Carvedilol tablets and a preparation method thereof

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and discloses a carvedilol tablet and a preparation method thereof. The carvedilol tablet is prepared by the following method: (1) Carvedilol is granulated with a partial first binder solution to obtain first granules; (2) The obtained first granules are coated with a second binder solution to obtain second granules; (3) A first filler, a second filler, a first disintegrant and the second granules are granulated with the remaining first binder solution to obtain third granules; (4) The obtained third granules are mixed with a second disintegrant; the obtained mixture is mixed with a lubricant; tableting and coating are carried out; the first binder is polyvinyl alcohol, and the second binder is hypromellose. In the present invention, the carvedilol active ingredient is granulated with an aqueous solution of polyvinyl alcohol and then coated with an isolating layer, so as to avoid the direct contact between carvedilol and lactose and corn starch while not affecting the release of the active ingredient, greatly improving the stability of the product.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a stable carvedilol tablet and a preparation method thereof. Background Art

[0002] Carvedilol, chemically named 1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]-2-propanol, is a third-generation non-selective adrenergic β-receptor blocker that also blocks α1, β1, and β2 receptors. Clinically, it is used for the treatment of primary hypertension, angina pectoris, and heart failure. With the in-depth research, carvedilol has also been found to have cardiovascular protection, antioxidant, and calcium ion channel blocking effects.

[0003] The carvedilol tablet was first developed by Roche and launched in the United States in 1990. Starch, sucrose, and lactose are widely used fillers in the pharmaceutical industry, and lactose has excellent fluidity, low hygroscopicity, and compressibility. Lactose was used as a filler in the original preparation. However, lactose is prone to directly react with the active substance carvedilol to occur the Maillard reaction, resulting in drug degradation and generating corresponding impurities. Such impurities often continue to increase during the stability study, bringing risks to the quality control of the preparation.

[0004] Chinese Patent Application No. CN201310682021.1 discloses a preparation method of a carvedilol tablet, using lactose as a filler, poloxamer as a surfactant, starch as a binder, talc as a lubricant, and microcrystalline silica as a glidant. After mixing evenly, it is added to a tableting machine to be pressed into tablets, which has the characteristics of rapid release. However, when carvedilol is directly mixed and contacted with lactose, the Maillard reaction is likely to occur to generate impurities.

[0005] Chinese Patent Application No. CN201410447344.7 discloses a preparation process of a carvedilol tablet by a wet granulation process, using microcrystalline cellulose and sodium carboxymethyl starch as a filler and a disintegrant respectively. After premixing, sodium dodecyl sulfate is dissolved in a starch paste as a binder. After wet granulation, the dry granules are mixed with the lubricant magnesium stearate and pressed into tablets. The starch paste as a binder is directly contacted with carvedilol to prepare the soft material, and the high-temperature and high-humidity environment in the drying step makes the Maillard reaction likely to occur during the preparation process to generate impurities.

[0006] Chinese Patent Application No. CN201410736946.4 discloses a preparation method of a freeze-dried tablet of a carvedilol composition. Carvedilol is added to a corn starch-sucrose solution and vacuum freeze-dried to obtain the freeze-dried tablet. The excipients starch and sucrose are both prone to react with carvedilol to generate corresponding impurities.

[0007] The structures of three impurities generated from the Maillard reaction between carvedilol and lactose are as follows Figure 1 shown. The presence of these three impurities will affect the quality of the preparation, reduce the content of carvedilol and the therapeutic effect of the preparation. In summary, in the existing preparation process, the direct contact between lactose, starch or sucrose as fillers and carvedilol increases the risk of generation and increase of Maillard impurities. The research results of the present inventors show that in conventional tablets under high temperature of 60 °C and high temperature and high humidity conditions of 60 °C + RH 75%, Maillard impurities will increase significantly. Therefore, it is necessary to develop a preparation process for carvedilol tablets that avoids the direct contact between carvedilol and lactose to ensure and improve the quality of the preparation and reduce the risk of impurity control. There have been no publicly reported preparation methods and patents for carvedilol tablets that reduce the content of impurities generated by the Maillard reaction before. Summary of the Invention

[0008] Object of the Invention: The technical problem to be solved by the present invention is to provide a carvedilol tablet and a preparation method thereof in view of the deficiencies of the prior art.

[0009] To solve the above technical problems, the present invention discloses the following technical solutions:

[0010] In the first aspect, the present invention discloses a carvedilol tablet.

