KR102545579B1 - Carvedilol sustained release tablet with improved compliance through reduction of tablet size using iLet (innovation low excipient tablet) technology - Google Patents

Abstract

The present invention relates to a sustained-release tablet containing carvedilol granules, characterized in that the carvedilol granules are included in 33 to 53% by weight of the total weight of the tablet, and a method for manufacturing the same.

Description

Carvedilol sustained release tablet with improved compliance through reduction of tablet size using iLet (innovation low excipient tablet) technology}

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

Carvedilol has “(±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine” as its chemical name. It is a drug used for hypertension and angina pectoris.

Carvedilol acts to dilate blood vessels by blocking α1 and β, and is used as a third-generation β-blocker with indications for hypertension, angina pectoris, and heart failure. Carvedilol is a drug that has excellent blood pressure lowering effect and does not have side effects such as edema, reflex tachycardia, dry cough, etc. that are frequently found in other antihypertensive drugs. Approved.

Carvedilol has two formulations, a tablet formulation and a sustained-release capsule formulation, and the dosage is different depending on the indication. In the case of carvedilol tablets, take 3.125 mg to 50 mg once or twice a day, depending on the indication, and in the case of sustained-release capsules, take 16 mg to 128 mg once a day, depending on the indication.

However, conventionally used carvedilol capsules are lighter than water and have disadvantages such as swallowing only water and not swallowing capsules when taking in actual clinical practice, or capsules sticking to the mouth. .

In addition, the dosage of carvedilol is different for each indication, and even in the same indication, the initial amount and maintenance amount are different from each other, and the amount is reduced and increased as needed. need.

As carvedilol sustained-release tablets, Dilathren SR Tablets 8mg ^TM containing 8 mg of carvedilol and Dilathrene SR Tablets 16mg ^TM containing 16 mg of carvedilol are commercially available, but since they are low-content preparations, It is necessary to develop a sustained-release tablet that contains carvedilol in an amount that can be administered once a day and at the same time has high medication compliance.

An object of the present invention is to provide a sustained-release tablet containing carvedilol granules, characterized in that the carvedilol granules are included in 33 to 53% by weight of the total weight of the tablet, and a method for producing the same. .

The present invention provides a sustained-release tablet comprising carvedilol granules, characterized in that the carvedilol granules are included in 33 to 53% by weight of the total weight of the tablet.

In the present invention, the carvedilol is (±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine as β1, It refers to a compound that has a vasodilator effect through 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 invention, carvedilol may be in the form of a free base or salt, solvate, or anhydrous form.

In the present invention, the carvedilol granules include any granules containing carvedilol without limitation.

Preferably, the carvedilol granules may include primary coated granules and secondary coated granules.

Also preferably, the carvedilol granules may include primary coated granules, secondary coated granules, and/or mixtures thereof.

Preferably, the weight ratio of the first coated granular material and the second coated granular material may be 1:1 to 1:10.

Also, preferably, the weight ratio of the first coated granular material and the second coated granular material may be 1:3 to 1:7.

The first coated granules of the present invention may be granules coated with a drug layer including carvedilol, a solubilizer and a coating agent on the surface of an inactive core.

The inactive nucleus of the present invention may be one or more selected from monosaccharides, disaccharides, polysaccharides, cellulose, microcrystalline cellulose, cellulose derivatives, and mixtures thereof commonly used as pharmaceutical excipients, preferably microcrystalline cellulose.

The solubilizing agent of the present invention is a material that contributes to increasing the water solubility of carvedilol, for example, light anhydrous silicic acid, glyceryl monooleate, docusate sodium, lauryldimethylaminoacetic acid betaine, sodium lauryl sulfate, Myristyl Alcohol, Benzalkonium Chloride, Vitamin E Polyethylene Glycol Succinate, Cetrimide, Cetylpyridinium Chloride, Sorbitan Sesquioleate, Sorbitan Ester, Sorbitan Trioleate, Phospholipid, Cocamidopropyl Betaine, Coca Mido DEA, Tricaprylin, Polysorbate, Polyoxylglyceride, Polyethylene Glycol Monostearic Acid, Polyoxyethylene Nonylphenyl Ether, Polyoxyethylene Alkyl Ester, Polyoxyethylene Sorbitan Fatty Acid Ester, Polyoxyethylene Stearate, Poly Oxyethylene castor oil, polyoxyl 40 hydrogenated castor oil, propylene glycol dilaurate, propylene glycol monolaurate, tyloxapol, TEA-cocoyl glutamate, phosphoric acid, sodium dihydrogenphosphate, calcium phosphate, citric acid, sodium citrate, ascorbic acid , sodium hydrogen sulfite, hydrochloric acid, tartaric fumaric acid, and mixtures thereof.

