Benidipine hydrochloride tablet and preparation method thereof
Patent Information
- Application Number
- CN202611405680.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-09-10
- Publication Date
- 2026-10-23
AI Technical Summary
[0004]因此，本发明要解决的技术问题在于克服现有盐酸贝尼地平片的制备工艺其对盐酸贝尼地平片的溶出性能提升有限的缺陷，进而提供了一种盐酸贝尼地平片及其制备方法
本发明首先将盐酸贝尼地平、玉米淀粉、乳糖、微晶纤维素进行混合，加入粘结剂水溶液进行湿法制粒；然后将湿颗粒置于沸腾干燥机中进行干燥，整粒；将润滑剂与整粒后的颗粒进行混合搅拌，压片，得到素片；将素片在密闭养护箱中进行养护，然后通入氮气和氩气混合气进行水平方向吹扫，之后关闭气流进行低频振动；振动结束后，将素片进行包衣，得到盐酸贝尼地平片。在压片之后将素片在密闭养护箱中进行养护，然后通入氮气和氩气混合气进行水平方向吹扫，之后关闭气流进行低频振动，可以有效提升片剂的溶出性能。
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a benidipine hydrochloride tablet and its preparation method. Background Technology
[0002] Hypertension, a chronic cardiovascular disease, can lead to stroke and kidney damage if blood pressure remains uncontrolled for a long time. Clinically, long-term oral antihypertensive medication is necessary to control blood pressure. Benidipine hydrochloride, a third-generation dihydropyridine calcium channel blocker, can effectively improve renal microcirculation and provide stable, long-lasting blood pressure reduction. Compared to drugs like amlodipine, benidipine hydrochloride has the advantage of a gentler antihypertensive effect.
[0003] Benidipine hydrochloride active pharmaceutical ingredient (API) is a yellow powder with poor water solubility. To improve the dissolution performance of benidipine hydrochloride tablets, existing methods mainly employ two approaches: formulation optimization and process improvement. From a formulation optimization perspective, most solutions improve tablet dissolution performance by replacing fillers, adjusting the type of disintegrant, or adding a small amount of surfactant. From a process improvement perspective, existing benidipine hydrochloride tablet preparation processes mostly involve directly mixing the API with excipients, wet granulation, drying, tableting, and then directly coating the tablets. However, existing benidipine hydrochloride tablet preparation processes offer limited improvement to the dissolution performance of benidipine hydrochloride tablets. Summary of the Invention
[0004] Therefore, the technical problem to be solved by the present invention is to overcome the defect that the existing preparation process of benidipine hydrochloride tablets has limited effect on improving the dissolution performance of benidipine hydrochloride tablets, and thus provides a benidipine hydrochloride tablet and its preparation method.
[0005] To solve the above problems, the present invention provides the following solution: A method for preparing benidipine hydrochloride tablets includes the following steps: 1) Mix benidipine hydrochloride, corn starch, lactose, and microcrystalline cellulose, and add an aqueous binder solution for wet granulation; 2) Place the wet granules in a fluidized bed dryer for drying and granulation; 3) Mix the lubricant with the granulated particles from step 2), stir, compress into tablets, and obtain plain tablets; 4) Curing the raw film in a sealed curing chamber, then purging it horizontally with a mixture of nitrogen and argon, and then shutting off the airflow to perform low-frequency vibration; 5) After vibration, the uncoated tablets are coated to obtain benidipine hydrochloride tablets.
[0006] In one optional implementation, in step 4), the raw film is kept in a sealed curing chamber at a constant temperature of 23-25°C and a relative humidity of 38-40% for 60-90 minutes.
[0007] In one optional embodiment, in step 4), the volume ratio of nitrogen to argon in the nitrogen-argon mixture is (3-6):1, the flow rate of the mixture is 0.04-0.07 m / s, and the horizontal purging time is 20-50 min; in the low-frequency vibration step, the vibration frequency is 3-5 Hz, the amplitude is 0.3-0.6 mm, and the time is 40-90 min.