[0011] Among them, the carvedilol tablet is prepared by the following method, and the method includes:

[0012] (1) Carvedilol is granulated with a partial first binder solution to obtain a first granule;

[0013] (2) The obtained first granule is coated with a second binder solution to obtain a second granule;

[0014] (3) The first filler, the second filler, the first disintegrant and the second granule are granulated with the remaining first binder solution to obtain a third granule;

[0015] (4) The obtained third granule is mixed with the second disintegrant; the obtained mixture is mixed with a lubricant; tableting and coating are carried out.

[0016] In the second aspect, the present invention discloses a preparation method of a carvedilol tablet, including:

[0017] (1) Carvedilol is granulated with a partial first binder solution to obtain a first granule;

[0018] (2) The obtained first granule is coated with a second binder solution to obtain a second granule;

[0019] (3) The first filler, the second filler, the first disintegrant and the second granule are granulated with the remaining first binder solution to obtain a third granule;

[0020] (4)The obtained third particles are mixed with the second disintegrant; the obtained mixture is mixed with the lubricant; tablet pressing and coating are carried out.

[0021] In the above first aspect and second aspect,

[0022] In step (1), the particle size D of the carvedilol 90 is 10 μm to 80 μm, such as 20 μm and 70 μm; in some embodiments, the carvedilol is sieved through a 40-mesh sieve before use.

[0023] In step (1), the first binder is polyvinyl alcohol, and the solid content of the first binder solution is 8% - 12%, such as 10%.

[0024] In step (1), the partial first binder is 20% - 40% of the total mass of the first binder, such as 25%, 30%, and 35%.

[0025] In step (1), the granulation is carried out in a fluidized bed. The carvedilol is placed in the fluidized bed, and when the temperature reaches above 35°C, a partial first binder solution is added for top-spray granulation; in some embodiments, when the temperature reaches above 40°C, a partial first binder solution is added for top-spray granulation; in some embodiments, the spraying speed is 5 - 19 rpm, such as 12 rpm.

[0026] In step (2), the second binder is hydroxypropyl methylcellulose.

[0027] In step (2), the coating is carried out in a fluidized bed. The first particles are placed in the fluidized bed, and when the temperature reaches above 40°C, a partial first binder solution is added for bottom-spray coating; in some embodiments, when the temperature reaches above 45°C, a partial first binder solution is added for bottom-spray coating; in some embodiments, the spraying speed is 5 - 19 rpm, such as 14 rpm.

[0028] In step (3), the first filler is lactose; the second filler is corn starch and / or mannitol.

[0029] In step (3), the first disintegrant is low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, cross-linked povidone, or a combination of any several of the foregoing, preferably low-substituted hydroxypropyl cellulose.

[0030] In step (3), the first filler, the second filler, and the first disintegrant are first sieved through a 20 - 28-mesh sieve to obtain a mixture, and then granulated with the second particles; in some embodiments, the first filler, the second filler, and the first disintegrant are sieved through a 24-mesh sieve.

[0031] In step (3), the granulation is performed in a fluidized bed. The mixture of the first filler, the second filler, and the first disintegrant and the second particles are placed in the fluidized bed. When the temperature reaches above 35°C, the remaining first binder solution is added for top-spray granulation; in some embodiments, when the temperature reaches above 40°C, the remaining first binder solution is added for top-spray granulation; in some embodiments, the spraying speed is 5 - 19 rpm, such as 12 rpm.

[0032] In step (4), the second disintegrant is low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose cross-linked, sodium carboxymethyl starch, crospovidone, or a combination of any several of the foregoing, preferably sodium carboxymethylcellulose cross-linked. In some embodiments, the second disintegrant passes through a 35 - 42 mesh sieve, such as passing through a 40 mesh sieve.

[0033] In step (4), the third particles and the second disintegrant are mixed in a mixer; the rotation speed of the mixer is 5 - 19 rpm, such as 12 rpm; the mixing time is 3 - 8 min, such as 5 min.

[0034] In step (4), the lubricant is selected from magnesium stearate, talc, calcium stearate, zinc stearate, sodium fumarate stearate, or a combination of any several of the foregoing. In some embodiments, the lubricant passes through an 80 mesh sieve.

[0035] In step (4), for tabletting, the control of the tablet weight variation is ±3%, and the hardness is 2 - 6 kg, such as 2.5 - 4 kg.

