An aprolol sustained-release tablet and its preparation method

Abstract

The invention provides an arotinolol sustained-release tablet and a preparation method thereof. The tablet comprises a tablet core and a coating. The tablet core comprises the following components, in terms of weight percentage of the tablet core: 5.5%-11.0% arotinolol, 10.5%-19.5% cetostearyl alcohol, 19.5%-31.0% hydroxyethyl cellulose, 3.0%-5.0% povidone, 38.0%-47.5% microcrystalline cellulose and 3.0%-5.0% magnesium stearate. The arotinolol sustained-release tablet is designed to be administered once a day, which is beneficial to improving the compliance of patients with medication, not only overcoming the inconvenience caused by multiple administrations and the disadvantages of large concentration fluctuation, but also providing convenience for patients and improving compliance; after accelerated placement for 6 months, the dissolution is substantially unchanged and the quality is stable.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations and relates to an arotinolol sustained-release tablet and a preparation method thereof. Background Art

[0002] Arotinolol hydrochloride was developed by Sumitomo Pharma Co., Ltd. of Japan and launched in Japan in 1985 under the trade name Almar. The structural formula is shown below.

[0003]

[0004] Arotinolol hydrochloride is known as the fourth generation of beta-blockers, and is mainly used clinically to treat mild to moderate essential hypertension and angina pectoris. This product is a selective beta-1-adrenaline receptor antagonist, and also has a weak alpha-1-adrenaline receptor blocking effect. It can inhibit the excitement of alpha-adrenaline receptors while lowering blood pressure, reduce the tension of sympathetic nerves, and has a more ideal antihypertensive effect, making it more suitable for the treatment of adolescent hypertension. In addition, arotinolol can inhibit hyperactive cardiac function, reduce myocardial oxygen consumption, and correct the uneven supply and demand of myocardial oxygen by blocking beta receptors, and has an anti-angina effect. This product also has anti-arrhythmic and anti-tremor effects.

[0005] Arotinolol hydrochloride tablets are usually taken orally twice a day, which has poor compliance compared to the once-a-day usage of commonly used hypertension drugs. There is no arotinolol hydrochloride preparation that can be taken once a day in the prior art.

[0006] Therefore, we still need to study the sustained-release technology of arotinolol hydrochloride and develop a sustained-release dosage form suitable for once-daily oral administration to enhance its clinical value. Summary of the invention

[0007] The invention provides an arotinolol hydrochloride sustained-release tablet, which is suitable for oral administration once a day, reduces the number of medications, and reduces the peak-to-valley ratio of blood drug concentration. At the same time, by selecting a suitable sustained-release skeleton material, the drug is slowly released within 24 hours, the drug absorption is improved, and the number of medications is reduced.

[0008] The present invention provides an arotinolol sustained-release tablet, comprising a tablet core and a coating, wherein the tablet core comprises the following components in percentage by weight:

[0009]

[0010]

[0011] In the present invention, the active ingredient is arotinolol, including arotinolol or a pharmaceutically acceptable salt of arotinolol, wherein the pharmaceutically acceptable salt of arotinolol refers to a pharmaceutically acceptable acid addition salt; such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid; preferably hydrochloride.

[0012] In the present invention, taking the content of cetostearyl alcohol as 100%, the proportion of cetyl alcohol in the cetostearyl alcohol is 36% to 45%, and the proportion of octadecyl alcohol is 55% to 64%.

[0013] In the present invention, taking the content of cetostearyl alcohol as 100%, the proportion of cetyl alcohol in the cetostearyl alcohol is 36% to 38%, and the proportion of octadecanol is 62% to 64%.

[0014] In the present invention, the viscosity of hydroxyethyl cellulose (1% aqueous solution) is 500-900 mPa·s, preferably 600-800 mPa·s.

[0015] In the present invention, the povidone is povidone K25.

[0016] In the present invention, the microcrystalline cellulose is microcrystalline cellulose KG801.

[0017] Furthermore, the weight of the core of the arotinolol sustained-release tablet is 150-250 mg, preferably 180-220 mg, and more preferably 200 mg.

[0018] Further, an arotinolol sustained-release tablet comprises a tablet core and a coating, wherein the tablet core comprises the following components in percentage by weight:

[0019]

[0020] In some embodiments, the arotinolol sustained-release tablet contains 10-20 mg of arotinolol per tablet.

[0021] In some embodiments, the arotinolol sustained-release tablet contains 10 mg of arotinolol per tablet.

[0022] In some embodiments, the arotinolol sustained-release tablet contains 20 mg of arotinolol per tablet.

[0023] The coating is a non-functional coating, and coating powder commonly used in the technical field can be selected, including but not limited to at least one of polyvinyl alcohol and polyethylene glycol, at least one of silicon dioxide and talc, and / or flavoring agents; in some specific embodiments of the present invention, based on the total weight of the arotinolol sustained-release tablets, the weight percentage of the coating powder can be 5%-10%, preferably 6%-7%.