[0008] In one optional embodiment, the mixing speed in step 1) is 90-100 rpm, the stirring time is 3-10 min, and the wet granulation time is 2-6 min; In step 2), the air inlet temperature is controlled at 60-70℃ and the moisture content is 1.0-2.5%.
[0009] In one optional embodiment, the adhesive aqueous solution is a polyvinyl alcohol aqueous solution with a concentration of 15-30 wt%. The lubricant is selected from at least one of talc, magnesium stearate, and calcium stearate.
[0010] In one optional embodiment, step 3) involves mixing and stirring at a speed of 10-20 rpm for 8-40 minutes.
[0011] In one alternative implementation, the coating step uses a gastrointestinal-soluble coating premix.
[0012] In one alternative embodiment, the particle size D90 of the benidipine hydrochloride is 10-15 μm.
[0013] In one alternative embodiment, the raw materials comprise the following components by weight percentage, based on the total weight of the unflakes: Benidipine hydrochloride: 4-6%; Corn starch: 30-35%; Lactose: 50-60%; Microcrystalline cellulose: 3-10%; Magnesium stearate: 0.5-1%; Polyvinyl alcohol: 2-5%.
[0014] The present invention also provides a benidipine hydrochloride tablet, which is prepared by the preparation method described above.
[0015] The technical solution of this invention has the following advantages: This invention first involves mixing benidipine hydrochloride, corn starch, lactose, and microcrystalline cellulose, then adding a binder aqueous solution for wet granulation. The wet granules are then dried and sized in a fluidized bed dryer. A lubricant is mixed and stirred with the sized granules, followed by tableting to obtain uncoated tablets. The uncoated tablets are then cured in a sealed curing chamber, followed by horizontal purging with a nitrogen and argon mixture, and then low-frequency vibration is applied with the gas flow stopped. After vibration, the uncoated tablets are coated to obtain benidipine hydrochloride tablets. Curing the uncoated tablets in a sealed curing chamber after tableting, followed by horizontal purging with a nitrogen and argon mixture, and then low-frequency vibration with the gas flow stopped, effectively improves the dissolution performance of the tablets. Detailed Implementation
[0016] The following embodiments are provided to further understand the present invention and are not limited to the preferred embodiments described herein, nor do they limit the scope of protection of the present invention.
[0017] Experimental steps or conditions not specified in the following embodiments of this invention can be implemented according to conventional experimental steps and conditions used in existing literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagents or instruments.
[0018] A method for preparing benidipine hydrochloride tablets includes the following steps: 1) Mix benidipine hydrochloride, corn starch, lactose, and microcrystalline cellulose, and add an aqueous binder solution for wet granulation; 2) Place the wet granules in a fluidized bed dryer for drying and granulation; 3) Mix the lubricant with the granulated particles from step 2), stir, compress into tablets, and obtain plain tablets; 4) Curing the raw film in a sealed curing chamber, then purging it horizontally with a mixture of nitrogen and argon, and then shutting off the airflow to perform low-frequency vibration; 5) After vibration, the uncoated tablets are coated to obtain benidipine hydrochloride tablets.
[0019] The existing preparation process of benidipine hydrochloride tablets mostly involves directly mixing the active pharmaceutical ingredient with excipients, wet granulation, drying, tableting, and direct coating after tableting. After tableting, the polymer excipient chains inside the tablet have a large amount of compression memory stress, and the internal micropores are disordered, with a large number of closed blind pores and semi-through pores, which affect the dissolution performance of the tablet. This invention involves curing the tablets in a sealed curing chamber after compression, followed by horizontal purging with a mixture of nitrogen and argon. The airflow is then shut off, and low-frequency vibration is applied. A nitrogen-argon mixture with a volume ratio of (3-6):1 is preferred for horizontal purging. Argon purging helps eliminate residual tribostatic charge on the surface and inner walls of micropores, reducing micropore blockage caused by electrostatic adsorption. Furthermore, argon's higher density allows the mixture to form a dense, inert gas film on the tablet surface, inhibiting drug oxidation. The mixture also provides suitable gas flow, progressively clearing surface, middle, and deep micropores from the outside in. Combined with subsequent low-frequency vibration, this achieves interconnection and bonding of disordered micropores, effectively improving the tablet's dissolution performance. In addition, the product prepared by this invention exhibits excellent content uniformity.