[0036] In some embodiments, the weight parts of each component in the carvedilol tablets are as follows: carvedilol 10 parts, the first filler 75 - 95 parts, the second filler 13 - 44 parts, the first disintegrant 9 - 13 parts, the second disintegrant 0.9 - 2.1 parts, the first binder 4 - 7 parts, the second binder 1.4 - 2.6 parts, the lubricant 1.4 - 2.6 parts, the coating powder 3.9 - 5.1 parts; in some embodiments, the weight parts of each component in the carvedilol tablets are as follows: carvedilol 10 parts, the first filler 80 - 90 parts, the second filler 23.5 - 33.5 parts, the first disintegrant 10 - 12 parts, the second disintegrant 1.2 - 1.8 parts, the first binder 5 - 6 parts, the second binder 1.7 - 2.3 parts, the lubricant 1.7 - 2.3 parts, the coating powder 4.2 - 4.8 parts.

[0037] In some embodiments, the method includes:

[0038] (1) In a fluidized bed, carvedilol is subjected to top-spray granulation with a part of the first binder solution to obtain first particles;

[0039] (2) In a fluidized bed, the obtained first particles are subjected to bottom-spray coating with the second binder solution to obtain second particles;

[0040] (3) In a fluidized bed, the second particles, and a mixture of the first filler, the second filler and the first disintegrant that has passed through a 20 - 28 mesh sieve are granulated by top - spraying with the remaining first binder solution to obtain the third particles;

[0041] (4) The obtained third particles are mixed with the second disintegrant; the obtained mixture is mixed with the lubricant; compression - molding and coating are carried out;

[0042] In step (1), the partial first binder is 20% - 40% of the total mass of the first binder;

[0043] The solid contents of the first binder solution and the second binder solution are independently selected from 8% - 12%;

[0044] The first binder is polyvinyl alcohol, and the second binder is hydroxypropyl methylcellulose.

[0045] In some embodiments, after coating, it is packaged with a solid pharmaceutical composite hard sheet of polyvinyl chloride / polyvinylidene chloride and pharmaceutical aluminum foil.

[0046] The carvedilol tablets are prepared by the above - mentioned method in the present invention. The growth rate of Maillard reaction impurities in this tablet is slower than that of conventional tablets under the conditions of 0 day, 60 °C high temperature, and 60 °C + RH75% high temperature and high humidity. Its stability is better than that of conventional tablets, and it can dissolve rapidly.

[0047] Beneficial effects:

[0048] The stable carvedilol tablets provided by the present invention are composed of an active ingredient carvedilol, a filler, a binder, a disintegrant, a lubricant, and a coating material. In the present invention, the carvedilol active ingredient is granulated with an aqueous solution of polyvinyl alcohol and then coated with a barrier layer to avoid the direct contact between carvedilol and lactose and corn starch while not affecting the release of the active ingredient, greatly improving the stability of the product. Description of the Drawings

[0049] The following further specifically describes the present invention in conjunction with the drawings and specific embodiments, and the above - mentioned and / or other advantages of the present invention will become clearer.

[0050] Figure 1 Structures of three impurities generated by the Maillard reaction between carvedilol and lactose.

[0051] Figure 2 Dissolution curves of the preparations obtained in Example 1 and Comparative Examples 1 - 3 in 0.1M hydrochloric acid.

[0052] Figure 3 Dissolution curves of the preparations obtained in Example 1 and Comparative Example 1 in pH1.2.

[0053] Figure 4 Dissolution curves of the preparations obtained in Example 1 and Comparative Example 1 at pH 4.0. Detailed implementation manners

[0054] The present invention can be better understood according to the following examples. However, those skilled in the art can easily understand that the content described in the examples is only used to illustrate the present invention and should not and will not limit the present invention described in detail in the claims.

[0055] In the following examples, unless otherwise specified, the experimental methods are all conventional methods; unless otherwise specified, the reagents and materials can all be obtained from commercial channels.

[0056] In the following examples, the lactose is GranuLac 200 (200 mesh) of German Merck KGaA, the manufacturer of corn starch is Anhui Shanhe, the low-substituted hydroxypropyl cellulose is the low-substituted hydroxypropyl cellulose of Shin-Etsu Chemical Co., Ltd. (model LH-21), the hydroxypropyl methylcellulose is the hydroxypropyl methylcellulose of DuPont Co., Ltd. (model E5), the polyvinyl alcohol is the polyvinyl alcohol of Japan Vam Poral Co., Ltd. (model PE-05JPS), and the coating powder is the gastric-soluble film coating premix 03F630028-CN of Colorcon Co., Ltd.

