Arotinolol hydrochloride quick-release tablet and preparation method thereof

Abstract

The invention provides an arotinolol hydrochloride quick-release tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations, the arotinolol hydrochloride quick-release tablet comprises a tablet core and a coating layer, the tablet core comprises arotinolol hydrochloride, dextran, a stabilizer, a diluent, a disintegrating agent and an adhesive, and the stabilizer is sodium laurate. According to the arotinolol hydrochloride quick-release tablet, the dextran is matched with the stabilizer sodium laurate, so that the defects of instability and poor solubility of arotinolol hydrochloride can be overcome, and the problems of slow dissolution and poor stability of the prepared arotinolol hydrochloride quick-release tablet are avoided.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a rapid-release arotinolol hydrochloride tablet and a preparation method of the tablet. Background Art

[0002] Arotinolol hydrochloride was developed by Sumitomo Pharma Co., Ltd. of Japan and was first launched in Japan in 1985. In 1996, the company imported arotinolol hydrochloride tablets to China. They are sugar-coated tablets with the trade name Arotinolol hydrochloride is a first-line beta-blocker. It is primarily used clinically to treat mild to moderate essential hypertension and angina pectoris. It is a selective β1-adrenergic receptor antagonist with a mild α1-adrenergic receptor blocking effect. It can simultaneously lower blood pressure by inhibiting α-adrenergic receptor excitation and reducing sympathetic nerve tone, resulting in a more effective antihypertensive effect and making it particularly suitable for the treatment of adolescent hypertension. Furthermore, by blocking β receptors, arotinolol can inhibit hyperactive cardiac function, reduce myocardial oxygen consumption, and correct the imbalance between myocardial oxygen supply and demand, thus exhibiting anti-anginal effects. It also has anti-arrhythmic and anti-tremor effects.

[0003] The chemical name of arotinolol hydrochloride is: (±)-5-[2-[(3-tert-butylamino-2-hydroxypropyl)thio]-4-thiazolyl]-2-carbamoylthiophene hydrochloride, and the structural formula is as follows:

[0004]

[0005] During the preparation of arotinolol hydrochloride preparations, the dosage of each raw material and the preparation process directly affect the drug's dissolution rate. However, existing arotinolol hydrochloride tablets have low dissolution rates and poor stability due to poor configuration of the raw material types and dosages, as well as the properties of the drug itself. Furthermore, the sugar-coating process creates dust and pollutes the environment.

[0006] Patent CN201510506618.X discloses a preparation of arotinolol hydrochloride and its preparation method, which consists of a coating film and a tablet core, wherein the tablet core is prepared from the following ingredients in percentage by weight: 10% arotinolol hydrochloride, 83-88% filler, 1-5% binder, 0.2-2% lubricant; the lubricant is magnesium stearate; the coating film is made of a water-soluble film coating powder accounting for 1.5-2.5% of the tablet core weight; wherein the filler is lactose, microcrystalline cellulose and starch mixed in a weight ratio of 60: (13-18): 10; the binder is selected from hydroxypropyl cellulose; the water-soluble film coating powder is Opadry gastric-soluble coating powder. The tablets using film coating in the patent have a higher dissolution rate than arotinolol hydrochloride sugar-coated tablets. , which overcomes the problem of delayed dissolution of sugar coating, but this patent still has the problem of poor initial dissolution, with the dissolution at 5 minutes being less than 20%. At the same time, the content of related substances cannot be well controlled, the stability is poor, it does not meet the quality standards, and it is not easy to carry out large-scale production.

[0007] Therefore, the research and development focus of the present invention is to select a suitable excipient to overcome the defects of instability and poor solubility of the arotinolol hydrochloride preparation and ensure the stable quality of the arotinolol hydrochloride preparation. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to overcome the problems of instability and poor dissolution of arotinolol hydrochloride preparations and develop a fast-release arotinolol hydrochloride tablet with good dissolution and stability.

[0009] The invention provides an arotinolol hydrochloride rapid-release tablet. The rapid-release tablet comprises a tablet core and a coating layer. The tablet core comprises arotinolol hydrochloride, dextran, a stabilizer, a diluent, a disintegrant and a binder, and the stabilizer is sodium laurate.

