Tablet calcium channel blocker and preparation method thereof

Abstract

The invention discloses a tablet calcium channel blocker and a preparation method thereof, the tablet calcium channel blocker is composed of a tablet core and a coating material, the tablet core comprises benidipine hydrochloride, a filler, a disintegrating agent, an adhesive and a lubricant; wherein the disintegrating agent is composed of potato starch and carboxymethyl starch sodium, and the obtained tablet calcium channel blocker has good dissolution rate, stability and bioequivalence.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical preparations, and in particular relates to a tablet calcium channel blocker and a preparation method thereof. Background Art

[0002] Benidipine hydrochloride is a calcium channel blocker antihypertensive drug. It acts on calcium ion channels on vascular smooth muscle cells, blocks the excitation-contraction coupling triggered by calcium ion influx, relaxes blood vessels and lowers blood pressure. It is particularly suitable for patients with hypertension whose main manifestation is increased systolic blood pressure. In addition to its antihypertensive effect, benidipine also has an anti-atherosclerotic effect. Therefore, it is particularly suitable for patients with hypertension accompanied by coronary heart disease, carotid artery stenosis, and lower limb artery occlusion. In addition to its antihypertensive effect, benidipine hydrochloride can also treat angina pectoris caused by coronary heart disease.

[0003] Benidipine hydrochloride tablets were developed by Kyowa Hakko Kirin Co., Ltd. of Japan and were approved for tablets in October 1991 under the trade name Coniel Tablets, with specifications of 2mg, 4mg, and 8mg. In 2005, the preparation and API were included in the Japanese Pharmacopoeia. In 2014, the original research was imported into China under the trade name of Coniel, with the marketed specifications of 4mg and 8mg.

[0004] In the study of the control preparation benidipine hydrochloride tablets (licensed by Kyowa Hakko Kirin Co., Ltd., specification: 8 mg), we found that the dissolution and bioequivalence of the existing product had significant fluctuations in in vitro and in vivo experiments. Such fluctuations may increase the safety risk of clinical medication.

[0005] At the same time, when studying the control preparation of benidipine hydrochloride tablets, we found that the content of related substances fluctuated greatly. The presence of these related substances directly affects the purity and efficacy of the drug, and thus is related to the safety of drug use. Since benidipine hydrochloride tablets need to strictly control the limits of related substances to ensure their safety and effectiveness, such fluctuations may bring certain risks to clinical drug use.

[0006] Patent CN102166212A discloses a method for rapidly dissolving benidipine hydrochloride from a tablet, wherein in a tablet containing benidipine hydrochloride, the volume average particle size of benidipine hydrochloride crystals is 4.5 to 30.0 μm, or the volume average particle size and number average particle size of benidipine hydrochloride crystals are 4.5 to 30.0 μm. The method mainly involves controlling the particle size of the raw materials to solve the problem of benidipine hydrochloride dissolution, but does not solve the problem of related substances and in vivo absorption.

[0007] Patent CN118717697A discloses a benidipine hydrochloride tablet composition and its preparation method and application, which solves the problem of content uniformity by loosening and calcifying the raw materials so that the granulation can be uniform even when a high-viscosity adhesive is used for granulation. However, it does not involve verification of in vivo absorption. Summary of the invention

[0008] In order to solve the problems existing in the prior art, the present invention provides a tablet calcium channel blocker, which consists of a tablet core and a coating material. The tablet core includes benidipine hydrochloride, a filler, a disintegrant, a binder and a lubricant; wherein the disintegrant is composed of potato starch and sodium starch glycolate.

[0009] Furthermore, the mass ratio of the potato starch to the sodium starch glycolate is 1:(1-3).

[0010] Furthermore, in parts by weight, the tablet core comprises 5 to 10 parts of benidipine hydrochloride, 100 to 120 parts of filler, 60 to 75 parts of disintegrant, 5 to 15 parts of binder and 1 to 5 parts of lubricant.

[0011] Furthermore, in parts by weight, the tablet core comprises 7 to 10 parts of benidipine hydrochloride, 111 to 114 parts of filler, 67 to 68 parts of disintegrant, 8 to 10 parts of binder and 2 to 3 parts of lubricant.

[0012] Furthermore, the particle size D90 of the benidipine hydrochloride is less than 5 μm.

