A kind of arotinolol sustained-release micropellet capsule and preparation method thereof

Abstract

The invention provides an arotinolol sustained-release micro-pellet capsule. The capsule content comprises the following components in parts by weight: 10-25 parts by weight of arotinolol, 50-70 parts by weight of powdered cellulose, 15-25 parts by weight of cetostearyl alcohol, 4-8 parts by weight of povidone, 4-8 parts by weight of hydroxypropyl methylcellulose, 2-3 parts by weight of talc, 4-8 parts by weight of ethyl cellulose aqueous dispersion, 0.5-2 parts by weight of triethyl citrate, 0.5-2 parts by weight of glyceryl monostearate, and 1-3 parts by weight of polyvinyl alcohol-polyethylene glycol copolymer. The arotinolol sustained-release micro-pellet capsule is designed as a once-a-day administration mode, 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 micropill capsule 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-receptor 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. Arotinolol 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 micro-pellet capsule, 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 hydrochloride sustained-release pellet capsule, comprising capsule contents and a hard capsule shell, wherein the capsule contents comprise the following components in parts by weight:

[0009]

[0010]

[0011] In the present invention, the arotinolol is a pharmaceutically active ingredient, 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, and hydroiodic acid; preferably arotinolol hydrochloride.

[0012] In the present invention, taking the content of cetostearyl alcohol as 100%, the proportion of cetyl alcohol in the cetostearyl alcohol is 25% to 30%, and the proportion of octadecanol is 70% to 75%.

[0013] In the present invention, the povidone is povidone K30.

[0014] The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E15.

[0015] The ethyl cellulose aqueous dispersion is of type B, and adopts the third method of the general rules of Chinese Pharmacopoeia 0633, and the viscosity value is 500-600 mPa·s.

[0016] In the sustained-release coating, the weight ratio of ethyl cellulose aqueous dispersion, polyvinyl alcohol-polyethylene glycol copolymer, and glyceryl monostearate is 6:2:1.

[0017] Furthermore, the weight of the arotinolol-loaded pill core is 80-120 mg, preferably 100 mg.

[0018] In some embodiments, each of the arotinolol sustained-release micropellet capsules contains 10-20 mg of arotinolol.

[0019] In some embodiments, the arotinolol sustained-release micropellet capsule contains 10 mg of arotinolol per capsule.

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

[0021] The arotinolol sustained-release micro-pellet capsule provided by the invention can realize the slow release of arotinolol for 24 hours, wherein the release rate is no more than 30% in 1 hour, preferably 20%-25%; 30%-40% in 2 hours, preferably 32%-38%; 40%-50% in 4 hours, preferably 42%-48%; 50%-70% in 8 hours, preferably 53%-68%; not less than 70% and no more than 85% in 12 hours, preferably 70%-80%, more preferably 72%-78%; not less than 80% in 16 hours, preferably not less than 85%; and not less than 90% in 24 hours, preferably not less than 95%.

[0022] The present invention further provides a method for preparing the above-mentioned arotinolol sustained-release pellet capsules, comprising the following steps:

[0023] 1. Preparation of drug-loaded pellet core

[0024] The prescribed amount of arotinol hydrochloride, powdered cellulose and cetostearyl alcohol are passed through an 80-mesh sieve and then placed in a wet granulator, and a 4% (weight) aqueous solution of povidone K30 is used to prepare a soft material; the soft material is placed in an extruder for extrusion, the sieve aperture is 0.2 mm, the extrusion speed is 60 rpm, and the spheronization is performed at a spheronization speed of 400 rpm, and the drug-loaded pill cores are dried in a fluidized bed.

[0025] 2. Preparation of isolation coated pellets

[0026] ① Preparation of isolation coating liquid: Take the formulated amount of hypromellose and talcum powder and add them into purified water, stir and set aside.

[0027] ②Isolation layer coating: Place the obtained drug-loaded pill cores in a fluidized bed and slowly spray the isolation coating liquid into the fluidized bed by bottom spraying. The parameters of the fluidized bed coating are as follows: air inlet temperature 50-60°C, air volume 120-160m 3 / h, material temperature 30-35°C, coating weight gain 6-10%.