[0020] In one optional implementation, in step 4), the raw film is kept in a sealed curing chamber at a constant temperature of 23-25°C and a relative humidity of 38-40% for 60-90 minutes.
[0021] In one optional embodiment, in step 4), the volume ratio of nitrogen to argon in the nitrogen-argon mixture is (3-6):1, the flow rate of the mixture is 0.04-0.07 m / s, and the horizontal purging time is 20-50 min; in the low-frequency vibration step, the vibration frequency is 3-5 Hz, the amplitude is 0.3-0.6 mm, and the time is 40-90 min.
[0022] In one optional embodiment, the mixing speed in step 1) is 90-100 rpm, the stirring time is 3-10 min, and the wet granulation time is 2-6 min; In step 2), the air inlet temperature is controlled at 60-70℃ and the moisture content is 1.0-2.5%.
[0023] In one optional embodiment, the adhesive aqueous solution is a polyvinyl alcohol aqueous solution with a concentration of 15-30 wt%. The lubricant is selected from at least one of talc, magnesium stearate, and calcium stearate.
[0024] In one optional embodiment, step 3) involves mixing and stirring at a speed of 10-20 rpm for 8-40 minutes.
[0025] In one optional embodiment, the coating step uses a gastric-soluble coating premix. This invention does not have special requirements for the gastric-soluble coating premix; any conventional gastric-soluble coating premix in the art can achieve the purpose of this invention, resulting in a coating weight gain of 3.5-5%. This invention selects a 10% gastric-soluble Opadry suspension, model Opadry 03F620040-CN.
[0026] In one optional embodiment, the particle size D90 of the benidipine hydrochloride is 10-15 μm. This invention does not specifically limit the source of the benidipine hydrochloride; it can be commercially available, such as that used in this invention, or prepared using conventional methods in the art. Optionally, it can be prepared in the following manner: .
[0027] In an alternative embodiment, step 1) further includes granulation in a 14-17 mesh oscillating granulator.
[0028] In an alternative embodiment, step 2) further includes the step of granulating the particles by placing them in a granulator and passing them through an 18-22 mesh sieve.
[0029] This invention does not specifically limit the selection of excipients. In one optional embodiment, based on the total weight of the unflakes, the raw materials include the following components by weight percentage: Benidipine hydrochloride: 4-6%; Corn starch: 30-35%; Lactose: 50-60%; Microcrystalline cellulose: 3-10%; Magnesium stearate: 0.5-1%; Polyvinyl alcohol: 2-5%.
[0030] The present invention also provides a benidipine hydrochloride tablet, which is prepared by the preparation method described above.
[0031] Example 1
[0032] This embodiment provides a method for preparing benidipine hydrochloride tablets, the raw material ratio of which is as follows:
[0033] Its preparation method includes the following steps: 1) Add benidipine hydrochloride, corn starch, lactose, and microcrystalline cellulose to a wet mixing granulator, turn on the stirring, the speed is 95 rpm, the stirring time is 5 min, add 25 wt% polyvinyl alcohol aqueous solution through atomization, wet granulate for 2 min, and then place it in a 16 mesh swing granulator for granulation. 2) Place the wet granules in a fluidized bed dryer to dry them, controlling the inlet air temperature to 65℃ and the moisture content to 1.8%. Then place the granules in a granulator and pass them through a 20-mesh sieve for granulation. 3) Add magnesium stearate and the granulated particles from step 2) to a mixer and mix at 12 rpm for 12 minutes. Compress the mixture into tablets with a hardness of 55 N to obtain uncoated tablets. 4) Curing in a sealed curing chamber at a constant temperature of 23℃ and relative humidity of 38% for 60 minutes, then purging with a mixture of dry nitrogen and argon gas (volume ratio of nitrogen to argon of 4:1) at a flow rate of 0.05m / s for 30 minutes in a horizontal direction, then turning off the airflow and placing it on a triaxial vibration table for low-frequency vibration at a frequency of 5Hz and an amplitude of 0.5mm for 60 minutes. 5) The uncoated tablets were coated with 10% gastric-soluble Opadry suspension, resulting in a 4.2% weight gain, thus obtaining benidipine hydrochloride tablets.
