, wherein the sustained-release tablet has a dissolution rate of carvedilol of 20% or more and 30% or less at 15 minutes in the dissolution test with 900 mL of 0.1 mol/L HCl at 100 rpm according to Dissolution Test Method 2 of General Test method of the Korean Pharmacopoeia.
3. The sustained-release tablet of claim 1, wherein the carvedilol granule contains a primary coated granulate and a secondary coated granulate.
4. The sustained-release tablet of claim 3, wherein a weight ratio of the primary coated granulate and the secondary coated granulate is 1 : 1 to 1 : 10.
5. The sustained-release tablet of claim 3, wherein a weight ratio of the primary coated granulate and the secondary coated granulate is 1 : 2 to 1 : 6.
6. The sustained-release tablet of claim 3, wherein the primary coated granulate is coated with a drug layer containing carvedilol, a solubilizer, and a coating agent on a surface of an inert core.
7. The sustained-release tablet of claim 3, wherein the secondary coated granulate is coated with a sustained-release layer containing a sustained-release agent and a plasticizer on a surface of the primary coated granulate.
8. The sustained-release tablet of claim 1, wherein the sustained-release tablet contains a disintegrant and a binder.
9. The sustained-release tablet of claim 1, wherein the sustained-release tablet contains a disintegrant in an amount of 3 wt% or more based on the total weight of the tablet.
10. The sustained-release tablet of claim 1, wherein the sustained-release tablet contains at least any one of disintegrant selected from the group consisting of sodium starch glycolate, croscarmellose sodium, and low-substituted hydroxypropyl cellulose.
11. The sustained-release tablet of claim 1, wherein the sustained-release tablet contains low-substituted hydroxypropyl cellulose as a disintegrant.
12. The sustained-release tablet of claim 1, wherein the sustained-release tablet contains a binder in an amount of 9 wt% or less based on the total weight of the tablet.
13. The sustained-release tablet of claim 1, wherein the sustained-release tablet contains copovidone as a binder.
14. The sustained-release tablet of claim 1, wherein the sustained-release tablet contains low-substituted hydroxypropyl cellulose and copovidone.
15. The sustained-release tablet of claim 14, wherein the sustained-release tablet contains 3 wt% or more of the low-substituted hydroxypropyl cellulose, and 9 wt% or less of the copovidone, based on the total weight of the tablet.
16. The sustained-release tablet of claim 1, wherein the sustained-release tablet contains a disintegrant and a binder in a weight ratio of 1 : 1.
17. The sustained-release tablet of claim 1, wherein the sustained-release tablet contains 64 mg of carvedilol.
18. The sustained-release tablet of claim 1, wherein the sustained-release tablet has a total weight of 1000 mg or less.
19. The sustained-release tablet of claim 1, wherein a dissolution rate of the carvedilol in the sustained-release tablet exhibits the area under the plasma concentration-time curve (AUC) and the peak blood concentration (C_max) at equivalent or bioequivalent levels compared with Dilatrend SR Capsule^TM having the same active ingredient dose.
20. The sustained-release tablet of claim 1, wherein the sustained-release tablet is administered once a day.
21. A method for preparing the sustained-release tablet according to any one of claims 1 to 20, wherein the method comprises:

    preparing carvedilol granules;

    forming a mixture by mixing the carvedilol granules with an excipient, a binder, and a disintegrant; and

    adding a lubricant to the mixture, and mixing the mixture, followed by tableting and coating.