[0024] The arotinolol sustained-release tablet provided by the invention can realize the slow release of arotinolol for 24 hours, wherein the release rate in 1 hour is no more than 30%, preferably 20%-25%; the release rate in 2 hours is 30%-40%, preferably 32%-38%; the release rate in 4 hours is 40%-50%, preferably 43%-48%; the release rate in 8 hours is 50%-70%, preferably 55%-65%; the release rate in 12 hours is not less than 70% and no more than 85%, preferably 70%-80%, more preferably 73%-78%; the release rate in 16 hours is not less than 80%, preferably not less than 85%; the release rate in 24 hours is not less than 90%, preferably not less than 95%.

[0025] The present invention further provides a method for preparing the above-mentioned arotinolol sustained-release tablets, comprising the following steps:

[0026] (1) Preparation of raw materials and auxiliary materials: Preparation of adhesive: Prepare a 5-8% aqueous solution of povidone;

[0027] (2) Premixing and wet granulation: Arotinolol, cetostearyl alcohol, microcrystalline cellulose, and hydroxyethyl cellulose are added to a wet mixer granulator for premixing, and then a binder is added under stirring conditions for wet granulation;

[0028] (3) Drying and granulation: Dry the granules at 50-55°C until the moisture content is less than 2.0%; add the dried granules to a granulator for granulation;

[0029] (4) Mixing: Add magnesium stearate to the granules and mix for a total of 10-20 minutes;

[0030] (5) Tableting: Tableting pressure is 10-20KN, and tablet hardness is 4-8Kgf;

[0031] (7) Coating: Film coating is performed to obtain arotinolol sustained-release tablets.

[0032] Compared with the prior art, the present invention has the following advantages:

[0033] (1) The present invention uses cetostearyl alcohol and hydroxyethyl cellulose in a specific weight ratio as sustained-release skeleton materials, and a certain amount of binder and lubricant to prepare arotinolol into arotinolol sustained-release tablet, which can well control the release of arotinolol, and the dissolution and release process is stable for a long time, the release rate in 24 hours is not less than 90%, the drug release is complete, and the bioavailability is high.

[0034] (2) The arotinolol sustained-release tablet of the present invention is designed to be administered once a day, which is beneficial to improving the patient's compliance with medication. It not only overcomes the inconvenience caused by multiple administrations and the disadvantages of large concentration fluctuations, but also provides convenience for patients and improves compliance.

[0035] (3) The arotinolol sustained-release tablets prepared by the present invention have stable quality. After accelerated storage for 6 months, the dissolution is basically unchanged and the quality is stable. DETAILED DESCRIPTION

[0036] The present invention discloses an arotinolol sustained-release tablet and a preparation method thereof. Those skilled in the art can refer to the contents of the present invention, combine the relevant principles of pharmaceutical preparations, and appropriately improve the process parameters to achieve the same. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included within the scope of the present invention.

[0037] In order to better understand the present invention but not to limit the scope of the present invention, all the numbers expressing the amount, percentage, and other numerical values ​​used in this application should be understood to be modified by the word "about" in all cases. Each numerical parameter should at least be considered to be obtained based on the reported significant figures and by conventional rounding methods.

[0038] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0039] Determination method of dissolution curve of arotinolol sustained-release tablets:

[0040] Dissolution method: Use 900ml of water as the dissolution medium, place it in each dissolution cup, lower the stirring paddle into the dissolution cup, install the filter head at the sampling needle of the dissolution instrument, and wait until the temperature of the dissolution medium is constant at 37±0.5℃, then take 6 tablets of this product and put them into 6 dissolution cups respectively. The speed is 50 rpm, and the timing is performed according to the law. After 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 20 hours, and 24 hours, 5ml of the dissolution solution is taken respectively, and the dissolution medium of the same volume and temperature is replenished in time.

[0041] Method for measuring viscosity of hydroxyethyl cellulose: 1% aqueous solution (calculated on the basis of dry product) is measured by a rotary viscometer with rotor No. 2 and 12 revolutions per minute at 25°C ± 0.1°C (Method 3 of General Rule 0633).

[0042] The main auxiliary materials used in the embodiments of the present invention are as follows:

[0043] Excipient name Manufacturer Remark Cetostearyl alcohol 1 Jiangxi Alpha Cetyl alcohol 36%, stearyl alcohol 64% Cetostearyl alcohol 2 Jiangxi Alpha Cetyl alcohol 38%, stearyl alcohol 62% Cetostearyl alcohol 3 Jiangxi Alpha Cetyl alcohol 30%, stearyl alcohol 70% Cetostearyl alcohol 4 Jiangxi Alpha Cetyl alcohol 47%, stearyl alcohol 53% Hydroxyethylcellulose 1 Ashland Viscosity: 653mPa·s Hydroxyethylcellulose 2 Ashland Viscosity: 735mPa·s Hydroxyethylcellulose 3 Ashland Viscosity: 486mPa·s Hydroxyethylcellulose 4 Ashland Viscosity: 1000mPa·s Povidone K25 BASF — Povidone K30 BASF — Microcrystalline Cellulose KG801 Jiangsu Xidian — Microcrystalline Cellulose KG1000 Jiangsu Xidian —

[0044] Example 1-2: Arotinolol sustained-release tablets

[0045] 1. Tablet formula composition:

[0046]

[0047] The materials were added according to the prescription quantity of 10,000 tablets to prepare arotinolol sustained-release tablets, the same below.