[0028] 3. Preparation of sustained-release pellets:

[0029] The aqueous dispersion of ethyl cellulose, triethyl citrate, glyceryl monostearate, polyvinyl alcohol-polyethylene glycol copolymer and water are uniformly mixed to prepare a sustained-release coating solution; the isolated coated pellets obtained in step 2 are added to a fluidized bed, and the sustained-release coating solution is sprayed onto the isolated coated pellets by bottom spray coating to prepare sustained-release pellets;

[0030] 4. Preparation of sustained-release pellet capsules:

[0031] The sustained-release pellets prepared in step 3 are filled into hollow capsules to obtain arotinolol sustained-release pellet capsules.

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

[0033] (1) The present invention uses a certain amount of cetostearyl alcohol as a sustained-release skeleton material to prepare a drug-loaded pill core, and uses a certain amount of an isolation layer and a sustained-release layer to prepare arotinolol into an arotinolol sustained-release micropellet capsule, 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 is completely released, and the bioavailability is high.

[0034] (2) Through a large number of experimental studies and explorations, the present invention unexpectedly found that when a certain amount of polyvinyl alcohol-polyethylene glycol copolymer and glyceryl monostearate are added to the ethyl cellulose aqueous dispersion, especially when the weight ratio of the ethyl cellulose aqueous dispersion to the polyvinyl alcohol-polyethylene glycol copolymer and glyceryl monostearate is 6:2:1, the prepared arotinolol sustained-release micropellet capsule has good dissolution stability under accelerated conditions, which is also the innovation of the present invention. This may be due to the polyvinyl alcohol-polyethylene glycol copolymer and glyceryl monostearate in the ethyl cellulose aqueous dispersion, thereby improving the stability of the sustained-release polymer film.

[0035] (3) The arotinolol sustained-release micropellet capsule 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.

[0036] (4) The quality of the arotinolol sustained-release micropellet capsules prepared by the present invention is stable. After accelerated storage for 6 months, the dissolution is basically unchanged, and the content of related substances changes little. DETAILED DESCRIPTION

[0037] The present invention discloses an arotinolol sustained-release micro-pellet capsule 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 considered to be included within the scope of the present invention.

[0038] 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.

[0039] 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.

[0040] Determination method of dissolution curve of arotinolol sustained-release micropellets:

[0041] 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 capsules of this product and put them into 6 dissolution cups respectively. The speed is 50 rpm, and the timing is carried out 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.

[0042] Viscosity determination method for ethyl cellulose aqueous dispersion (type B): Take this product and use a Brookfield DV-S rotational viscometer, rotor No. 2, 20 revolutions per minute, adjust the temperature to 25℃±0.1℃, and determine the dynamic viscosity (General Rule 0633 Method 3).

[0043] The main auxiliary materials used in the embodiments of the present invention are as follows:

[0044] Excipient name Manufacturer Remark Cetostearyl alcohol 1 Jiangxi Alpha Cetyl alcohol 27%, stearyl alcohol 73% Cetostearyl alcohol 2 Jiangxi Alpha Cetyl alcohol 38%, stearyl alcohol 62% Ethyl cellulose aqueous dispersion (type B) 1 Colorcon Viscosity: 531mPa·s Ethyl cellulose aqueous dispersion (type B)2 Colorcon Viscosity: 685mPa·s Ethyl cellulose aqueous dispersion (type B) 3 Colorcon Viscosity: 442mPa·s Povidone K90 BASF — Povidone K30 BASF — Hydroxypropyl methylcellulose E15 Hunan Erkang —

[0045] Example 1-2: Arotinolol sustained-release pellet capsules

[0046] 1. Composition of sustained-release pellets:

[0047]

[0048]

[0049] The material was added according to the prescription quantity of 10,000 capsules to prepare arotinolol sustained-release micropellet capsules, the same below.

[0050] 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.

[0051] 2. Preparation method

[0052] 1. Preparation of drug-loaded pellet core

[0053] The prescribed amount of arotinol hydrochloride, powdered cellulose and cetostearyl alcohol are passed through an 80-mesh sieve and then placed in a wet granulator, and a 4% (weight) aqueous solution of povidone K30 is used to prepare a soft material; the soft material is placed in an extruder for extrusion, the sieve aperture is 0.2 mm, the extrusion speed is 60 rpm, and the spheronization is performed at a spheronization speed of 400 rpm, and the drug-loaded pill cores are dried in a fluidized bed.