[0013] Furthermore, it is characterized in that the filler is lactose, the binder is polyvinyl alcohol, and the lubricant is magnesium stearate.

[0014] Furthermore, the coating material is a gastric soluble film coating premix.

[0015] On the other hand, the present invention provides a method for preparing the above-mentioned tablet calcium channel blocker, comprising the following steps: (1) pretreatment of raw materials and auxiliary materials; (2) premixing: mixing benidipine hydrochloride, a filler and a disintegrant to obtain a premixed material; (3) wet granulation: preparing an aqueous binder solution; adding the aqueous binder solution to the premixed material obtained in step (2) by a peristaltic pump; and wet granulating after granulation; (4) drying: drying the wet granules obtained in step (3) to control the moisture content of the material to be ≤4%; (5) granulating: granulating the dried granules; (6) total mixing: mixing the granules obtained in step (5) with a lubricant; (7) tableting: tableting according to a predetermined tablet weight; (8) coating: using a fluidized bed for coating to control the coating weight gain to be 2% to 4%; drying the coated material to obtain a tablet calcium channel blocker.

[0016] Furthermore, the pretreatment of the lactose is to pass through a 200-mesh sieve.

[0017] Furthermore, the preparation process of the adhesive aqueous solution in step (3) is as follows: polyvinyl alcohol is added to purified water at 60-70° C. and stirred to dissolve to prepare a polyvinyl alcohol aqueous solution with a concentration of 25% (w / w).

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] (1) The present invention ensures that the content of related substances of the calcium channel blocker tablet (hereinafter referred to as "benidipine hydrochloride tablet") meets the limit requirements and has good in vitro dissolution through precise control of the particle size of the disintegrant and the raw material drug.

[0020] (2) At the same time, the prepared benidipine hydrochloride tablets can achieve bioequivalence with commercially available products in terms of in vivo absorption.

[0021] (3) In addition, the preparation process of the present invention is simple, easy to implement large-scale production, and has good application prospects. DETAILED DESCRIPTION

[0022] The technical solutions in the embodiments of the present application are clearly described below. Obviously, the described embodiments are part of the embodiments of the present application, rather than all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments in the present application belong to the scope of protection of the present application.

[0023] The terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated with each other are in an "or" relationship.

[0024] 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.

[0025] After an in-depth analysis of commercially available benidipine hydrochloride tablets, we reproduced the original preparation scheme to obtain benidipine hydrochloride tablets, whose content, related substances and dissolution indicators are similar to those of commercially available products. However, in the in vivo bioequivalence study, it was found that its absorption stability was not ideal. This instability in absorption may pose a certain risk to the clinical safety of the drug. In order to solve this problem, we further optimized the existing prescription and process to ensure the bioequivalence and safety of the drug, thereby improving its reliability in clinical application. The details are as follows:

[0026] A benidipine hydrochloride tablet consists of a tablet core and a coating material. The tablet core comprises benidipine hydrochloride, a filler, a disintegrant, a binder and a lubricant; wherein the disintegrant is composed of potato starch and sodium starch glycolate.

[0027] In one embodiment of the present invention, the mass ratio of the potato starch to the sodium starch glycolate is 1:(1-3), such as 1:1, 1:2 or 1:3, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0028] In the benidipine hydrochloride tablet preparation of the present invention, potato starch is carefully selected as a disintegrant, which is a multi-purpose excipient, mainly used in oral solid preparations, as an adhesive, diluent and disintegrant. Sodium carboxymethyl starch, as another commonly used disintegrant, although its specific mechanism of action is not yet fully clear, the innovation of the present invention is that the inventor has found a specific proportional relationship by finely adjusting the ratio of potato starch and sodium carboxymethyl starch. This proportional relationship not only effectively ensures the control of the content of related substances in benidipine hydrochloride tablets, but also ensures its bioequivalence, thereby improving the efficacy and safety of the drug.

[0029] In one embodiment of the present invention, the core of the benidipine hydrochloride tablet comprises, by weight, 5-10 parts of benidipine hydrochloride, 100-120 parts of filler, 60-75 parts of disintegrant, 5-15 parts of binder and 1-5 parts of lubricant, preferably 7-10 parts of benidipine hydrochloride, 111-114 parts of filler, 67-68 parts of disintegrant, 8-10 parts of binder and 2-3 parts of lubricant, further preferably 8 parts of benidipine hydrochloride, 111-114 parts of filler, 67-68 parts of disintegrant, 9-10 parts of binder and 2-3 parts of lubricant.