[0057] The solid content described in the present invention is in mass percentage.

[0058] Example 1

[0059] The preparation method of carvedilol tablets, when producing 10,000 tablets, includes the following steps:

[0060] (1) Weighing and sieving: Weigh each raw material and auxiliary material according to the weight ratio.

[0061] 10 parts of carvedilol, 85 parts of lactose, 28.5 parts of corn starch, 11 parts of low-substituted hydroxypropyl cellulose, 1.5 parts of cross-linked carboxymethyl cellulose sodium, 5.5 parts of polyvinyl alcohol, 2.0 parts of hydroxypropyl methylcellulose, 2.0 parts of magnesium stearate, 4.5 parts of coating powder.

[0062] Among them, lactose, corn starch, and low-substituted hydroxypropyl cellulose are sieved together through 24 meshes to obtain a lactose-corn starch-low-substituted hydroxypropyl cellulose mixture; cross-linked carboxymethyl cellulose sodium is sieved through 40 meshes; magnesium stearate is sieved through 80 meshes; the D90 of carvedilol is 20 - 70 μm and it is sieved through 40 meshes.

[0063] (2) Granulation of API: Take 30% of the formulated amount of polyvinyl alcohol, add water to prepare a binder solution with a solid content of 10%; place the formulated amount of carvedilol in a fluidized bed, start adding the binder solution for top-spray granulation when the temperature reaches above 40°C, and the spraying speed is 12 rpm to obtain carvedilol polyvinyl alcohol granules.

[0064] (3) Coating of particle isolation layer: Take the formulated amount of hypromellose, add water to prepare an isolation coat solution with a solid content of 10%; place the carvedilol polyvinyl alcohol granules in a fluidized bed, start adding the isolation coat solution for bottom-spray coating when the temperature reaches above 45°C, and the spraying speed is 14 rpm to obtain carvedilol polyvinyl alcohol hypromellose granules.

[0065] (4) Top-spray granulation: Take 70% of the formulated amount of polyvinyl alcohol, add water to prepare a binder solution with a solid content of 10%; place the mixture of carvedilol polyvinyl alcohol hypromellose granules, lactose, corn starch, and low-substituted hydroxypropyl cellulose in a fluidized bed, start adding the binder solution for top-spray granulation when the temperature reaches above 40°C, and the spraying speed is 12 rpm to obtain intermediate granules A.

[0066] (5) Mixing: Sequentially add the intermediate granules A from step (4) and the cross-linked carboxymethyl cellulose sodium from step (1) into a mixer and mix at 12 revolutions per minute for 5 minutes.

[0067] (6) Lubrication: Add magnesium stearate to the mixture obtained in step (5) and mix at 12 revolutions per minute for 3 minutes, and sample to detect the content of intermediate B.

[0068] (7) Tabletting: Install the intermediate B obtained in step (6) in a mold, calculate the tablet weight to be pressed according to the result of the content of intermediate B, and control the tablet weight difference within ±3% and the hardness within 2.5 kg to 4.0 kg.

[0069] (8) Coating: Place the plain tablets obtained in step (7) in a coating pan for coating, and the coating weight gain is 2% to 3%.

[0070] (9) Packaging: Use polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil for packaging.

[0071] Comparative Example 1

[0072] Replace the preparation method with ordinary one-step granulation. When producing 10,000 tablets, it includes the following steps:

[0073] (1) Weighing and sieving: Weigh each raw material and auxiliary material according to the weight ratio.

[0074] 10 parts of carvedilol, 87 parts of lactose, 28.5 parts of corn starch, 11 parts of low-substituted hydroxypropyl cellulose, 1.5 parts of cross-linked carboxymethyl cellulose sodium, 5.5 parts of polyvinyl alcohol, 2.0 parts of magnesium stearate, 4.5 parts of coating powder.

[0075] Among them, lactose, corn starch, and low-substituted hydroxypropyl cellulose are passed through a 24-mesh sieve together to obtain a lactose-corn starch-low-substituted hydroxypropyl cellulose mixture. Cross-linked carboxymethyl cellulose sodium is passed through a 40-mesh sieve, and magnesium stearate is passed through an 80-mesh sieve. The D90 of carvedilol is 20 - 70 μm and it is passed through a 40-mesh sieve.