Preferably, the solubilizing agent included in the primary coating granules of the present invention may be phosphoric acid.

The coating agent of the present invention may be a water-soluble polymer that contributes to the formation of a coating film of the drug layer and the dispersion of the drug. Preferably, the coating agent may be selected from methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and mixtures thereof, or polyvinyl alcohol, poly One or more may be selected from vinylpyrrolidone and mixtures thereof.

Preferably, the coating agent included in the primary coated granules of the present invention may be hydroxypropylmethylcellulose.

The first coated granules of the present invention may additionally include pharmaceutical additives selected from the group consisting of solubilizers, excipients, binders, and any combination thereof.

The solubilizing agent is, for example, light anhydrous silicic acid, glyceryl monooleate, docusate sodium, lauryldimethylaminoacetic acid betaine, sodium lauryl sulfate, myristyl alcohol, benzalkonium chloride, vitamin E polyethylene glycol succinate, set Limid, cetylpyridinium chloride, sorbitan sesquioleate, sorbitan ester, sorbitan trioleate, phospholipid, cocamidopropyl betaine, cocamido DEA, tricaprylin, polysorbate, polyoxylglyceride, 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, tartrate fumaric acid, and mixtures thereof. can be chosen

Preferably, the solubilizing agent included in the first coated granules of the present invention may be polyoxyl 40 hydrogenated castor oil.

The excipient may be any disintegrant known in the art, for example, a disintegrant selected from sodium starch glycolate, pregelatinized starch, sodium croscarboxymethylcellulose, crospovidone, and mixtures thereof. can

Preferably, the excipient included in the first coated granules of the present invention may be crospovidone.

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

Preferably, the binder included in the first coated granules of the present invention may be povidone.

The second coated granules of the present invention may be granules coated with a sustained release layer containing a sustained release agent and a plasticizer on the surface of the first coated granules.

The sustained-release agent of the present invention is a release-modifying material for the controlled release of pharmacologically active substances, and as a methacrylic acid copolymer, 2-dimethylaminoethyl methacrylate, methyl methacrylate, methacrylic acid, ethyl acrylate, butyl methacrylic acid Selecting one or more of cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and mixtures thereof as a cellulose-based polymer that dissolves at pH 5.5 to pH 7.4 and a mixture thereof It can be.

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

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

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

The secondary coated granules of the present invention may additionally 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 stabilizer may be used.

The solid fat component of the present invention is included in the secondary coating granules to induce continuous controlled release of the drug, and sorbitan fatty acid ester, sucrose fatty acid ester, fatty acid, fatty acid glycerol ester, fatty alcohol, fatty acid fatty alcohol ester, fatty acid At least one may be selected from propylene glycol and mixtures thereof. Preferably, the fatty acids and fatty alcohols of the components may be selected from saturated fatty acids and saturated fatty alcohols. Specifically, the solid fat component of the present invention is hydrogenated vegetable oil, hydrogenated castor oil, hydrogenated soybean oil, hydrogenated cottonseed oil, hydrogenated coconut oil, glyceryl monostearic acid, glyceryl behenate, glyceryl palmitostearic acid, sorbitan monostearic acid, sorbitan At least one kind may be selected from monopalmitate, stearic acid, stearyl alcohol, sucrose lauric acid, sucrose stearic acid, and mixtures thereof.

Preferably, the solid fat component included as an excipient in the secondary coated granules of the present invention may be hydrogenated vegetable oil.

The stabilizer is 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, At least one selected from sodium dihydrogenphosphate, calcium phosphate, L-phenylalanine, tartaric acid, talc, tocopherol, tocopherol acetate, glucose, poloxamer, fumaric acid, sodium pyrosulfite, sulfuric acid, and mixtures thereof.