[0010] The present inventors have found through experimental research that the addition of dextran to arotinolol hydrochloride rapid-release tablets can overcome the problem of the slow initial dissolution of arotinolol hydrochloride rapid-release tablets, ensuring that arotinolol hydrochloride rapid-release tablets can be quickly released. Further, dextran can be coordinated with other excipients, significantly improving the initial dissolution of the tablets, and quickly achieving release, prompting arotinolol hydrochloride rapid-release tablets to have good dissolution. At the same time, the addition of sodium laurate in arotinolol hydrochloride rapid-release tablets can ensure the stability of the preparation quality during drug storage, effectively solving the problem that arotinolol hydrochloride is easily degraded to produce impurities due to its own properties; and the inventors unexpectedly found that the coordination of sodium laurate and dextran can also increase the dissolution and stability of arotinolol hydrochloride rapid-release tablets, thereby ensuring the quality and efficacy of the pharmaceutical preparation.

[0011] In the above-mentioned arotinolol hydrochloride rapid-release tablets, the stabilizer further contains magnesium aspartate. The combination of magnesium aspartate and sodium laurate can better achieve the control of related substances in the arotinolol hydrochloride rapid-release tablets and meet the quality stability requirements.

[0012] In the aforementioned arotinolol hydrochloride rapid-release tablets, the diluent is one or more of calcium hydrogen phosphate, microcrystalline cellulose, corn starch, lactose, mannitol, and pregelatinized starch.

[0013] In the above-mentioned arotinolol hydrochloride rapid-release tablets, the disintegrant is one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose.

[0014] In the above-mentioned arotinolol hydrochloride rapid-release tablets, the binder is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, and sodium carboxymethyl cellulose.

[0015] In the aforementioned arotinolol hydrochloride rapid-release tablets, the coating layer comprises propyl gallate, hypromellose, polyethylene glycol, and talc. The combination of propyl gallate, hypromellose, polyethylene glycol, and talc in the coating layer enables rapid dissolution of the coating layer and promotes the release of arotinolol hydrochloride from the tablet core. The amounts of propyl gallate, hypromellose, polyethylene glycol, and talc used can be determined based on the general knowledge of those skilled in the art.

[0016] In the above-mentioned arotinolol hydrochloride rapid-release tablets, the amounts of the tablet core components are calculated in parts by mass as follows: 10 parts of arotinolol hydrochloride, 5-15 parts of dextran, 1-5 parts of stabilizer, 65-85 parts of diluent, 1-5 parts of disintegrant, and 1-5 parts of binder.

[0017] The aforementioned arotinolol hydrochloride immediate-release tablets further contain a lubricant, which is one or more of micropowdered silica gel, magnesium stearate, stearic acid, calcium stearate, talc, and hard sodium fumarate. The amount of the lubricant used can be determined based on the general knowledge of those skilled in the art.

[0018] The present invention also provides a method for preparing arotinolol hydrochloride rapid-release tablets, comprising the following steps:

[0019] a. Arotinolol hydrochloride and dextran, a stabilizer, a diluent, a disintegrant and a binder are mixed to prepare a mixed powder;

[0020] b. The mixed powder obtained in step a was dry granulated to obtain drug granules;

[0021] c. The drug particles obtained in step b are compressed to obtain tablet cores;

[0022] d. coating the tablet core obtained in step c with a coating layer.

[0023] In the above-mentioned method for preparing arotinolol hydrochloride rapid-release tablets, step a and / or step c further includes the step of adding a lubricant.

[0024] The arotinolol hydrochloride rapid-release tablets provided by the present invention can provide the prepared tablets with good dissolution through the combination of dextran and sodium laurate, and can also provide the arotinolol hydrochloride rapid-release tablets with good stability under long-term storage conditions. The present invention can be prepared using conventional preparation processes such as dry granulation and wet granulation, and is more suitable for industrial production. DETAILED DESCRIPTION

[0025] Example 1

[0026]

[0027]

[0028] Preparation method:

[0029] a. Arotinolol hydrochloride was mixed with dextran, sodium laurate, microcrystalline cellulose, pregelatinized starch, povidone and low-substituted hydroxypropyl cellulose to prepare a mixed powder;

[0030] b. The mixed powder obtained in step a was dry granulated to obtain drug granules;

[0031] c. The drug particles obtained in step b are compressed to obtain tablet cores;

[0032] d. Propyl gallate, hypromellose, polyethylene glycol and talc are added to an appropriate amount of purified water to prepare a coating solution, which is then applied to the core tablets to achieve a coating weight gain of 2-4%.