[0076] (2) Top-spray granulation: Take the polyvinyl alcohol in step (1), add water to prepare a binder solution with a solid content of 10%; premix carvedilol and the lactose-corn starch-low-substituted hydroxypropyl cellulose mixture in a wet granulator, then place the mixture in a fluidized bed. When the temperature reaches above 40°C, start adding the binder solution for top-spray granulation, and the spraying speed is 12 rpm to obtain intermediate granules A.

[0077] (3) Mixing: Sequentially add the intermediate granules A from step (2) and the cross-linked carboxymethyl cellulose sodium from step (1) into a mixer and mix at 12 revolutions per minute for 5 minutes.

[0078] (4) Lubrication: Add magnesium stearate to the mixture obtained in step (3) and mix at 12 revolutions per minute for 3 minutes, and take a sample to detect the content of intermediate B.

[0079] (5) Tabletting: Install the intermediate B obtained in step (4) in a mold, calculate the tablet weight to be pressed according to the result of the content of intermediate B, and control the tablet weight difference within ±3% and the hardness within 2.5 kg - 4.0 kg.

[0080] (6) Coating: Place the plain tablets obtained in step (5) in a coating pan for coating, and the coating weight gain is 2% - 3%.

[0081] (7) Packaging: Use polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil for packaging.

[0082] Example 2

[0083] Same as Example 1, the difference is that 5.5 parts of polyvinyl alcohol and 2.0 parts of hydroxypropyl methylcellulose are replaced with other binders, specifically as follows:

[0084] Example 2-1, replaced with 5.5 parts of polyvinyl alcohol and 2.0 parts of polyvinylpyrrolidone;

[0085] Example 2-2, replaced with 5.5 parts of hydroxypropyl cellulose and 2.0 parts of hydroxypropyl methylcellulose.

[0086] Example 3

[0087] Same as Example 1, except that 11 parts of low-substituted hydroxypropyl cellulose and 1.5 parts of cross-linked carboxymethyl cellulose sodium are replaced with other disintegrants, specifically as follows:

[0088] Example 3-1: Replace with 11 parts of sodium carboxymethyl starch and 1.5 parts of cross-linked carboxymethyl cellulose sodium;

[0089] Example 3-2: Replace with 11 parts of low-substituted hydroxypropyl cellulose and 1.5 parts of cross-linked povidone.

[0090] Example 4

[0091] Same as Example 1, except that the amounts of each component are different, specifically as follows:

[0092] Example 4-1: Carvedilol 10 parts, lactose 75 parts, corn starch 43.8 parts, low-substituted hydroxypropyl cellulose 9 parts, cross-linked carboxymethyl cellulose sodium 0.9 parts, polyvinyl alcohol 4 parts, hypromellose 1.4 parts, magnesium stearate 1.4 parts, coating powder 4.5 parts.

[0093] Example 4-2: Carvedilol 10 parts, lactose 95 parts, corn starch 13.2 parts, low-substituted hydroxypropyl cellulose 13 parts, cross-linked carboxymethyl cellulose sodium 2.1 parts, polyvinyl alcohol 7 parts, hypromellose 2.6 parts, magnesium stearate 2.6 parts, coating powder 4.5 parts.

[0094] Example 4-3: Carvedilol 10 parts, lactose 105 parts, corn starch 8.5 parts, low-substituted hydroxypropyl cellulose 6 parts, cross-linked carboxymethyl cellulose sodium 6.5 parts, polyvinyl alcohol 5.5 parts, hypromellose 2.0 parts, magnesium stearate 2.0 parts, coating powder 4.5 parts.

[0095] Example 4-4: Carvedilol 10 parts, lactose 105 parts, corn starch 8.5 parts, low-substituted hydroxypropyl cellulose 11 parts, cross-linked carboxymethyl cellulose sodium 1.5 parts, polyvinyl alcohol 5.5 parts, hypromellose 2.0 parts, magnesium stearate 2.0 parts, coating powder 4.5 parts.