Preferably, the stabilizer included as an excipient in the secondary coated granules of the present invention may be talc.

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

The sustained-release tablet of the present invention is characterized in that it contains the carvedilol granules in 33 to 53% by weight of the total weight of the tablet.

Also, preferably, the sustained-release tablet of the present invention may contain 38 to 48% by weight of the carvedilol granules based on the total weight of the tablet.

The sustained-release tablet of the present invention includes a high content of carvedilol granules in the tablet, thereby preventing an increase in tablet size and thereby providing ease of swallowing.

The carvedilol granules of the present invention may contain 64 mg of carvedilol.

The sustained-release tablet of the present invention has a dissolution rate of 20% or more and 30% of carvedilol at 15 minutes in the dissolution test at 900 mL of 0.1 mol/L HCl, 100 rpm, according to Method 2 of the dissolution test of the General Test Methods of the Korean Pharmacopoeia. It is characterized by the following.

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

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

The disintegrant of the present invention may be included in an amount of 3% by weight or more of the total weight of the sustained-release tablet. When the disintegrant is included in an amount of less than 3% by weight, there is a concern that there is no sufficient disintegration effect or the initial drug release rate is slowed down due to delayed disintegration.

In one experimental example, in the case of the sustained-release tablet (Example 3) containing 42.6% by weight of the carvedilol granules and 1.9% by weight of the disintegrant while containing 42.6% by weight of the total weight of the tablet, the disintegration time was 35 minutes, resulting in delayed disintegration. It was confirmed (Experimental Example 3).

The binder of the present invention 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 included in the sustained-release tablet of the present invention may be copovidone.

The binder of the present invention may be included in 9% by weight or less of the total weight of the sustained-release tablet. When the binder is included in an amount of more than 9% by weight, aggregation of the granules and initial release may be reduced.

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

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

The sustained-release tablet of the present invention contains the disintegrant at 3% by weight or more of the total weight of the sustained-release tablet and the binder at 9% by weight or less of the total weight of the sustained-release tablet, thereby providing optimal disintegration time of around 10 minutes and granule aggregation An excellent dissolution pattern without initial release degradation is secured.

In one experiment, in the case of a sustained-release tablet (Example 4) containing 41.2% by weight of carvedilol granules, 5% by weight of disintegrant and 5% by weight of binder, disintegration time of 10 minutes, During the dissolution test, it was confirmed that the dissolution rate was about 23.9% at 15 minutes, indicating excellent disintegration ability and dissolution pattern (Experimental Examples 6 and 7).

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

The sustained-release tablet of the present invention contains carvedilol granules in a high content but has a small total tablet weight, so it has excellent medication convenience. It can overcome the disadvantage of having to feed capsules that are not easy to take.

The carvedilol dissolution rate of the sustained-release tablet of the present invention is equal or bioequivalent to that of Dilatren SR Capsule ^TM having the same active ingredient dose, and the area under the plasma concentration-time curve (AUC) and maximum blood concentration (C _max ) Characterized in that it represents.

Here, whether the area under the blood concentration-time curve (AUC) and the maximum blood concentration (C _max ) show bioequivalent levels can be determined according to pharmaceutical equivalence criteria. For example, when the area under the blood concentration-time curve (AUC) and the maximum blood concentration (C _max ) of the control drug and the test drug are log-converted and statistically processed according to the bioequivalence test of the Pharmaceutical Equivalence Test Criteria of the Pharmaceutical Affairs Regulations, the log In the 90 wt% confidence interval of the converted mean difference, if both items satisfy within log 0.8 ~ log 1.25, the pharmaceutical equivalence test is considered equivalent. However, as an exception to bioequivalence, 1) if the difference between log-transformed mean values of comparative evaluation items between the reference drug and the test drug is within log 0.9 to log 1.11, 2) All prescribed dissolution tests are conducted in accordance with the pharmaceutical equivalence test standard. When all of the cases are equal under the conditions, they are judged as equal.