[0054] 2. Preparation of isolation coated pellets

[0055] ① Preparation of isolation coating liquid: Take the formulated amount of hypromellose and talcum powder and add them into purified water, stir and set aside.

[0056] ②Isolation layer coating: Place the obtained drug-loaded pill cores in a fluidized bed and slowly spray the isolation coating liquid into the fluidized bed by bottom spraying. The parameters of the fluidized bed coating are as follows: air inlet temperature 50-60°C, air volume 120-160m 3 / h, material temperature 30-35°C, coating weight gain 6-10%.

[0057] 3. Preparation of sustained-release pellets:

[0058] The aqueous dispersion of ethyl cellulose, triethyl citrate, glyceryl monostearate, polyvinyl alcohol-polyethylene glycol copolymer and water are uniformly mixed to prepare a sustained-release coating solution; the isolated coated pellets obtained in step 2 are added to a fluidized bed, and the sustained-release coating solution is sprayed onto the isolated coated pellets by bottom spray coating to prepare sustained-release pellets;

[0059] 4. Preparation of sustained-release pellet capsules:

[0060] The sustained-release pellets prepared in step 3 are filled into hollow capsules to obtain arotinolol sustained-release pellet capsules.

[0061] 3. Test results:

[0062] The dissolution test of the arotinolol hydrochloride sustained-release micropellet capsules prepared in Example 1-2 was performed, and the results are shown in Table 1.

[0063] Table 1: Dissolution results of arotinolol hydrochloride sustained-release pellets prepared in Example 1-2

[0064]

[0065]

[0066] Example 3-4: Arotinolol sustained-release pellet capsules

[0067] 1. Composition of sustained-release pellets:

[0068]

[0069] 2. Preparation method: Same as Example 1-2.

[0070] 3. Test results:

[0071] 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.

[0072] Table 2: Dissolution results of arotinolol hydrochloride sustained-release pellets prepared in Example 3-4

[0073]

[0074] Comparative Example 1: Arotinolol sustained-release pellet capsules

[0075] 1. Composition of sustained-release pellets:

[0076] The cetostearyl alcohol in Comparative Example 1 is shown below, and the rest is the same as in Example 1.

[0077] Comparative Example Cetostearyl alcohol Comparative Example 1 Cetostearyl alcohol 2

[0078] 2. Preparation method: Same as Example 1-2.

[0079] 3. Test results:

[0080] 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.

[0081] Table 3: Dissolution results of Arotinolol Hydrochloride Sustained Release Micropellets Capsules prepared in Comparative Example 1

[0082]

[0083]

[0084] 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.

[0085] (1) Taking the content of cetostearyl alcohol as 100%, the proportion of cetostearyl alcohol in the cetostearyl alcohol is 25%-30%, and the proportion of octadecanol is 70%-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.

[0086] (2) 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.

[0087] 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%.

[0088] Comparative Example 2-3: Arotinolol Sustained Release Micropellets Capsules

[0089] 1. Composition of sustained-release pellets:

[0090] 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.

[0091] 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

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

[0093] 3. Test results:

[0094] 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.

[0095] Table 4: Dissolution results of Arotinolol Hydrochloride Sustained Release Micropellets Capsules prepared in Comparative Examples 2-3

[0096]

[0097] 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.

[0098] (1) 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.

[0099] (2) 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.

[0100] (3) 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.

[0101] 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

[0102] 1. Composition of sustained-release pellets:

[0103] In Comparative Example 4, povidone K90 was used instead of povidone K30, and the rest was the same as in Example 1.

[0104] 2. Preparation method: Same as Example 1-2.

[0105] 3. Test results:

[0106] 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.

[0107] Table 5: Dissolution results of Arotinolol Hydrochloride Sustained Release Micropellets Capsules prepared in Comparative Example 4

[0108]

[0109] 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.

[0110] Comparative Example 5-7: Arotinolol Sustained Release Micropellets Capsules

[0111] 1. Composition of sustained-release pellets:

[0112]

[0113]

[0114] 2. Preparation method: Same as Example 1-2.

[0115] 3. Test results:

[0116] 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.

[0117] Table 6: Dissolution results of Arotinolol Hydrochloride Sustained Release Micropellets Capsules prepared in Comparative Examples 5-7

[0118]

[0119] 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.