[0048] 10.98 mg of arotinolol hydrochloride is equivalent to 10 mg of arotinolol; 21.96 mg of arotinolol hydrochloride is equivalent to 20 mg of arotinolol.

[0049] 2. Preparation method

[0050] (1) Preparation of raw materials and auxiliary materials: Preparation of adhesive: Prepare a 6% aqueous solution of povidone;

[0051] (2) Premixing and wet granulation: Arotinolol, cetostearyl alcohol, microcrystalline cellulose, and hydroxyethyl cellulose are added to a wet mixer granulator for premixing, and then a binder is added under stirring conditions for wet granulation;

[0052] (3) Drying and granulation: Dry the granules at 50-55°C until the moisture content is less than 2.0%; add the dried granules to a granulator for granulation;

[0053] (4) Mixing: Add magnesium stearate to the granules and mix for a total of 15 minutes;

[0054] (5) Tableting: Tableting pressure is 18KN, tablet hardness is 5Kgf;

[0055] (8) Coating: Film coating is performed to obtain arotinolol sustained-release tablets.

[0056] 3. Test results:

[0057] The dissolution test of the arotinolol hydrochloride sustained-release tablets prepared in Example 1-2 was performed, and the results are shown in Table 1.

[0058] Table 1: Dissolution results of Arotinolol Hydrochloride Sustained Release Tablets prepared in Example 1-2

[0059]

[0060] Example 3-4: Arotinolol sustained-release tablets

[0061] 1. Tablet formula composition:

[0062]

[0063] 2. Preparation method: Same as Example 1-2.

[0064] 3. Test results:

[0065] The dissolution test of the arotinolol hydrochloride sustained-release tablets prepared in Example 3-4 was performed, and the results are shown in Table 2.

[0066] Table 2: Dissolution results of Arotinolol Hydrochloride Sustained Release Tablets prepared in Example 3-4

[0067]

[0068] Example 5-6: Arotinolol sustained-release tablets

[0069] 1. Tablet formula composition:

[0070]

[0071] 2. Preparation method: Same as Example 1-2

[0072] 3. Test results:

[0073] The dissolution test of the arotinolol hydrochloride sustained-release tablets prepared in Examples 5-6 was performed. The results are shown in Table 3.

[0074] Table 3: Dissolution results of Arotinolol Hydrochloride Sustained Release Tablets prepared in Examples 5-6

[0075]

[0076] Example 7-8: Arotinolol sustained-release tablets

[0077] 1. Tablet formula composition:

[0078]

[0079] 2. Preparation method: Same as Example 1-2.

[0080] 3. Test results:

[0081] The dissolution test of the arotinolol hydrochloride sustained-release tablets prepared in Examples 7-8 was performed, and the results are shown in Table 4.

[0082] Table 4: Dissolution results of Arotinolol Hydrochloride Sustained Release Tablets prepared in Examples 7-8

[0083]

[0084] By comparing and analyzing Examples 1-2, Examples 7-8 and Example 9, it was found that the weight ratio of the sustained-release skeleton cetostearyl alcohol and hydroxyethylcellulose affects the dissolution behavior of the arotinolol hydrochloride sustained-release tablets.

[0085] (1) When the content of cetostearyl alcohol is 14.0%-15.0% and the content of hydroxyethylcellulose is 25.5%-27.5%, as shown in Examples 1-2, the prepared arotinolol hydrochloride sustained-release tablets can achieve a 24-hour slow release of arotinolol, with a release of 20%-25% in 1 hour, 32%-38% in 2 hours, 43%-48% in 4 hours, 55%-65% in 8 hours, 73%-78% in 12 hours, not less than 85% in 16 hours, and not less than 98% in 24 hours.

[0086] (2) When the content of cetostearyl alcohol is 12% and the content of hydroxyethylcellulose is 27.5%, as shown in Example 7, after accelerated storage for 6 months, the release rate is 80% in 16 hours and 90% in 24 hours; the dissolution of the arotinolol hydrochloride sustained-release tablets is slightly slowed down, and the therapeutic effect of the sustained-release tablets is basically achieved, but the effect is slightly worse than that of Example 1-2.

[0087] (3) When the content of cetostearyl alcohol is 18% and the content of hydroxyethylcellulose is 24.5%, as shown in Example 8, after accelerated storage for 6 months, the release rate reaches 80% in 12 hours, and the dissolution rate becomes slightly faster, which basically meets the requirements of sustained-release tablets taken once a day, but the effect is slightly worse than that of Example 1-2.

[0088] Comparative Example 1-2: Arotinolol sustained-release tablets

[0089] 1. Tablet formula composition:

[0090] In Comparative Example 1-2, cetostearyl alcohol is shown below, and the rest is the same as in Example 1.