[0030] In one embodiment of the present invention, the particle size D90 of the benidipine hydrochloride is less than 5 μm, such as 1 μm, 2 μm, 3 μm or 4 μm, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0031] Benidipine hydrochloride, as a BCS Class II drug, has low solubility in water but high permeability. Therefore, controlling its particle size is one of the key strategies to improve dissolution rate and bioavailability. Reducing the particle size can significantly improve the dissolution performance, but it may also increase the risk of impurities during the production process. In order to balance this contradiction, the particle size must be carefully controlled to ensure the quality and efficacy of the drug. By optimizing the particle size control, the generation of related substances can be effectively reduced, thereby ensuring the bioequivalence of the drug in vivo, which is crucial to improving the clinical safety and efficacy of the drug. In addition, particle size control also involves the stability of the drug and the consistency of the production process.

[0032] In one embodiment of the present invention, the filler is selected from lactose, the binder is selected from polyvinyl alcohol, the lubricant is selected from magnesium stearate, and the coating material is selected from gastric soluble film coating premix. The present invention does not limit the source and type of raw materials and auxiliary materials, as long as they can meet the pharmaceutical requirements.

[0033] In one embodiment of the present invention, the preparation method of the benidipine hydrochloride tablets comprises the following steps: (1) pretreatment of raw materials and auxiliary materials; (2) premixing: mixing benidipine hydrochloride, a filler and a disintegrant to obtain a premixed material; (3) wet granulation: preparing an aqueous binder solution; adding the aqueous binder solution to the premixed material obtained in step (2) by a peristaltic pump; and wet granulating after granulation; (4) drying: drying the wet granules obtained in step (3) to control the moisture content of the material to be ≤4%; (5) granulating: granulating the dried granules; (6) total mixing: mixing the granules obtained in step (5) with a lubricant; (7) tableting: tableting according to a predetermined tablet weight; (8) coating: using a fluidized bed for coating to control the coating weight gain to be 2% to 4%; drying the coated material to obtain benidipine hydrochloride tablets.

[0034] In one embodiment of the present invention, the pretreatment of the lactose is passing through a 200-mesh sieve.

[0035] In the present invention, lactose plays a vital role as the main filler in the prescription. It not only promotes the formation of particles, but also helps the penetration of water into the interior of the tablet, thereby accelerating the disintegration and dissolution of the drug. Lactose monohydrate has a high solubility in water due to its hydrophilic nature, which makes it an ideal filler choice in oral solid preparations. In addition, lactose can also be used as a binder to enhance the adhesion of particles.

[0036] By precisely controlling the particle size of lactose, the dissolution performance of benidipine hydrochloride tablets can be significantly improved, which is critical for improving the bioavailability of drugs. However, the reduction in particle size may bring the risk of increased impurities. To this end, we have implemented fine control of the particle size of lactose to ensure that while improving the dissolution, the purity and quality of the drug are maintained, thereby ensuring that the content of related substances and bioequivalence of benidipine hydrochloride tablets meet the specified standards.

[0037] This precise control of lactose particle size not only optimizes the drug release characteristics, but also ensures the consistency and stability of the formulation, providing patients with a safer and more effective treatment option.

[0038] In one embodiment of the present invention, the binder aqueous solution in step (3) is prepared as follows: polyvinyl alcohol is added to purified water at 60-70° C. and stirred to dissolve to prepare a polyvinyl alcohol aqueous solution with a concentration of 25% (w / w).

[0039] The present invention does not impose any restrictions on the specific parameters in the preparation process, as long as the corresponding functions can be achieved.

[0040] The following are specific examples of the present invention and comparative examples, but the present invention is not limited to the following examples.

[0041] Table 1 Source information of raw materials and auxiliary materials of Examples and Comparative Examples

[0042]

[0043]

[0044] Table 2 Main equipment information used in the examples and comparative examples

[0045] Device Name model Manufacturer Tablet Press ZPS8 Shanghai Xinyuan Pharmaceutical Machinery Co., Ltd. Wet Mixing Granulator Mini-CG Chuangzhi Technology (Jiangsu) Co., Ltd. Fluidized Bed FLZB-3.0 Chuangzhi Technology (Jiangsu) Co., Ltd.