[0034] Example 2
[0035] This embodiment provides a method for preparing benidipine hydrochloride tablets, which differs from Example 1 in that it includes the following steps: 1) Add benidipine hydrochloride, corn starch, lactose, and microcrystalline cellulose to a wet mixing granulator, turn on the stirring, the speed is 98 rpm, the stirring time is 7 min, add 25 wt% polyvinyl alcohol aqueous solution through atomization, wet granulate for 4 min, and then place it in a 16 mesh swing granulator for granulation. 2) Place the wet granules in a fluidized bed dryer to dry them, controlling the inlet air temperature to 65℃ and the moisture content to 1.5%. Then place the granules in a granulator and pass them through a 20-mesh sieve for granulation. 3) Add magnesium stearate and the granulated particles from step 2) to a mixer and mix at 12 rpm for 15 minutes. Compress the mixture into tablets with a hardness of 58 N to obtain uncoated tablets. 4) Curing in a sealed curing chamber at a constant temperature of 23℃ and relative humidity of 38% for 70 minutes, then introducing a mixture of dry nitrogen and argon gas (volume ratio of nitrogen to argon of 4:1) at a flow rate of 0.05m / s for horizontal purging for 40 minutes, then turning off the airflow and placing it on a triaxial vibration table for low-frequency vibration at a frequency of 5Hz and an amplitude of 0.5mm for 50 minutes. 5) The uncoated tablets were coated with 10% gastric-soluble Opadry suspension, resulting in a 4.4% weight gain, thus obtaining benidipine hydrochloride tablets.
[0036] Example 3
[0037] This embodiment provides a method for preparing benidipine hydrochloride tablets, which differs from Example 1 in that it includes the following steps: 1) Add benidipine hydrochloride, corn starch, lactose, and microcrystalline cellulose to a wet mixing granulator, turn on the stirring, the speed is 95 rpm, the stirring time is 7 min, add 28 wt% polyvinyl alcohol aqueous solution through atomization, wet granulate for 3 min, and then place it in a 16 mesh swing granulator for granulation. 2) Place the wet granules in a fluidized bed dryer to dry them, controlling the inlet air temperature to 65℃ and the moisture content to 1.6%. Then place the granules in a granulator and pass them through a 20-mesh sieve for granulation. 3) Add magnesium stearate and the granulated particles from step 2) to a mixer and mix at 12 rpm for 20 minutes. Compress the mixture into tablets with a hardness of 53 N to obtain unprocessed tablets. 4) Curing in a sealed curing chamber at a constant temperature of 23℃ and relative humidity of 38% for 60 minutes, then purging with a mixture of dry nitrogen and argon gas (volume ratio of nitrogen to argon of 4:1) at a flow rate of 0.05 m / s for 40 minutes in a horizontal direction, then turning off the airflow and placing it on a triaxial vibration table for low-frequency vibration at a frequency of 5 Hz and an amplitude of 0.5 mm for 70 minutes. 5) The uncoated tablets were coated with 10% Opadryl suspension for gastric dissolution. The coating weight increased by 4.1%, resulting in benidipine hydrochloride tablets.