[0096] Comparative Example 2

[0097] Same as Example 1, except that step (5) is omitted, and cross-linked carboxymethyl cellulose sodium is directly added in step (4), that is

[0098] (4) Top-spray granulation: Take 70% of the formula amount of polyvinyl alcohol and add water to prepare a binder solution with a solid content of 10%; Place the carvedilol polyvinyl alcohol hypromellose granules, lactose corn starch low-substituted hydroxypropyl cellulose mixture, and cross-linked carboxymethyl cellulose sodium in a fluidized bed. When the temperature reaches above 40°C, start adding the binder solution for top-spray granulation, and the spraying speed is 12 rpm to obtain intermediate granules A.

[0099] Comparative Example 3

[0100] Same as Example 1, except that the particle size of carvedilol is different. The D90 of carvedilol is 100 - 150 μm and it passes through 40 mesh.

[0101] Test 1

[0102] By measuring the multi - medium dissolution curves of the samples prepared in Example 1 and Comparative Example 1, in 0.1M hydrochloric acid solution, pH1.2 hydrochloric acid solution medium, pH4.0 sodium acetate - acetic acid buffer solution, and 900 ml, it was measured at 37°C using the dissolution apparatus 1 of the Chinese Pharmacopoeia. The experimental results are shown in Table 1 and Figures 2-4 As shown, the dissolution curves of the samples prepared in Example 1 and Comparative Example 1 of the present invention are relatively similar in different media and are all rapid dissolution. After the disintegrant cross - linked carboxymethylcellulose sodium in Comparative Example 2 became internal addition, and after the particle size of the raw material drug in Comparative Example 3 increased, the dissolution rates of the preparations obtained in Comparative Example 2 and Comparative Example 3 both became slower.

[0103] Table 1 Dissolution (%) of the preparations obtained in Example 1 and Comparative Example 1 in different media

[0104]

[0105] Test 2

[0106] The coated tablets prepared in the above - mentioned Example 1 and Comparative Example 1 were simultaneously studied for the effects of factors (high temperature 60°C, high temperature and high humidity 60°C + RH75%) on the comparison of appearance, related substances, and content. The detection method for related substances was area normalization method. HPLC method: Chromatographic column: Kromasil 100 - 5 - C18 4.6×250mm, 5μm; Mobile phase A: 0.1% formic acid; Mobile phase B: acetonitrile; Column temperature: 35°C; Flow rate: 1.0 ml / min; Injection volume: 10 μL; Diluent: 0.1% formic acid - acetonitrile (75:25); Sample concentration: 1.0 mg / ml; The gradient is as shown in Table 2 below.

[0107] Table 2

[0108]

[0109] Sample preparation: Take 2 carvedilol tablets and place them in a 20 ml volumetric flask, add diluent, shake and ultrasonicate for 15 min, make up the volume with diluent, shake well, filter with a 0.45 μm nylon membrane, discard the first 2 ml of the filtrate, and take the subsequent filtrate to obtain the sample.

[0110] The results show that the appearance of the products in Example 1 and Comparative Example 1 at each time point is similar. The content in Example 1 is higher than that in Comparative Example 1 on the 10th day and the 30th day, and the change trend of related substances in Example 1 is significantly better than that in Comparative Example 1, as shown in Table 3 below.

[0111] Table 3

[0112]

[0113] Other examples and comparative examples were detected according to Test 2, and the results are shown in Table 4. The impurities in Example 2 after replacing the binder were significantly higher than those in Example 1; the impurities in Example 3 after replacing the disintegrant were not significantly affected; the impurities in Examples 4-1 and 4-2 were not significantly affected, and the impurities in Examples 4-3 and 4-4 were slightly higher than those in Example 1; the impurities in Comparative Example 2 where the disintegrant cross-linked carboxymethyl cellulose sodium was changed to internal addition were not significantly affected; the impurities in Comparative Example 3 with an increased particle size of the active ingredient were slightly higher than those in Example 1.

[0114] Impurity content of each group / (%)

[0115]

[0116] The above-described examples only represent several embodiments of the present invention, and the description thereof is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent for the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention shall be subject to the appended claims.