[0046] The prescription compositions (by weight) of the benidipine hydrochloride tablets of Examples 1 to 4 and Comparative Examples 1 to 4 are shown in Table 3:

[0047] Table 3 Example and Comparative Example Benidipine Hydrochloride Tablets Prescription Composition (mg / tablet)

[0048]

[0049] The preparation methods of the benidipine hydrochloride tablets provided in Examples 1 to 4 and Comparative Examples 1 to 4 are as follows: (taking 5000 tablets as an example)

[0050] (1) Pretreatment

[0051] 1) Check the particle size of benidipine hydrochloride to ensure that D90 < 5 μm. If the particle size exceeds the standard, it needs to be re-crushed.

[0052] 2) Pass lactose through a 200-mesh sieve.

[0053] 3) Pass potato starch and sodium carboxymethyl starch through a 60-mesh sieve respectively.

[0054] (2) Premix

[0055] Add the prescribed amount of lactose, potato starch (if any), sodium starch glycolate (if any), and benidipine hydrochloride into a wet granulator, set the stirring speed of the granulator to 150 rpm and the cutting speed to 900 rpm, and mix for 10 minutes.

[0056] (3) Wet granulation

[0057] 1) Preparation of adhesive aqueous solution: Add the prescribed amount of polyvinyl alcohol into purified water at 60-70° C. and stir to dissolve to prepare a polyvinyl alcohol aqueous solution with a concentration of 25% (w / w).

[0058] 2) Set the stirring speed to 150 rpm, the cutting speed to 1200 rpm, start the wet granulator and the peristaltic pump, control the liquid addition time to 4 to 6 minutes, and continue granulation for 5 to 7 minutes after the liquid addition is completed.

[0059] 3) After granulation, pass through a 2.0 mm sieve for wet granulation.

[0060] (4) Drying

[0061] Control the inlet air temperature of the fluidized bed at 60±5℃, place the wet particles in the fluidized bed for drying, adjust the inlet air volume until the material is in a fluidized state, when the material temperature reaches 40-45℃, stop heating, take samples to test the moisture, and stop discharging when the moisture is ≤4%.

[0062] (5) Whole grain

[0063] The dried granules were sized using a granulator (sieve size 1.0 mm).

[0064] (6) Total Mixing

[0065] The granules after granulation and the prescribed amount of magnesium stearate were placed in a hopper mixer for mixing at a mixing speed of 10 rpm and a mixing time of 5 min.

[0066] (7) Tableting

[0067] Use 8 mm round punch for tableting, control the tablet weight to 200 mg (190-210 mg), and the hardness to 50-70 N to obtain benidipine hydrochloride tablets.

[0068] (8) Coating

[0069] 1) Preparation of the coating solution (12%): Weigh the film coating premix and purified water. Pour the purified water into a beaker, slowly add the film coating premix, and stir while adding. After adding all the coating powder, stir for at least 45 minutes and keep stirring continuously until the coating is completed.

[0070] 2) Add the plain tablets into a high - efficiency coating machine. Set the inlet air temperature at 60 °C and pre - heat until the tablet bed temperature reaches 40 ± 5 °C, then start spraying the liquid. When spraying the liquid, set the main machine rotation speed at 3 - 5 rpm, the atomization pressure at 0.2 - 0.5 MPa, and control the tablet bed temperature at 40 ± 5 °C during the coating process. Stop spraying the coating solution when the coating weight gain reaches 2% - 4%.

[0071] 3) Drying: Continue drying for 10 minutes, turn off the heating, wait until the material temperature cools below 35 °C, stop the machine and discharge the material to obtain benidipine hydrochloride tablets.

[0072] Comparative Example 5

[0073] In the pretreatment of step (1), control the particle size of benidipine hydrochloride to be 5 μm < D90 < 15 μm. The prescription composition and other preparation methods are the same as those in Example 1.