[0120] 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.

[0121] 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.

[0122] Comparative Example 8-9: Arotinolol Sustained Release Micropellets Capsules

[0123] 1. Composition of sustained-release pellets:

[0124]

[0125] 2. Preparation method: Same as Example 1-2.

[0126] 3. Test results:

[0127] 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.

[0128] Table 7: Dissolution results of the Arotinolol Hydrochloride Sustained Release Micropellets Capsules prepared in Comparative Examples 8-9

[0129]

[0130]

[0131] 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.

[0132] (1) 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.

[0133] (2) 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 the arotinolol sustained-release micro-pellets became faster, with a 12h release rate of 85%. The dissolution rate was too fast and could not meet the requirements of a sustained-release micro-pellet capsule taken once a day.

[0134] 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.

[0135] Example 9: Stability Test

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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

[0141]

Claims

1. A sustained-release micropellet capsule of arotinolol hydrochloride, comprising capsule contents and a hard capsule shell, wherein the capsule contents comprise the following components in parts by weight: The arotinolol described is arotinolol hydrochloride; The cetostearyl alcohol, with the content of cetostearyl alcohol being 100%, the proportion of cetyl alcohol in the cetostearyl alcohol is 25% to 30%, and the proportion of octadecanol is 70% to 75%; The povidone is povidone K30; The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E15; The ethyl cellulose aqueous dispersion is of type B, and has a viscosity of 500-600 mPa·s.

2. The arotinolol hydrochloride sustained-release pellet capsule according to claim 1, characterized in that: In the sustained-release coating, the weight ratio of ethyl cellulose aqueous dispersion, polyvinyl alcohol-polyethylene glycol copolymer, and glyceryl monostearate is 6:2:

1.

3. The arotinolol hydrochloride sustained-release pellet capsule according to claim 1, characterized in that: The weight of the arotinolol-loaded pill core is 80-120 mg.

4. The arotinolol hydrochloride sustained-release micropellet capsule according to claim 3, wherein the weight of the arotinolol-loaded pellet core is 100 mg.

5. The sustained-release micropellet capsule of Arotinolol Hydrochloride according to any one of claims 1 to 4, characterized in that: Calculated as arotinolol, each capsule contains 10-20 mg of arotinolol.

6. The arotinolol hydrochloride sustained-release pellet capsule according to claim 5, characterized in that: Each tablet contains 10 mg of arotinolol.

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

8. A method for preparing the sustained-release arotinolol hydrochloride pellet capsule according to any one of claims 1 to 5, comprising the following steps: (1) Preparation of drug-loaded pellet core The prescribed amount of arotinol hydrochloride, powdered cellulose and cetostearyl alcohol are passed through an 80-mesh sieve, and then put into a wet granulator, and a 4 wt % aqueous solution of povidone K30 is used to prepare a soft material; the soft material is placed in an extruder for extrusion, the mesh size is 0.2 mm, the extrusion speed is 60 rpm, and the spheronization is performed at a spheronization speed of 400 rpm, and the drug-loaded pill cores are dried in a fluidized bed; (2) Preparation of isolation coated pellets ① Preparation of isolation coating liquid: Take the formula amount of hypromellose and talcum powder and add them into purified water, stir and set aside; ②Isolation layer coating: Place the obtained drug-loaded pill cores in a fluidized bed and slowly spray the isolation coating liquid into the fluidized bed by bottom spraying. The parameters of the fluidized bed coating are as follows: air inlet temperature 50-60°C, air volume 120-160m 3 / h, material temperature 30-35°C, coating weight gain 6-10%; (3) Preparation of sustained-release pellets: The aqueous dispersion of ethyl cellulose, triethyl citrate, glyceryl monostearate, polyvinyl alcohol-polyethylene glycol copolymer and water are uniformly mixed to prepare a sustained-release coating solution; the isolated coated pellets obtained in step 2 are added to a fluidized bed, and the sustained-release coating solution is sprayed onto the isolated coated pellets by bottom spray coating to prepare sustained-release pellets; (4) Preparation of sustained-release pellet capsules: The sustained-release pellets prepared in step 3 are filled into hollow capsules to obtain arotinolol hydrochloride sustained-release pellet capsules.

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