[0038] Example 4
[0039] This embodiment provides a method for preparing benidipine hydrochloride tablets, which differs from Example 1 in that it includes the following steps: 1) Add benidipine hydrochloride, corn starch, lactose, and microcrystalline cellulose to a wet mixing granulator, turn on the stirring, the speed is 95 rpm, the stirring time is 7 min, add 25 wt% polyvinyl alcohol aqueous solution through atomization, wet granulate for 3.5 min, and then place it in a 15 mesh swing granulator for granulation. 2) Place the wet granules in a fluidized bed dryer to dry them, controlling the inlet air temperature to 65℃ and the moisture content to 1.7%. Then place the granules in a granulator and pass them through a 20-mesh sieve for granulation. 3) Add magnesium stearate and the granulated particles from step 2) to a mixer and mix at 15 rpm for 28 minutes. Compress the mixture into tablets with a hardness of 49 N to obtain uncoated tablets. 4) Curing in a sealed curing chamber at a constant temperature of 23℃ and relative humidity of 38% for 60 minutes, then purging with a mixture of dry nitrogen and argon gas (volume ratio of nitrogen to argon of 4:1) at a flow rate of 0.07 m / s for 45 minutes in the horizontal direction, then turning off the airflow, and placing it on a triaxial vibration table for low-frequency vibration at a frequency of 5 Hz and an amplitude of 0.5 mm for 70 minutes; 5) The uncoated tablets were coated with 10% gastric-soluble Opadry suspension, resulting in a 3.8% weight gain, thus obtaining benidipine hydrochloride tablets.
[0040] Example 5
[0041] This embodiment provides a method for preparing benidipine hydrochloride tablets, which differs from Example 1 in that it includes the following steps: 1) Add benidipine hydrochloride, corn starch, lactose, and microcrystalline cellulose to a wet mixing granulator, turn on the stirring, the speed is 98 rpm, the stirring time is 6 min, add 25 wt% polyvinyl alcohol aqueous solution through atomization, wet granulate for 2.5 min, and then place it in a 16 mesh swing granulator for granulation. 2) Place the wet granules in a fluidized bed dryer to dry them, controlling the inlet air temperature to 65℃ and the moisture content to 1.2%. Then place the granules in a granulator and pass them through a 20-mesh sieve for granulation. 3) Add magnesium stearate and the granulated particles from step 2) to a mixer and mix at 18 rpm for 24 min. Compress the mixture into tablets with a hardness of 51 N to obtain uncoated tablets. 4) Curing in a sealed curing chamber at a constant temperature of 23℃ and relative humidity of 38% for 60 minutes, then purging with a mixture of dry nitrogen and argon gas (volume ratio of nitrogen to argon of 4:1) at a flow rate of 0.07 m / s for 40 minutes in a horizontal direction, then turning off the airflow and placing it on a triaxial vibration table for low-frequency vibration at a frequency of 5 Hz and an amplitude of 0.5 mm for 65 minutes; 5) The uncoated tablets were coated with 10% gastric-soluble Opadry suspension, resulting in a 4.7% weight gain, thus obtaining benidipine hydrochloride tablets.
[0042] Comparative Example 1 This comparative example provides a method for preparing benidipine hydrochloride tablets, which differs from Example 1 in that step 4) is omitted, and the uncoated tablets are directly coated in step 5).
[0043] Comparative Example 2 This comparative example provides a method for preparing benidipine hydrochloride tablets, which differs from Example 1 in that in step 4), the tablets are cured in a sealed curing chamber at a constant temperature of 23°C and a relative humidity of 38% for 60 minutes. Then, dry nitrogen gas with a flow rate of 0.05 m / s is introduced and the tablets are purged horizontally for 30 minutes. After that, the airflow is turned off and the tablets are placed on a triaxial vibration table for low-frequency vibration at a frequency of 5 Hz and an amplitude of 0.5 mm for 60 minutes.
[0044] Comparative Example 3 This comparative example provides a method for preparing benidipine hydrochloride tablets, which differs from Example 1 in that in step 4), the tablets are cured in a sealed curing chamber at a constant temperature of 23°C and a relative humidity of 38% for 60 minutes, and then a mixture of dry nitrogen and argon gas (volume ratio of nitrogen to argon gas of 4:1) is introduced at a flow rate of 0.05 m / s for horizontal purging for 30 minutes.