[0074] Comparative Example 6

[0075] Refer to Example 1 of CN1794993A to prepare benidipine hydrochloride tablets. The specific prescription and process are as follows:

[0076] 5000 g of benidipine hydrochloride raw drug is pulverized. Control the volume - average particle size of benidipine hydrochloride to be 9.4 μm and the number - average particle size to be 4.9 μm. The prescription composition is as follows:

[0077] Table 4 Prescription composition of Comparative Example 6

[0078] Crushed benidipine hydrochloride crystals 4.33kg lactose 68.69kg Potato starch 41.38kg Polyvinyl alcohol 4.2kg Magnesium Stearate 1.4kg total 120.0kg

[0079] Preparation process:

[0080] Under the spray of an aqueous solution of polyvinyl alcohol, granulate the pulverized benidipine hydrochloride crystals, lactose, and potato starch with a fluidized - bed granulator, and then mix magnesium stearate as a lubricant with a V - type mixer to obtain granules for tableting. Use these granules for tableting to obtain tablets with a tablet diameter Tablets with a tablet weight of 130 mg.

[0081] Determine the disintegration time limit, dissolution rate, related substances, and in - vivo absorption of the benidipine hydrochloride tablets obtained in Examples 1 - 4 and Comparative Examples 1 - 6 and the commercially available product ( Batch number: 712ABL, Manufacturer: Kyowa Kirin Co,Ltd.):

[0082] The disintegration time of the film coating was determined according to the method of 0921 of the General Rules of Part IV of the Chinese Pharmacopoeia 2020, and the results are as follows:

[0083] Table 5 Disintegration time results

[0084]

[0085]

[0086] Disintegration time reflects the initial dispersion speed of drug preparation in vivo, and is the prerequisite for whether drug can be effectively released and absorbed. According to the pharmacopoeia, chemical drug film-coated tablets should be completely disintegrated within 30 minutes, and the benidipine hydrochloride tablets obtained by the embodiment can be completely disintegrated within 30 minutes, but the complete disintegration time of the benidipine hydrochloride tablets obtained by the comparative example is greater than 30 minutes, which can not meet the requirement of disintegration time, and the disintegration time difference with commercially available products is large at the same time. This difference may be one of the important reasons causing subsequent bioequivalence. In order to ensure the effectiveness and safety of the drug, it is necessary to further optimize the formulation and production process, to reduce the fluctuation of disintegration time, improve the bioavailability and clinical efficacy of the drug.

[0087] According to the second method of 0931 of the fourth volume of the 2020 edition of the Chinese Pharmacopoeia, the dissolution rate at 45 minutes is determined, which requires that the dissolution rate at 45 minutes should not be less than 85% of the labeled amount. The results are as follows:

[0088] Table 6 Dissolution results

[0089] batch 45 minutes solubility (≥85%) batch 45 minutes solubility (≥85%) Commercially available products 95 Comparative Example 1 83 Example 1 99 Comparative Example 2 80 Example 2 97 Comparative Example 3 81 Example 3 95 Comparative Example 4 81 Example 4 93 Comparative Example 5 80 —— —— Comparative Example 6 82

[0090] From the dissolution data in Table 6, it can be seen that the solubility of benidipine hydrochloride tablets using specific formulations (such as Examples 1 to 4) can reach or exceed 85% within 45 minutes. In contrast, the solubility of benidipine hydrochloride tablets obtained by using too much or too little potato starch and sodium hydroxymethyl starch in the disintegrant (such as Comparative Examples 1 to 4) at the same time point failed to reach this standard. This shows that the type and amount of disintegrant have a significant effect on the dissolution performance of benidipine hydrochloride tablets.

[0091] Determine the relevant substances as follows:

[0092] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512)

[0093] Solvent methanol-dilute phosphoric acid (1→500) (1:1)

[0094] Test solution: Take an appropriate amount of fine powder of this product (approximately equivalent to 20 mg of benidipine hydrochloride), place it in a 100 ml volumetric flask, dissolve and dilute to the scale with solvent, shake well, filter, and take the filtrate.

[0095] Control solution: Accurately measure an appropriate amount of the test solution and add solvent to quantitatively dilute it to make a solution containing approximately 2 μg of benidipine hydrochloride per 1 ml.

[0096] System suitability solution Weigh about 10 mg of benidipine hydrochloride reference substance, place in a 50 ml volumetric flask, add 1 ml of each impurity reference substance solution (weigh about 2 mg of impurity 1 and impurity 2 respectively, place in a 10 ml volumetric flask, add solvent to dissolve and dilute to the scale, shake well; accurately measure 2 ml of each impurity solution, place in the same 20 ml volumetric flask, add solvent to dilute to the scale, shake well), dissolve and dilute to the scale with solvent, and shake well.