[0091] Comparative Example Cetostearyl alcohol Comparative Example 1 Cetostearyl alcohol 3 Comparative Example 2 Cetostearyl alcohol 4

[0092] 2. Preparation method: Same as Example 1-2.

[0093] 3. Test results:

[0094] The dissolution test of the arotinolol hydrochloride sustained-release tablets prepared in Comparative Example 1-2 was performed, and the results are shown in Table 5.

[0095] Table 5: Dissolution results of Arotinolol Hydrochloride Sustained Release Tablets prepared in Comparative Example 1-2

[0096]

[0097]

[0098] It can be seen from Examples 1 to 6 and Comparative Examples 1-2 that the ratio of cetyl alcohol to octadecanol in the sustained-release skeleton cetostearyl alcohol affects the dissolution behavior of arotinolol hydrochloride sustained-release tablets.

[0099] (1) Taking the content of cetostearyl alcohol as 100%, the proportion of cetyl alcohol in the cetostearyl alcohol is 36% to 38%, and the proportion of octadecanol is 62% to 64%. As shown in Examples 1-6, the prepared arotinolol hydrochloride sustained-release tablets can achieve a 24-hour slow release of arotinolol, with a release of 20%-25% in 1 hour; 32%-38% in 2 hours; 43%-48% in 4 hours; 55%-65% in 8 hours; 73%-78% in 12 hours; not less than 85% in 16 hours; and not less than 98% in 24 hours.

[0100] (2) Taking the content of cetostearyl alcohol as 100%, the proportion of cetostearyl alcohol in the cetostearyl alcohol is less than 36% (e.g., 30%), and the proportion of octadecanol is greater than 64% (e.g., 70%). As shown in Comparative Example 1, the dissolution of the arotinolol hydrochloride sustained-release tablets slows down, with the release rate in 16 hours being less than 80%; and the release rate in 24 hours being less than 90%. The dissolution rate is too slow, which affects the therapeutic effect of the sustained-release tablets.

[0101] (3) Taking the content of cetostearyl alcohol as 100%, the proportion of cetostearyl alcohol in the cetostearyl alcohol is higher than 45% (e.g., 47%), and the proportion of octadecanol is lower than 55% (e.g., 53%). As shown in Comparative Example 2, the dissolution of the arotinolol hydrochloride sustained-release tablet becomes faster, and the release rate exceeds 85% in 12 hours. The dissolution rate is too fast and cannot meet the requirement of a sustained-release tablet taken once a day.

[0102] Therefore, in the present invention, based on 100% of the content of cetostearyl alcohol, the proportion of cetostearyl alcohol in the cetostearyl alcohol is 36% to 45%, and the proportion of octadecanol is 55% to 64%. Preferably, the proportion of cetostearyl alcohol in the cetostearyl alcohol is 36% to 38%, and the proportion of octadecanol is 62% to 64%.

[0103] Comparative Example 3-4: Arotinolol Sustained Release Tablets

[0104] 1. Tablet formula composition:

[0105] The hydroxyethyl cellulose in Comparative Example 3-4 is as follows, and the rest is the same as in Example 1.

[0106] Comparative Example Hydroxyethylcellulose Comparative Example 3 Hydroxyethylcellulose 3 Comparative Example 4 Hydroxyethylcellulose 4

[0107] 2. Preparation method: Same as Example 1-2.

[0108] 3. Test results:

[0109] The dissolution test of the arotinolol sustained-release tablets prepared in Comparative Examples 3-4 was performed, and the results are shown in Table 6.

[0110] Table 6: Dissolution results of Arotinolol Hydrochloride Sustained Release Tablets prepared in Comparative Examples 3-4

[0111]

[0112] It can be seen from Examples 1 to 6 and Comparative Examples 3-4 that the viscosity of the sustained-release matrix hydroxyethylcellulose affects the dissolution behavior of the arotinolol hydrochloride sustained-release tablets.

[0113] (1) When the viscosity of hydroxyethyl cellulose (1% aqueous solution) is 600-800 mPa·s, as shown in Examples 1-6, the prepared arotinolol hydrochloride sustained-release tablets can achieve a 24-hour slow release of arotinolol, with a release of 20%-25% in 1 hour; 32%-38% in 2 hours; 43%-48% in 4 hours; 55%-65% in 8 hours; 73%-78% in 12 hours; not less than 85% in 16 hours; and not less than 95% in 24 hours.

[0114] (2) When the viscosity of hydroxyethylcellulose (1% aqueous solution) is lower than 500 mPa·s (e.g., 480 mPa·s), as shown in Comparative Example 3, the dissolution of the arotinolol sustained-release tablet becomes faster, with the release reaching 85% in 12 hours. The dissolution rate is too fast and cannot meet the requirement of a sustained-release tablet taken once a day.

[0115] (3) When the viscosity of hydroxyethyl cellulose (1% aqueous solution) is higher than 900 mPa·s (e.g., 1000 mPa·s), as shown in Comparative Example 4, the dissolution of the arotinolol hydrochloride sustained-release tablets slows down, with the release rate in 16 h being less than 80% and the release rate in 24 h being less than 90%. The dissolution rate is too slow, affecting the therapeutic effect of the sustained-release tablets.