In one experimental example, the sustained-release tablet of the present invention (Example 4) had AUC T/R before meals of 0.88 and C _max T/R of 1.00 when using Dilatren SR Capsule 64mg ^TM having the same active ingredient dose as a control drug. , postprandial AUC T/R was 0.91 and _Cmax T/R was 0.94, all four values showing equivalence (Experimental Example 8).

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

The sustained-release formulation of the present invention may further include pharmaceutically acceptable additives as needed, including additives such as pharmaceutically acceptable excipients, lubricants, coating agents, etc., within a range that does not impair the effects of the present invention. can be formulated.

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

Preferably, silicified microcrystalline cellulose may be used in the sustained-release tablet of the present invention. The excipient may be included in 10 to 67% by weight, preferably 36 to 65% by weight, more preferably 45 to 55% by weight of the total weight of the tablet.

The lubricant is added to smoothly perform the compression operation of the granules, and serves to improve the fluidity of the powder or granular material to increase filling, reduce friction, and prevent sticking of the granules.

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

Preferably, magnesium aluminometasilicate and glyceryl behenate may be used in the sustained-release tablet of the present invention.

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

In addition, the present invention comprises the steps of 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, mixing, tableting, and coating.

The step of preparing the carvedilol granules is, for example, preparing the first coated granules, performing the second coating on the first coated granules to prepare the second coated granules, and then the first coated granules Carvedilol granules may be prepared by mixing the granules with the secondary coating.

The details of the preparation method of the sustained-release formulation may be applied as it is to the description of the sustained-release formulation of the present invention. Specifically, the carvedilol granules, excipients, binders, disintegrants, and lubricants are as described above.

The method for preparing the sustained-release tablet according to the present invention may be prepared using any means and methods known in the art for the preparation method, mixing method, tableting method, and coating method of granules.

Since the sustained-release tablet of the present invention contains carvedilol granules in a high content, the size of the tablet is small and it is convenient to take. In addition, the sustained-release tablet of the present invention exhibits an appropriate disintegration rate and dissolution rate, and in particular, exhibits bioequivalence to Dilatren SR Capsule ^TM , ensuring safety and effectiveness, and fundamentally improving the inconvenient intake of conventional capsule formulations sticking to the mouth It is a once-a-day sustained-release formulation with excellent medication compliance.

Hereinafter, the present invention will be described in detail through examples and experimental examples. However, these Examples and Experimental Examples are only examples of the present invention, and the scope of the present invention is not limited only to these.

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

Preparation of primary coated granules

According to the amounts in Table 1 below, hypromellose and povidone were added to ethanol and purified water to dissolve, polyoxyl 40 hydrogenated castor oil and carvedilol were added, and after stirring and dispersing, phosphoric acid was added and left to stir to prepare a coating solution 1.

Coating solution 2 was prepared by adding ethanol and purified water and dispersing crospovidone while stirring.

Coating solution 2 was put into the coating solution 1 and mixed by stirring.

Microcrystalline cellulose was put into a fluidized bed granule coater, and the mixed coating liquid was sprayed to first coat and then dried to form the first coated granules.

division Blending purpose ingredient name Comparative Example 2 Example 1 mg/T % mg/T % 1st coating granulate chief ingredient carvedilol 16.00 26.4 64.00 26.4 solubilizing agent phosphoric acid 5.00 7.0 20.00 7.0 (as phosphoric acid) (4.25) (17) solubility 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 granules

According to the amount of Table 2 below, 75% of the first coated granules were subjected to a second coating.

Ethanol, purified water, sodium hydroxide, aqueous ammonia, triethyl citrate, glycerin fatty acid ester, and polysorbate 80 were added to dissolve with stirring, and then Eudragit L100-55 and 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 stirred to disperse to prepare coating solution 4, and coating solution 3 was stirred and dispersed.