[0097] Sensitivity solution: Accurately measure 1 ml of the control solution, place it in a 10 ml volumetric flask, dilute to the mark with solvent, and shake well.

[0098] The chromatographic conditions were as follows: octadecylsilane bonded silica gel as filler (Yuexu Xtimate XB-C18, 4.6 mm × 150 mm, 3 μm or a chromatographic column of equivalent performance), a trapping column (4.6 mm × 50 mm or a chromatographic column of equivalent performance); 0.05 mol / L potassium dihydrogen phosphate solution (pH 3.0)-methanol-tetrahydrofuran (65:27:8) as the mobile phase; a flow rate of 1.0 ml per minute; a column temperature of 30°C; a detection wavelength of 237 nm; and an injection volume of 10 μl.

[0099] System suitability requirements In the system suitability solution chromatogram, the peak order is impurity 1, impurity 2, and benidipine hydrochloride. In the sensitivity solution chromatogram, the signal-to-noise ratio of the main component chromatographic peak height should be no less than 10.

[0100] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram until twice the retention time of the main component.

[0101] If there is a chromatographic peak in the chromatogram of the limit test solution with the same retention time as the known impurity, impurity 1 (multiplied by the correction factor 1.6) shall not be greater than 0.2 times (0.2%) the main peak area of ​​the control solution, impurity 2 (multiplied by the correction factor 1.7) shall not be greater than 0.5 times (0.5%) the main peak area of ​​the control solution, other individual impurities shall not be greater than 0.2 times (0.2%) the main peak area of ​​the control solution, and the total impurity shall not be greater than the main peak area of ​​the control solution (1.0%).

[0102] Table 7 Impurity information

[0103]

[0104]

[0105] Table 8 Related substances results

[0106]

[0107]

[0108] As can be seen from Table 8, for benidipine hydrochloride prepared in Examples 1 to 4, the contents of related substances are all within the specified limits and are comparable to the level of the reference preparation. In addition, there are fewer types of impurities in these samples, and they remain stable after storage for 0 days, 10 days, and 30 days under light, high temperature, and high humidity conditions.

[0109] Under the same other conditions, compared with Example 1, benidipine hydrochloride tablets prepared in Comparative Example 1 (using only potato starch), Comparative Example 2 (using only sodium carboxymethyl starch), Comparative Example 3 (the mass ratio of potato starch to sodium carboxymethyl starch is 1:0.5, and the amount of sodium carboxymethyl starch is too small), and Comparative Example 4 (the mass ratio of potato starch to sodium carboxymethyl starch is 1:4, and the amount of sodium carboxymethyl starch is too large) all showed more types of impurities, including some unknown single impurities, and the corresponding impurity contents were also significantly higher.

[0110] In Comparative Example 5, a larger particle size of the raw material drug benidipine hydrochloride (5μm < D90 < 15μm) was used, and as a result, the types of impurities in the prepared benidipine hydrochloride tablets increased, including some unknown single impurities, and the corresponding impurity contents were also significantly higher than those in Example 1.

[0111] Comparative Example 6 prepared benidipine hydrochloride tablets with reference to the original research patent CN1794993A. From the perspective of related substances, although the impurity contents in the prepared tablets are all within the specified limits, when placed under light, high temperature, and high humidity conditions, the impurity contents fluctuate greatly, showing poor stability.

[0112] From this, it can be known that during the preparation process of benidipine hydrochloride tablets, when the mass ratio of the disintegrants potato starch to sodium carboxymethyl starch is controlled between 1:1 and 1:3, and the particle size D90 of the raw material drug is less than 5μm, these two factors cooperate and interact with each other, which helps to better control the impurity level in the preparation, thereby obtaining a more stable benidipine hydrochloride tablet.

[0113] In vivo absorption assay: HPLC-MS / MS method was used to determine bioequivalence. Refer to the Guidelines for Bioavailability and Bioequivalence Studies of Pharmaceutical Preparations in Humans (General Chapter 9011, Volume IV of Chinese Pharmacopoeia 2020 Edition). If the 90% confidence intervals of the ratios of Cmax of the logarithm-transformed values of the investigational preparation and the reference preparation, the ratios of AUC(0→t), and the ratios of AUC(0→∞) fall between 80% and 125%, it is considered that the investigational preparation and the reference preparation are bioequivalent.