[0116] Therefore, in the present invention, the viscosity of hydroxyethyl cellulose (1% aqueous solution) is 500-900 mPa·s, preferably 600-800 mPa·s.

[0117] Comparative Example 5: Arotinolol Sustained Release Tablets

[0118] 1. Tablet formula composition:

[0119] In Comparative Example 5, povidone K30 was used instead of povidone K25, and the rest was the same as in Example 1.

[0120] 2. Preparation method: Same as Example 1-2.

[0121] 3. Test results:

[0122] The dissolution test of the arotinolol hydrochloride sustained-release tablets prepared in Comparative Example 5 was performed, and the results are shown in Table 7.

[0123] Table 7: Dissolution results of Arotinolol Hydrochloride Sustained Release Tablets prepared in Comparative Example 5

[0124]

[0125] Comparative Example 6: Arotinolol Sustained Release Tablets

[0126] 1. Tablet formula composition:

[0127] In Comparative Example 6, microcrystalline cellulose KG1000 was used instead of microcrystalline cellulose KG801, and the rest was the same as in Example 1. 2. Preparation method: the same as in Example 1-2.

[0128] 3. Test results:

[0129] The dissolution test of the arotinolol hydrochloride sustained-release tablets prepared in Comparative Example 6 was performed, and the results are shown in Table 8.

[0130] Table 8: Dissolution results of Arotinolol Hydrochloride Sustained Release Tablets prepared in Comparative Example 6

[0131]

[0132] Comparative Example 7-8: Arotinolol Sustained Release Tablets

[0133] 1. Tablet formula composition:

[0134]

[0135] 2. Preparation method: Same as Example 1-2.

[0136] 3. Test results:

[0137] The dissolution test of the arotinolol hydrochloride sustained-release tablets prepared in Comparative Examples 7-8 was performed, and the results are shown in Table 9.

[0138] Table 9: Dissolution results of Arotinolol Hydrochloride Sustained Release Tablets prepared in Comparative Examples 7-8

[0139]

[0140] It can be seen from Examples 1 to 2 and Comparative Examples 7 to 8 that the weight ratio of the sustained-release skeleton cetostearyl alcohol and hydroxyethylcellulose affects the dissolution behavior of the arotinolol hydrochloride sustained-release tablets.

[0141] (4) When the content of cetostearyl alcohol is 14.0%-15.0% and the content of hydroxyethylcellulose is 25.5%-27.5%, as shown in Examples 1-2, the prepared arotinolol hydrochloride sustained-release tablets can achieve a 24-hour slow release of arotinolol, with a release of 20%-25% in 1 hour, 32%-38% in 2 hours, 43%-48% in 4 hours, 55%-65% in 8 hours, 73%-78% in 12 hours, not less than 85% in 16 hours, and not less than 98% in 24 hours.

[0142] (5) When the content of cetostearyl alcohol is lower than 10.5% (e.g., 8.0%) and the content of hydroxyethylcellulose is higher than 31.0% (e.g., 31.5%), as shown in Comparative Example 7, the dissolution of the arotinolol hydrochloride sustained-release tablets slows down, with the release rate at 16h lower than 80% and the release rate at 24h lower than 90%. The dissolution rate is too slow, which affects the therapeutic effect of the sustained-release tablets.

[0143] (6) When the content of cetostearyl alcohol is higher than 19.5% (e.g., 23.5%) and the content of hydroxyethylcellulose is lower than 19.5% (e.g., 19.0%), as shown in Comparative Example 8, the dissolution of the arotinolol hydrochloride sustained-release tablet becomes faster, and the release rate in 12 hours exceeds 85%, reaching 88%. The dissolution rate is too fast and cannot meet the requirement of a sustained-release tablet taken once a day.

[0144] Therefore, in the present invention, 10.5%-19.5% of cetostearyl alcohol and 19.5%-31.0% of hydroxyethylcellulose are used, preferably 14.0%-15.0% of cetostearyl alcohol and 25.5%-27.5% of hydroxyethylcellulose.

[0145] Example 9: Stability Test

[0146] The arotinolol hydrochloride sustained-release tablets prepared in Examples 1 to 8 and Comparative Examples 5 to 6 were placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% (accelerated) for 6 months. Samples were taken at the end of the 6th month, and the dissolution curve was measured. The results are shown in Table 10.

[0147] The arotinolol hydrochloride sustained-release tablets prepared in Examples 1 to 6 of the present invention, after being placed under accelerated conditions for 6 months, showed no significant change in the dissolution curve compared with 0 month, indicating that the arotinolol hydrochloride sustained-release tablets prepared in the present invention have stable quality.

[0148] The arotinolol hydrochloride sustained-release tablets prepared in Comparative Examples 5-6, after being placed under accelerated conditions for 6 months, had a significant change in the dissolution curve compared with 0 months, with the 16h release being less than 80%; the 24h release being less than 90%; the dissolution rate being too slow, affecting the therapeutic effect of the sustained-release tablets; it can be seen that the quality of the arotinolol sustained-release tablets prepared in Comparative Examples 5-6 is unstable.