[0045] Test case 1. The properties, friability, and content uniformity of the benidipine hydrochloride tablets prepared in Examples 1-5 were tested. The friability was tested according to the tablet friability test method in the General Chapter of Part IV of the 2020 Chinese Pharmacopoeia. The content uniformity was tested according to the content uniformity test method in General Chapter 0941 of the 2020 Chinese Pharmacopoeia (n=10), and A+2.2S was calculated.
[0046] The test results are shown in Table 1.
[0047] Table 1
[0048] 2. The dissolution performance of Examples 1 and Comparative Examples 1-3 was tested according to the second method (paddle method) of General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia. The dissolution medium was 500 mL of 0.1 M hydrochloric acid solution, and the dissolution rate was 50 rpm. The control sample was a marketed product, Kyowa Kirin Benidipine Hydrochloride Tablets. The test results are shown in Table 2.
[0049] Table 2 Cumulative dissolution percentage (%)
[0050] Obviously, those skilled in the art can make other modifications based on the above embodiments, and the obvious modifications therefrom are still within the protection scope of this invention.
Claims
1. A method for preparing benidipine hydrochloride tablets, characterized in that, Includes the following steps: 1) Mix benidipine hydrochloride, corn starch, lactose, and microcrystalline cellulose, and add an aqueous binder solution for wet granulation; 2) Place the wet granules in a fluidized bed dryer for drying and granulation; 3) Mix the lubricant with the granulated particles from step 2), stir, compress into tablets, and obtain plain tablets; 4) Curing the raw film in a sealed curing chamber, then purging it horizontally with a mixture of nitrogen and argon, and then shutting off the airflow to perform low-frequency vibration; 5) After vibration, the uncoated tablets are coated to obtain benidipine hydrochloride tablets.
2. The method for preparing benidipine hydrochloride tablets according to claim 1, characterized in that, In step 4), the raw film is kept in a sealed curing chamber at a constant temperature of 23-25℃ and a relative humidity of 38-40% for 60-90 minutes.
3. The method for preparing benidipine hydrochloride tablets according to claim 1 or 2, characterized in that, In step 4), the volume ratio of nitrogen to argon in the nitrogen-argon mixture is (3-6):1, the flow rate of the mixture is 0.04-0.07 m / s, and the horizontal purging time is 20-50 min; in the low-frequency vibration step, the vibration frequency is 3-5 Hz, the amplitude is 0.3-0.6 mm, and the time is 40-90 min.
4. The method for preparing benidipine hydrochloride tablets according to claim 1 or 2, characterized in that, In step 1), the mixing speed is 90-100 rpm and the stirring time is 3-10 min; the wet granulation time is 2-6 min. In step 2), the air inlet temperature is controlled at 60-70℃ and the moisture content is 1.0-2.5%.
5. The method for preparing benidipine hydrochloride tablets according to claim 1 or 2, characterized in that, The adhesive aqueous solution is a polyvinyl alcohol aqueous solution with a concentration of 15-30 wt%. The lubricant is selected from at least one of talc, magnesium stearate, and calcium stearate.
6. The method for preparing benidipine hydrochloride tablets according to claim 1 or 2, characterized in that, Step 3) Mix and stir at 10-20 rpm for 8-40 minutes.
7. The method for preparing benidipine hydrochloride tablets according to claim 1 or 2, characterized in that, The coating process uses a gastrointestinal-soluble coating premix.
8. The method for preparing benidipine hydrochloride tablets according to claim 1 or 2, characterized in that, The particle size D90 of the benidipine hydrochloride is 10-15 μm.
9. The method for preparing benidipine hydrochloride tablets according to claim 1 or 2, characterized in that, Based on the total weight of the unflakes, the raw materials consist of the following components by weight percentage: Benidipine hydrochloride: 4-6%; Corn starch: 30-35%; Lactose: 50-60%; Microcrystalline cellulose: 3-10%; Magnesium stearate: 0.5-1%; Polyvinyl alcohol: 2-5%.
10. A benidipine hydrochloride tablet, characterized in that, It is prepared by the preparation method according to any one of claims 1-9.