The mixed coating liquid was sprayed on 75% of the first coated granules, and after the second coating, they were dried to form the second coated granules.

division Blending purpose ingredient name Comparative Example 2 Example 1 mg/T % mg/T % 2nd coating granulate chief ingredient 1st coating granules 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 regulator sodium hydroxide 0.09 0.1 0.34 0.1 pH regulator ammonia 0.11 0.2 0.45 0.2 Total 70.89 100.0 283.579 100.0

postmix

Carvedilol granules to be used in the preparation of tablets of Comparative Example 2 and Example 1, respectively, by putting the first coated granules, the second coated granules, and talc into a double cone mixer according to the amounts shown in Table 3 and mixing them at 15 rpm for 20 minutes. was manufactured.

division Blending purpose ingredient name Comparative Example 2 Example 1 mg/T % mg/T % postmix chief ingredient 1st coating granulate 15.16 17.3 60.63 17.3 chief ingredient 2nd coating granulate 70.89 80.7 283.58 80.7 glidant 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 Dilatren SR Capsule 64mg ^TM , which is commercially available in Korea.

Comparative Example 2 and Example 1: Preparation of Carvedilol Sustained Release Tablets

Carvedilol granules, silicified microcrystalline cellulose, and crospovidone, respectively prepared in Preparation Example 1 according to the quantities shown in Table 4 below, were put into a Bin mixer and mixed at 6 rpm for 60 minutes. Thereafter, magnesium aluminometasilicate and glyceryl behenate according to the amounts shown in Table 4 were added 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. .

Blending purpose ingredient name Comparative Example 2 Example 1 mg/T % mg/T % chief ingredient carvedilol granules 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 glidant Magnesium Metasilicate Aluminate 4.00 1.0 16.00 1.0 glidant 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 tablet of Comparative Example 2 and the tablet of Example 1 was tested according to the disintegration test method of the General Test Methods of the Korean Pharmacopoeia.

the results are as follow.

division Comparative Example 2 Example 1 Disintegration time (minutes) 5 minutes 5 minutes

Compared to Comparative Example 2, Example 1 is a tablet in which the weights of the main ingredient, excipients, disintegrants, lubricants, and coating agents contained in Example 1 are all increased 4 times as the ratio of the main ingredient. In the case of Example 1 containing 64 mg of carvedilol and containing 22% by weight of carvedilol granules, it was disintegrated over 5 minutes as in Comparative Example 2, and it was confirmed 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 capsules of Comparative Example 1, the tablets of Comparative Example 2, and the tablets of Example 1. The dissolution test was performed with 900 mL of 0.1 mol/L HCl, 100 rpm, 100 rpm, Dissolution Test Method 2 of the General Test Methods of the Korean Pharmacopoeia.

<Dissolution test analysis conditions>

- Detector: Ultraviolet absorbance photometer (measurement wavelength: 285 nm)

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

- Injection amount: 50 μl

- Flow rate: 1.5 ml/min

- Column temperature: constant temperature around 35 ℃

- Sample temperature: constant temperature around 25℃

- Mobile phase: a mixture 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 One 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 (Dilathrene SR Capsule 64mg ^TM ), the tablets of Comparative Example 2, and the tablets of Example 1 showed similar dissolution rates, confirming that the drug release behavior of carvedilol was similar. Among these, Example 1 compared to Comparative Example 2 showed an excellent dissolution pattern even though the weights of the main component, excipient, disintegrant, lubricant, and coating agent in the tablet were all increased 4 times the same as the ratio of the active ingredient. . However, since the tablet of Example 1 has a low content in which the carvedilol granules are included at 22% by weight of the total weight of the tablet, the total tablet weight is 1,648 mg, and the tablet size is large, so there is a problem in that medication compliance is reduced.

Examples 2 and 3: Carvedilol sustained-release tablets

The sustained-release tablet of Example 1 had excellent disintegration time and dissolution pattern, but the medication compliance was poor due to the large tablet size. 3 was prepared as follows.

According to the quantities shown in Table 7 below, the carvedilol granules of Example 1 prepared in Preparation Example 1, silicified microcrystalline cellulose, copovidone and crospovidone were put into a Bin mixer and mixed at 6 rpm for 60 minutes. Thereafter, magnesium aluminometasilicate and glyceryl behenate according to the amounts shown in Table 7 were added and mixed at 6 rpm for 60 minutes, followed by tableting and coating with Opadry Beige to prepare Examples 2 and 3.

Blending purpose ingredient name Example 2 Example 3 mg/T % mg/T % chief ingredient carvedilol granules 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 glidant Magnesium Metasilicate Aluminate 8.40 0.7 5.3 0.6 glidant 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 tested according to the disintegration test method of the General Test Methods of the Korean Pharmacopoeia.

the results are as follow.