[0033] Example 2

[0034]

[0035] Preparation method:

[0036] a. Arotinolol hydrochloride was mixed with dextran, sodium laurate, lactose, mannitol, hydroxypropyl methylcellulose and cross-linked polyvinylpyrrolidone to obtain a mixed powder;

[0037] b. The mixed powder obtained in step a was dry granulated to obtain drug granules;

[0038] c. The drug particles obtained in step b are compressed to obtain tablet cores;

[0039] d. Propyl gallate, hypromellose, polyethylene glycol and talc are added to an appropriate amount of purified water to prepare a coating solution, which is then applied to the core tablets to achieve a coating weight gain of 2-4%.

[0040] Example 3

[0041]

[0042] Preparation method:

[0043] a. Arotinolol hydrochloride was mixed with dextran, sodium laurate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose and sodium carboxymethyl starch to prepare a mixed powder;

[0044] b. The mixed powder obtained in step a was dry granulated to obtain drug granules;

[0045] c. The drug particles obtained in step b are compressed to obtain tablet cores;

[0046] d. Propyl gallate, hypromellose, polyethylene glycol and talc are added to an appropriate amount of purified water to prepare a coating solution, which is then applied to the core tablets to achieve a coating weight gain of 2-4%.

[0047] Example 4

[0048]

[0049] Preparation method:

[0050] a. Arotinolol hydrochloride and dextran, sodium laurate, magnesium aspartate, calcium hydrogen phosphate, lactose, sodium carboxymethyl cellulose, croscarmellose sodium and low-substituted hydroxypropyl cellulose were mixed to prepare a mixed powder;

[0051] b. The mixed powder obtained in step a was dry granulated to obtain drug granules;

[0052] c. The drug particles obtained in step b are compressed to obtain tablet cores;

[0053] d. Propyl gallate, hypromellose, polyethylene glycol and talc are added to an appropriate amount of purified water to prepare a coating solution, which is then applied to the core tablets to achieve a coating weight gain of 2-4%.

[0054] Example 5

[0055]

[0056] Preparation method:

[0057] a. Arotinolol hydrochloride and dextran, sodium laurate, magnesium aspartate, microcrystalline cellulose, hydroxypropyl cellulose, povidone and croscarmellose sodium were uniformly mixed to prepare a mixed powder;

[0058] b. The mixed powder obtained in step a was dry granulated to obtain drug granules;

[0059] c The drug particles obtained in step b and talc were mixed uniformly and tableted to obtain core tablets;

[0060] d. Propyl gallate, hypromellose, polyethylene glycol and talc are added to an appropriate amount of purified water to prepare a coating solution, which is then applied to the core tablets to achieve a coating weight gain of 2-4%.

[0061] Example 6

[0062]

[0063]

[0064] Preparation method:

[0065] a. Arotinolol hydrochloride was mixed with dextran, sodium laurate, magnesium aspartate, microcrystalline cellulose, corn starch, povidone, sodium carboxymethyl starch and micropowdered silica gel to prepare a mixed powder;

[0066] b. The mixed powder obtained in step a was dry granulated to obtain drug granules;

[0067] c. The drug particles obtained in step b are mixed uniformly and tableted to obtain tablet cores;

[0068] d. Propyl gallate, hypromellose, polyethylene glycol and talc are added to an appropriate amount of purified water to prepare a coating solution, which is then applied to the core tablets to achieve a coating weight gain of 2-4%.

[0069] Example 7

[0070]

[0071] Preparation method:

[0072] a. Arotinolol hydrochloride was mixed with dextran, sodium laurate, magnesium aspartate, microcrystalline cellulose, mannitol, povidone and sodium carboxymethyl starch to prepare a mixed powder;

[0073] b. The mixed powder obtained in step a was dry granulated to obtain drug granules;

[0074] c The drug particles obtained in step b and hard sodium fumarate, talc are mixed uniformly and tableted to obtain a core tablet;

[0075] d. Propyl gallate, hypromellose, polyethylene glycol and talc are added to an appropriate amount of purified water to prepare a coating solution, which is then applied to the core tablets to achieve a coating weight gain of 2-4%.

[0076] Comparative Example

[0077]

[0078] The preparation method is the same as that of Example 1.

[0079] Comparative Example 7

[0080]

[0081]

[0082] Preparation method:

[0083] a. Arotinolol hydrochloride was mixed with dextran, sodium laurate, microcrystalline cellulose, pregelatinized starch, povidone and low-substituted hydroxypropyl cellulose to prepare a mixed powder;

[0084] b. The mixed powder obtained in step a was dry granulated to obtain drug granules;

[0085] c. The drug particles obtained in step b are compressed to obtain tablet cores;

[0086] d. Add an appropriate amount of purified water to Opadry to prepare a coating solution, and coat the core tablets with the coating solution to a coating weight gain of 2-4%.