[0149] Table 10: Accelerated dissolution results of arotinolol hydrochloride sustained-release tablets prepared in Examples 1-8 and Comparative Examples 5-6 for 6 months

[0150]

[0151] Example 3-4: Arotinolol sustained-release pellet capsules

[0152] 1. Composition of sustained-release pellets:

[0153]

[0154]

[0155] 2. Preparation method: Same as Example 1-2.

[0156] 3. Test results:

[0157] The dissolution test of the arotinolol hydrochloride sustained-release micropellet capsules prepared in Example 3-4 was performed, and the results are shown in Table 2.

[0158] Table 2: Dissolution results of arotinolol hydrochloride sustained-release pellets prepared in Example 3-4

[0159]

[0160] Comparative Example 1: Arotinolol sustained-release pellet capsules

[0161] 1. Composition of sustained-release pellets:

[0162] The cetostearyl alcohol in Comparative Example 1 is shown below, and the rest is the same as in Example 1.

[0163]

[0164]

[0165] 2. Preparation method: Same as Example 1-2.

[0166] 3. Test results:

[0167] The dissolution of the arotinolol hydrochloride sustained-release micropellet capsules prepared in Comparative Example 1 was tested, and the results are shown in Table 3.

[0168] Table 3: Dissolution results of Arotinolol Hydrochloride Sustained Release Micropellets Capsules prepared in Comparative Example 1

[0169]

[0170] It can be seen from Examples 1 to 4 and Comparative Example 1 that the ratio of cetyl alcohol to octadecanol in cetostearyl alcohol in the drug-loaded pellets affects the dissolution behavior of the arotinolol hydrochloride sustained-release pellet capsules.

[0171] (4) Taking the content of cetostearyl alcohol as 100%, the proportion of cetostearyl alcohol in the cetostearyl alcohol is 25% to 30%, and the proportion of octadecanol is 70% to 75%. As shown in Examples 1-4, the prepared arotinol hydrochloride sustained-release micropellet capsules can achieve a 24-hour slow release of arotinolol, with a release of 20%-25% in 11 hours; 32%-38% in 2 hours; 42%-48% in 4 hours; 53%-68% in 8 hours; 72%-78% in 12 hours; not less than 85% in 16 hours; and not less than 95% in 24 hours.

[0172] (5) Taking the content of cetostearyl alcohol as 100%, the proportion of cetostearyl alcohol in the cetostearyl alcohol is higher than 30% (e.g., 38%), and the proportion of octadecanol is lower than 70% (e.g., 62%). As shown in Comparative Example 1, the dissolution of the arotinolol hydrochloride sustained-release micropellet capsule becomes faster, and the release rate exceeds 85% in 12 hours. The dissolution rate is too fast and cannot meet the requirement of the sustained-release micropellet capsule to be taken once a day.

[0173] Therefore, in the present invention, taking the content of cetostearyl alcohol as 100%, the best effect is achieved when the proportion of cetyl alcohol in the cetostearyl alcohol is 25% to 30% and the proportion of octadecanol is 70% to 75%.

[0174] Comparative Example 2-3: Arotinolol Sustained Release Micropellets Capsules

[0175] 1. Composition of sustained-release pellets:

[0176] The ethyl cellulose aqueous dispersion (type B) in Comparative Example 2-3 is shown below, and the rest is the same as in Example 1.

[0177] Comparative Example Ethylcellulose aqueous dispersion Comparative Example 2 Ethyl cellulose aqueous dispersion (type B)2 Comparative Example 3 Ethyl cellulose aqueous dispersion (type B) 3

[0178] 2. Preparation method: Same as Example 1-2.

[0179] 3. Test results:

[0180] The dissolution of the arotinolol sustained-release pellet capsules prepared in Comparative Example 2-3 was tested, and the results are shown in Table 4.

[0181] Table 4: Dissolution results of Arotinolol Hydrochloride Sustained Release Micropellets Capsules prepared in Comparative Example 2-3

[0182]

[0183] It can be seen from Examples 1 to 4 and Comparative Examples 2-3 that the viscosity of the ethylcellulose aqueous dispersion (type B) in the sustained-release coating affects the dissolution behavior of the arotinolol hydrochloride sustained-release micropellet capsules.

[0184] (4) When the viscosity of the ethylcellulose aqueous dispersion (type B) is 500-600 mPa·s, as shown in Examples 1-4, the prepared arotinolol hydrochloride sustained-release micropellet capsules can achieve a 24-hour slow release of arotinolol, with a release of 20%-25% in 1 hour, 32%-38% in 2 hours, 42%-48% in 4 hours, 53%-68% in 8 hours, 72%-78% in 12 hours, not less than 85% in 16 hours, and not less than 95% in 24 hours.