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

Example 3, which has a lower weight than Example 2, has a high content ratio of carvedilol granules in one tablet, and the binding force is weakened, so that a higher tableting pressure is required to secure hardness suitable for the wearability standard (0.5% or less). Confirmed.

Accordingly, the tablet of Example 2 containing 28.8% by weight of carvedilol granules was well disintegrated over 10 minutes, whereas the tablet of Example 3 containing 42.6% by weight of carvedilol granules showed poor disintegration. It took 35 minutes to confirm that disintegration was delayed.

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

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

<Dissolution test analysis conditions>

- Detector: Ultraviolet absorbance photometer (measurement wavelength: 285 nm)

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

- Injection amount: 50 μl

- Flow rate: 1.5 ml/min

- Column temperature: constant temperature around 35 ℃

- Sample temperature: constant temperature around 25℃

- Mobile phase: a mixture 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 One 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, Comparative Example 1 (Dilathrene SR Capsule 64mg ^TM ) and the tablet of Example 2 containing 28.8% by weight of carvedilol granules showed similar dissolution patterns, but 42.6% by weight of carvedilol granules. It was confirmed that the tablet of Example 3 containing the significantly reduced initial drug dissolution. In particular, at 15 minutes of the dissolution test, Example 2 showed a dissolution rate of 20 to 30% by weight, but the tablet of Example 3 showed a dissolution rate of 7.1% by weight, confirming that the initial dissolution was reduced.

On the other hand, since the tablet of Example 2 contains 28.8% by weight of the carvedilol granules of the total weight of the tablet, which is still relatively low, the total weight of the tablet is 1,257 mg, and the tablet size is large, so there is a problem of reduced medication compliance.

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

A PK test was performed on the tablets of Examples 2 and 3 using the capsule of Comparative Example 1 as a control drug, and the results are shown in Table 10 below.

division Example 2 Example 3 PK ceremony AUC T/R - 0.98 (equivalent) C _max T/R - 0.69 (non-equivalent) after meal AUC T/R 0.99 (equivalent) 0.99 (equivalent) C _max T/R 0.95 (equivalent) 1.06 (equivalent)

As can be seen in Table 10 above, the tablet of Example 3 containing ^42.6 % by weight of carvedilol granules showed C _max T /R was 0.69, indicating inequality.

Example 4: Carvedilol sustained-release tablet

According to the quantities shown in Table 11 below, 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 and mixed at 6 rpm for 60 minutes. Thereafter, magnesium metasilicate and glyceryl behenate according to the amounts shown in Table 11 were added and mixed at 6 rpm for 60 minutes, followed by tableting and coating with Opadry Beige to prepare Example 4.

Blending purpose ingredient name Example 4 mg/T % chief ingredient carvedilol granules 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 glidant Magnesium metasilicate aluminate 5.30 0.6 glidant 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 tested according to the disintegration test method of the General Test Methods of the Korean Pharmacopoeia.

the results are as follow.

division Example 3 Example 4 Disintegration time (minutes) 35 minutes 10 minutes Tableting pressure (kgf) 1,140 950

By using low-substituted hydroxypropyl cellulose as a fibrous disintegrant, it was possible to maintain binding force and increase disintegration force. Although the amount of binder was reduced, the disintegration time was shortened because the compression pressure was lowered. Accordingly, the tablet of Example 3 containing 42.6% by weight of carvedilol granules, 10.2% by weight of binder, and 1.9% by weight of disintegrant took 35 minutes to disintegrate, resulting in delayed disintegration, whereas 41.2% by weight of carvedilol granules It was confirmed that the tablet of Example 4 containing 5% by weight of the binder and 5% by weight of the disintegrant was well disintegrated with a disintegration time of 10 minutes.