[0114] The specific test results are as follows:

[0115] Table 9 In vivo drug absorption results

[0116]

[0117]

[0118] As can be seen from Table 9, the 90% confidence intervals of the ratios of the logarithmic transformed values ​​of Cmax, AUC(0→t) and AUC(0→∞) of the preparations obtained in Examples 1 to 4 and the reference preparation fall between 80% and 125%, which are equivalent to the reference preparation; while Comparative Examples 1 to 6 do not fall between 80% and 125%, which are not equivalent to the reference preparation.

[0119] Comprehensive in vivo and in vitro data show that the benidipine hydrochloride tablets obtained by the general particle size control method (such as comparative example 5) and the preparation scheme provided by the original research (such as comparative example 6) failed to meet the specified requirements in terms of in vitro dissolution. At the same time, in terms of in vivo absorption, the tablets obtained by these two methods showed significant differences. Therefore, under the same other conditions, from the perspective of absorption and safety of the final drug, only by using specific disintegrant types and proportions, combined with strict control of the particle size of the benidipine hydrochloride raw material, these factors work together to effectively ensure that the benidipine hydrochloride tablets have good dissolution, bioequivalence and stability.

[0120] The embodiments of the present application are described above, but the present application is not limited to the above-mentioned specific implementation modes. The above-mentioned specific implementation modes are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can also make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are within the protection of the present application.

Claims

1. A tablet calcium channel blocker, characterized in that The tablet comprises a tablet core and a coating material, wherein the tablet core comprises benidipine hydrochloride, a filler, a disintegrant, a binder and a lubricant; wherein the disintegrant is composed of potato starch and sodium carboxymethyl starch.

2. The tablet calcium channel blocker according to claim 1, characterized in that The mass ratio of the potato starch to the sodium carboxymethyl starch is 1:(1-3).

3. The tablet calcium channel blocker according to claim 2, characterized in that In parts by weight, the tablet core comprises 5 to 10 parts of benidipine hydrochloride, 100 to 120 parts of filler, 60 to 75 parts of disintegrant, 5 to 15 parts of binder and 1 to 5 parts of lubricant.

4. The tablet calcium channel blocker according to claim 3, characterized in that In parts by weight, the tablet core comprises 7 to 10 parts of benidipine hydrochloride, 111 to 114 parts of filler, 67 to 68 parts of disintegrant, 8 to 10 parts of binder and 2 to 3 parts of lubricant.

5. The tablet calcium channel blocker according to claim 4, characterized in that The particle size D90 of the benidipine hydrochloride is less than 5 μm.

6. The tablet calcium channel blocker according to claim 5, characterized in that: The filler is lactose, the binder is polyvinyl alcohol, and the lubricant is magnesium stearate.

7. The tablet calcium channel blocker according to claim 6, characterized in that: The coating material is a gastric soluble film coating premix.

8. The method for preparing the calcium channel blocker tablet according to any one of claims 1 to 7, characterized in that: The method comprises the following steps: (1) pretreatment of raw materials and auxiliary materials; (2) premixing: mixing benidipine hydrochloride, a filler and a disintegrant to obtain a premixed material; (3) wet granulation: preparing an aqueous binder solution; adding the aqueous binder solution to the premixed material obtained in step (2) by a peristaltic pump; and wet granulating after granulation; (4) drying: drying the wet granules obtained in step (3) to control the moisture content of the material to be ≤4%; (5) granulating: granulating the dried granules; (6) total mixing: mixing the granules obtained in step (5) with a lubricant; (7) tableting: tableting according to a predetermined tablet weight; and (8) coating: coating using a fluidized bed to control the coating weight gain to be 2% to 4%; and drying the coated material to obtain a tablet calcium channel blocker.

9. The method for preparing a tablet calcium channel blocker according to claim 8, characterized in that: The lactose is pretreated by passing through a 200-mesh sieve.

10. The method for preparing a tablet calcium channel blocker according to claim 9, characterized in that: The preparation process of the adhesive aqueous solution in step (3) is as follows: polyvinyl alcohol is added to purified water at 60-70° C. and stirred to dissolve to prepare a polyvinyl alcohol aqueous solution with a concentration of 25% (w / w).

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