[0087] Dissolution assay

[0088] Take the arotinolol hydrochloride rapid-release tablets of Example 1-7 and Comparative Example 1-7, use water as the dissolution medium, and follow the dissolution method (Chinese Pharmacopoeia 2020 Edition Part IV 0931 Dissolution and Dissolution Assay (Second Method)), the speed is 50 revolutions per minute, and the dissolution solution is taken at 5min, 10min, 15min, 30min, 45min, and 60min. HPLC determination is used to measure the dissolution (%), and the results are as follows:

[0089]

[0090] From the above data, it can be seen that the arotinolol hydrochloride rapid-release tablets prepared in Examples 1-7 of the present invention have an initial dissolution rate of more than 70% in 5 minutes, and can quickly achieve complete dissolution, with good dissolution. However, in Comparative Examples 1-7, dextran and the stabilizer sodium laurate were not added at the same time, and the resulting arotinolol hydrochloride rapid-release tablets had an initial dissolution rate of less than 45% in 5 minutes, which resulted in problems of slow dissolution and incomplete dissolution.

[0091] Stability test

[0092] Samples of arotinolol hydrochloride rapid-release tablets prepared in Examples 1-7 and Comparative Examples 1-7 were placed continuously at 25° C. and RH 60% for 24 months. The total impurity content (%) of arotinolol hydrochloride at 0 day and 24 months was determined by high performance liquid chromatography. The results are as follows:

[0093]

[0094] The tablets obtained in the above-described embodiments and comparative examples were subjected to stability tests and investigations. In Examples 1-7 of the present invention, the obtained arotinolol hydrochloride rapid-release tablets have good stability by the cooperation of dextran and the stabilizer sodium laurate. The increase in total impurities can be well controlled by long-term placement, thereby ensuring the patient's medication safety. The increase in magnesium aspartate helps to control the stability of the arotinolol hydrochloride rapid-release tablets, while dextran and the stabilizer sodium laurate are not added simultaneously in Comparative Examples 1-7. After 24 months of experiments, the related substances of the obtained arotinolol hydrochloride rapid-release tablets are significantly increased.

Claims

1. A rapid-release arotinolol hydrochloride tablet, characterized in that: The rapid-release tablet comprises a tablet core and a coating layer, wherein the tablet core comprises arotinolol hydrochloride, dextran, a stabilizer, a diluent, a disintegrant and a binder, and the stabilizer is sodium laurate.

2. The arotinolol hydrochloride rapid-release tablet according to claim 1, characterized in that The stabilizer further contains magnesium aspartate.

3. The arotinolol hydrochloride rapid-release tablet according to claim 1, characterized in that The diluent is one or more of calcium hydrogen phosphate, microcrystalline cellulose, corn starch, lactose, mannitol, and pregelatinized starch.

4. The arotinolol hydrochloride rapid-release tablet according to claim 1, characterized in that The disintegrant is one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose.

5. The arotinolol hydrochloride rapid-release tablet according to claim 1, characterized in that The binder is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, and sodium carboxymethyl cellulose.

6. The arotinolol hydrochloride rapid-release tablet according to claim 1, characterized in that The coating layer comprises propyl gallate, hypromellose, polyethylene glycol and talc.

7. The arotinolol hydrochloride rapid-release tablet according to claim 1, characterized in that The dosage of each component of the tablet core is calculated by mass as follows: 10 parts of arotinolol hydrochloride, 5-15 parts of dextran, 1-5 parts of stabilizer, 65-85 parts of diluent, 1-5 parts of disintegrant, and 1-5 parts of binder.

8. The arotinolol hydrochloride rapid-release tablet according to claim 1, characterized in that The tablet further contains a lubricant, which is one or more of micro powder silica gel, magnesium stearate, stearic acid, calcium stearate, talc, and hard sodium fumarate.

9. A method for preparing the arotinolol hydrochloride rapid-release tablets according to claim 1, characterized in that: The following steps are involved: a. Arotinolol hydrochloride and dextran, a stabilizer, a diluent, a disintegrant and a binder are mixed to prepare a mixed powder; b. The mixed powder obtained in step a was dry granulated to obtain drug granules; c. The drug particles obtained in step b are compressed to obtain tablet cores; d. coating the tablet core obtained in step c with a coating layer.

10. The method for preparing the arotinolol hydrochloride rapid-release tablets according to claim 9, wherein: The step a and / or step c further comprises the step of adding a lubricant.

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