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

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

<Dissolution test analysis conditions>

- Detector: Ultraviolet absorbance photometer (measurement wavelength: 285 nm)

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

- Injection amount: 50 μl

- Flow rate: 1.5 ml/min

- Column temperature: constant temperature around 35 ℃

- Sample temperature: constant temperature around 25℃

- Mobile phase: a mixture 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 One 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, the tablet of Example 3 had a significantly lower initial dissolution of the drug, and in particular, a dissolution rate of 7.1% was confirmed at 15 minutes of the dissolution test. On the other hand, the tablet of Example 4 showed a dissolution rate of 23.9% at 15 minutes of the dissolution test, confirming that the initial dissolution occurred well, and was useful as a sustained-release formulation once a day showing a dissolution pattern similar to Comparative Example 1 overall. It was confirmed that it can be used.

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

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

division Example 3 Example 4 PK ceremony AUC T/R 0.98 (equivalent) 0.88 (equivalent) C _max T/R 0.69 (non-equivalent) 1.00 (equivalent) after meal AUC T/R 0.99 (equivalent) 0.91 (equivalent) C _max T/R 1.06 (equivalent) 0.94 (equivalent)

As can be seen in Table 14 above, in the bioequivalence test using Comparative Example 1 (Dilathrene SR Capsule 64mg ^TM ) as a control drug, the tablet of Example 3 showed inequality with a pre-meal _Cmax T/R of 0.69, but , The tablets of Example 4 showed equivalence in both AUC T/R and C _max T/R values before and after meals.

Claims (20)

A sustained-release tablet comprising carvedilol granules, a disintegrant and a binder, wherein the carvedilol granules are contained in 33 to 53% by weight of the total weight of the tablet,
The carvedilol granules include primary coated granules and secondary coated granules,
The first coated granules are characterized in that a drug layer containing carvedilol, a solubilizer and a coating agent is coated on the surface of the inactive core,
The secondary coated granules are characterized in that a sustained release layer containing a sustained release agent and a plasticizer is coated on the surface of the primary coated granules,
The disintegrant is included in 3% by weight or more of the total weight of the tablet,
The binder is included in 9% by weight or less of the total weight of the tablet,
The disintegrant is at least one selected from the group consisting of sodium starch glycolate, sodium croscarmellose and low-substituted hydroxypropyl cellulose,
The binder is selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, povidone, copovidone, macrogol, and any combination thereof,
The sustained-release tablet is prepared by mixing carvedilol granules with an excipient, a disintegrant and a binder. The method according to claim 1, wherein the sustained-release tablet has a dissolution rate of 20 at 15 minutes when dissolution test is performed at 900 mL of 0.1 mol/L HCl and 100 rpm according to Method 2 of the dissolution test of the General Test Methods of the Korean Pharmacopoeia. % or more and 30% or less, sustained-release tablet. delete The sustained-release tablet according to claim 1, wherein the weight ratio of the first coated granulate and the second coated granulate is 1:1 to 1:10. delete delete delete delete delete The sustained-release tablet according to claim 1, wherein the sustained-release tablet contains low-substituted hydroxypropyl cellulose as a disintegrant. delete The sustained-release tablet according to claim 1, wherein the sustained-release tablet contains copovidone as a binder. The sustained-release tablet according to claim 1, wherein the sustained-release tablet contains low-substituted hydroxypropyl cellulose and copovidone. The sustained-release tablet according to claim 13, wherein the low-substituted hydroxypropyl cellulose is contained in an amount of 3 wt% or more and the copovidone is included in an amount of 9 wt% or less based on the total weight of the tablet. The sustained-release tablet according to claim 1, wherein the sustained-release tablet contains a disintegrant and a binder in a weight ratio of 1:1. The sustained-release tablet according to claim 1, wherein the sustained-release tablet contains 64 mg of carvedilol. The sustained-release tablet according to claim 1, wherein the total weight of the tablet is 1000 mg or less. The method of claim 1, wherein the sustained-release tablet has an equivalent or bioequivalent level of area under the plasma concentration-time curve (AUC) and peak blood compared to Dilatren SR Capsule ^TM having the same active ingredient dose. A sustained-release tablet, characterized in that it exhibits a concentration (C _max ). The sustained-release tablet according to claim 1, wherein the sustained-release tablet is administered once a day. 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, mixing, tableting, and coating the mixture according to any one of claims 1, 2, 4, 10, and 12 to 19. Manufacturing method of sexual tablets.