[0185] (5) When the viscosity of the ethylcellulose aqueous dispersion (type B) is lower than 500 mPa·s (e.g., 442 mPa·s), as shown in Comparative Example 3, the dissolution of the arotinolol sustained-release micropellet capsule becomes faster, with the release rate exceeding 85% in 12 h. The dissolution rate is too fast and cannot meet the requirement of the sustained-release micropellet capsule to be taken once a day.

[0186] (6) When the viscosity of the ethylcellulose aqueous dispersion (type B) is higher than 600 mPa·s (e.g., 685 mPa·s), as shown in Comparative Example 2, the dissolution of the arotinolol hydrochloride sustained-release pellet capsules slows down, with the release rate at 16 h being less than 80% and the release rate at 24 h being less than 90%. The dissolution rate is too slow, affecting the therapeutic effect of the sustained-release pellet capsules.

[0187] Therefore, the viscosity of the ethylcellulose aqueous dispersion (type B) of the present invention is preferably 500-600 mPa·s. Comparative Example 4: Arotinolol sustained-release pellet capsules

[0188] 1. Composition of sustained-release pellets:

[0189] In Comparative Example 4, povidone K90 was used instead of povidone K30, and the rest was the same as in Example 1.

[0190] 2. Preparation method: Same as Example 1-2.

[0191] 3. Test results:

[0192] The dissolution of the arotinolol hydrochloride sustained-release micropellet capsules prepared in Comparative Example 4 was tested, and the results are shown in Table 5.

[0193] Table 5: Dissolution results of Arotinolol Hydrochloride Sustained Release Micropellets Capsules prepared in Comparative Example 4

[0194]

[0195] Comparative Example 4 and Example 1 were compared and analyzed. The dissolution of the prepared arotinolol sustained-release micro-pellet capsules was similar with no significant difference when using povidone K90 instead of povidone K30. However, combined with the accelerated stability test of Example 5, it can be seen that after 6 months of accelerated placement, the dissolution of Comparative Example 4 slowed down significantly, with a 16h release rate of less than 80% and a 24h release rate of less than 90%. The dissolution rate was too slow, affecting the therapeutic effect of the sustained-release micro-pellet capsules.

[0196] Comparative Example 5-7: Arotinolol Sustained Release Micropellets Capsules

[0197] 1. Composition of sustained-release pellets:

[0198]

[0199] 2. Preparation method: Same as Example 1-2.

[0200] 3. Test results:

[0201] The dissolution of the arotinolol hydrochloride sustained-release pellet capsules prepared in Comparative Examples 5-7 was tested, and the results are shown in Table 6.

[0202] Table 6: Dissolution results of Arotinolol Hydrochloride Sustained Release Micropellets Capsules prepared in Comparative Examples 5-7

[0203]

[0204] By comparing and analyzing Example 1 and Comparative Example 5, when the drug-loaded pellets do not contain cetostearyl alcohol, the dissolution of the arotinolol sustained-release pellets capsules becomes faster, and the release rate reaches 85% in 12 hours. The dissolution rate is too fast and cannot meet the requirement of taking the sustained-release pellets capsules once a day.

[0205] By comparing and analyzing Example 1 and Comparative Example 6, when the sustained-release coating does not contain polyvinyl alcohol-polyethylene glycol copolymer, the dissolution is normal in 1-8 hours, and the dissolution of the arotinolol sustained-release micropellet capsule becomes faster after 8 hours, and the release reaches 85% in 12 hours. The dissolution rate is too fast and cannot meet the requirement of taking the sustained-release micropellet capsule once a day.

[0206] By comparing and analyzing Example 1 and Comparative Example 7, when the sustained-release coating does not contain glyceryl monostearate, the dissolution of the arotinolol sustained-release micropellet capsule becomes faster, and the release rate reaches 85% in 12 hours. The dissolution rate is too fast and cannot meet the requirement of taking the sustained-release micropellet capsule once a day.

[0207] Comparative Example 8-9: Arotinolol Sustained Release Micropellets Capsules

[0208] 1. Composition of sustained-release pellets:

[0209]

[0210] 2. Preparation method: Same as Example 1-2.

[0211] 3. Test results:

[0212] The dissolution test of the arotinolol hydrochloride sustained-release micropellet capsules prepared in Comparative Examples 8-9 was performed, and the results are shown in Table 7.

[0213] Table 7: Dissolution results of the Arotinolol Hydrochloride Sustained Release Micropellets Capsules prepared in Comparative Examples 8-9

[0214]

[0215]

[0216] It can be seen from Example 1 and Comparative Examples 7-8 that the weight ratio of ethyl cellulose aqueous dispersion, polyvinyl alcohol-polyethylene glycol copolymer and glyceryl monostearate in the sustained-release coating affects the dissolution behavior of arotinolol hydrochloride sustained-release micropellet capsules.

[0217] (7) When the weight ratio of ethyl cellulose aqueous dispersion, polyvinyl alcohol polyethylene glycol copolymer, and glyceryl monostearate is 6:2:1, as shown in Example 1, the prepared arotinolol hydrochloride sustained-release micropellet capsules can achieve a 24-hour slow release of arotinolol, with a release of 20%-25% in 11 hours; 32%-38% in 2 hours; 42%-48% in 4 hours; 53%-68% in 8 hours; 72%-78% in 12 hours; not less than 85% in 16 hours; and not less than 95% in 24 hours.