Claims

1. A carvedilol tablet, characterized in that, The weight parts of each component in the carvedilol tablets are as follows: carvedilol 10 parts, first filler 75 - 95 parts, second filler 13 - 44 parts, first disintegrant 9 - 13 parts, second disintegrant 0.9 - 2.1 parts, first binder 4 - 7 parts, second binder 1.4 - 2.6 parts, lubricant 1.4 - 2.6 parts, coating powder 3.9 - 5.1 parts; The first filler is lactose; the second filler is corn starch and / or mannitol; the first disintegrant and the second disintegrant are independently selected from low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, cross-linked povidone, or any combination of the foregoing; the first binder is polyvinyl alcohol, and the second binder is hypromellose; The particle size D of carvedilol 90 is 10 μm to 80 μm; The carvedilol tablets are prepared by the following method, which includes: (1) Carvedilol is granulated with a partial first binder solution to obtain first granules; (2) The obtained first granules are coated with a second binder solution to obtain second granules; (3) The first filler, the second filler, the first disintegrant and the second granules are granulated with the remaining first binder solution to obtain third granules; (4) The obtained third granules are mixed with the second disintegrant to obtain a mixture; the obtained mixture is mixed with the lubricant; tableting and coating are carried out; In step (1), the partial first binder is 20% - 40% of the total mass of the first binder.

2. A preparation method of carvedilol tablets, characterized in that, The weight parts of each component in the carvedilol tablets are as follows: carvedilol 10 parts, first filler 75 - 95 parts, second filler 13 - 44 parts, first disintegrant 9 - 13 parts, second disintegrant 0.9 - 2.1 parts, first binder 4 - 7 parts, second binder 1.4 - 2.6 parts, lubricant 1.4 - 2.6 parts, coating powder 3.9 - 5.1 parts; The first filler is lactose; the second filler is corn starch and / or mannitol; the first disintegrant and the second disintegrant are independently selected from low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, cross-linked povidone, or any combination of the foregoing; the first binder is polyvinyl alcohol, and the second binder is hypromellose; The particle size D of the carvedilol 90 is 10 μm to 80 μm; The preparation method includes: (1) Carvedilol is granulated with a partial first binder solution to obtain first granules; (2) The obtained first granules are coated with a second binder solution to obtain second granules; (3) The first filler, the second filler, the first disintegrant and the second granules are granulated with the remaining first binder solution to obtain third granules; (4) The obtained third granules are mixed with the second disintegrant to obtain a mixture; the obtained mixture is mixed with the lubricant; tableting and coating are carried out; In step (1), the partial first binder is 20% - 40% of the total mass of the first binder.

3. The carvedilol tablets according to claim 1 or the method according to claim 2, characterized in that, The particle size D of the carvedilol 90 is 20 μm to 70 μm.

4. The carvedilol tablets according to claim 1 or the method according to claim 2, wherein The first disintegrant is low-substituted hydroxypropyl cellulose, and the second disintegrant is cross-linked carboxymethyl cellulose sodium.

5. The carvedilol tablets according to claim 1 or the method according to claim 2, characterized in that, The lubricant is selected from magnesium stearate, talc, calcium stearate, zinc stearate, sodium fumarate stearate or any combination of the foregoing.

6. The carvedilol tablets according to claim 1 or the method according to claim 2, characterized in that The solid content of the first binder solution is 8 - 12%wt.

7. The carvedilol tablets according to claim 1 or the method according to claim 2, characterized in that, In step (1), the granulation is performed in a fluidized bed. Carvedilol is placed in the fluidized bed, and when the temperature reaches above 35°C, part of the first binder solution is added for top-spray granulation.

8. The carvedilol tablets according to claim 1 or the method according to claim 2, characterized in that, In step (3), the granulation is performed in a fluidized bed. A mixture of the first filler, the second filler, and the first disintegrant and the second granules are placed in the fluidized bed, and when the temperature reaches above 35°C, the remaining first binder solution is added for top-spray granulation.

9. The carvedilol tablets according to claim 1 or the method according to claim 2, characterized in that The method comprises: (1) In a fluidized bed, carvedilol is subjected to top-spray granulation with part of the first binder solution to obtain first granules; (2) In a fluidized bed, the obtained first granules are subjected to bottom-spray coating with a second binder solution to obtain second granules; (3) In a fluidized bed, the second granules and a mixture of the first filler, the second filler, and the first disintegrant that have passed through a 20-28 mesh sieve are subjected to top-spray granulation with the remaining first binder solution to obtain third granules; (4) The obtained third granules are mixed with a second disintegrant; the obtained mixture is mixed with a lubricant; tableting and coating are performed; In step (1), the part of the first binder is 20%-40% of the total mass of the first binder; The solid contents of the first binder solution and the second binder solution are independently selected from 8%-12% respectively; The first binder is polyvinyl alcohol, and the second binder is hypromellose.

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