[0218] (8) When the weight ratio of ethyl cellulose aqueous dispersion, polyvinyl alcohol-polyethylene glycol copolymer, and glyceryl monostearate is 4:4:1 and 4:3:2, as shown in Comparative Examples 8-9, the prepared arotinolol sustained-release micro-pellets have similar dissolution rates, with no significant difference. However, in combination with the accelerated stability test of Example 5, it can be seen that after Comparative Examples 8-9 were placed for 6 months, the dissolution of arotinolol sustained-release micro-pellets became faster, with a release rate of 85% in 12 hours. The dissolution rate was too fast and could not meet the requirements of sustained-release micro-pellets for once-daily administration.

[0219] Therefore, the weight ratio of ethylcellulose aqueous dispersion, polyvinyl alcohol-polyethylene glycol copolymer, and glyceryl monostearate in the sustained-release coating is preferably 6:2:1.

[0220] Example 9: Stability Test

[0221] The arotinolol hydrochloride sustained-release micropellets capsules prepared in Examples 1 to 4, Comparative Example 4, and Comparative Examples 8-9 were placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% (accelerated) for 6 months. Samples were taken at the end of the 6th month, and the dissolution curve was measured. The results are shown in Table 8.

[0222] The arotinolol hydrochloride sustained-release micropellets capsules prepared in Examples 1 to 4 of the present invention, after being placed under accelerated conditions for 6 months, showed no significant change in the dissolution curve compared with 0 month, indicating that the quality of the arotinolol hydrochloride sustained-release micropellets capsules prepared by the present invention is stable.

[0223] The arotinolol hydrochloride sustained-release micro-pellets prepared in Comparative Example 4, after being placed under accelerated conditions for 6 months, showed a significant change in the dissolution curve compared with 0 months, and the dissolution was significantly slowed down, with the 16h release rate being less than 80%; the 24h release rate being less than 90%; the dissolution rate was too slow, affecting the therapeutic effect of the sustained-release micro-pellets. It can be seen that the quality of the arotinolol sustained-release micro-pellets prepared in Comparative Example 4 is unstable.

[0224] The arotinolol hydrochloride sustained-release micropellets prepared in Comparative Examples 8-9, after being placed under accelerated conditions for 6 months, had a significant change in the dissolution curve compared with 0 months, with faster dissolution, and the 12h release reaching 85%. The dissolution rate was too fast and could not meet the requirements of sustained-release micropellets taken once a day. It can be seen that the quality of the arotinolol sustained-release micropellets prepared in Comparative Examples 8-9 was unstable.

[0225] Table 8: Accelerated 6-month dissolution results of arotinolol hydrochloride sustained-release pellets prepared in Examples 1-4, Comparative Example 4, and Comparative Examples 8-9

[0226]

Claims

1. An arotinolol sustained-release tablet, comprising a tablet core and a coating, wherein the tablet core comprises the following components in percentage by weight: The arotinolol described is arotinolol hydrochloride; The cetostearyl alcohol, taking the content of cetostearyl alcohol as 100%, the proportion of cetyl alcohol in the cetostearyl alcohol is 36% to 38%, and the proportion of octadecanol is 62% to 64%; The viscosity of the 1% aqueous solution of the hydroxyethyl cellulose is 600-800 mPa·s; The povidone is povidone K25; The microcrystalline cellulose is microcrystalline cellulose KG801; The weight of the core of the arotinolol sustained-release tablet is 150-250 mg.

2. The arotinolol sustained-release tablet according to claim 1, wherein the weight of the arotinolol sustained-release tablet core is 200 mg.

3. The sustained-release tablet of arotinolol according to claim 1, characterized in that: In terms of arotinolol, each tablet contains 10-20 mg of arotinolol.

4. The sustained-release tablet of arotinolol according to claim 3, characterized in that: Each tablet contains 10 mg of arotinolol.

5. The sustained-release tablet of arotinolol according to claim 3, characterized in that: Each tablet contains 20 mg of arotinolol.

6. A method for preparing any one of claims 1 to 5 of the arotinolol sustained-release tablets, comprising the following steps: (1) Preparation of raw materials and auxiliary materials: Preparation of adhesive: Prepare a 5-8% aqueous solution of povidone; (2) Premixing and wet granulation: Arotinolol, cetostearyl alcohol, microcrystalline cellulose, and hydroxyethyl cellulose are added to a wet mixer granulator for premixing, and then a binder is added under stirring conditions for wet granulation; (3) Drying and granulation: Dry the granules at 50-55°C until the moisture content is less than 2.0%; add the dried granules to a granulator for granulation; (4) Mixing: Add magnesium stearate to the granules and mix for a total of 10-20 minutes; (5) Tableting: Tableting pressure is 10-20KN, and tablet hardness is 4-8Kgf; (6) Coating: Film coating is performed to obtain arotinolol sustained-release tablets.

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