Preparation method of lercanidipine hydrochloride tablets

Abstract

The present invention discloses a lercanidipine hydrochloride tablet preparation method, the tablet comprises lercanidipine hydrochloride, microcrystalline cellulose, lactose, carboxymethyl starch sodium, povidone and magnesium stearate, the method comprises: adding a part of povidone in a powder form, using purified water as a wetting agent to carry out granulation, preparing the other part of povidone into a solution, adding the solution, and carrying out granulation to obtain the lercanidipine hydrochloride tablet. And granulating as an adhesive. The tablet prepared by the method has high dissolution rate, is stable in dissolution without slowing down in the storage process, and is simple in production process, low in cost and suitable for industrial mass production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a method for preparing lercanidipine hydrochloride tablets. Background Technology

[0002] Lercanidipine hydrochloride is a third-generation dihydropyridine calcium channel antagonist developed by Recordati SPA in Italy.

[0003] Lercanidipine hydrochloride is used to treat hypertension by blocking L-type calcium channels on the cell membrane of vascular smooth muscle cells, inhibiting the influx of calcium ions into the cells, thereby dilating arteries and lowering blood pressure. Lercanidipine is highly lipophilic, able to bind tightly to the lipid bilayer on the cell membrane, and is slowly released into the calcium channels, exhibiting membrane-controlled kinetics. It has a relatively stable onset of action and a long duration of effect after a single dose, making it a long-acting and stable antihypertensive drug.

[0004] The main dosage form of this product is tablets. Studies have found that lercanidipine hydrochloride tablets exhibit slower dissolution during storage, significantly affected by high temperature and humidity conditions. Slower dissolution relates to product stability, and addressing this issue is crucial for improving product quality.

[0005] Existing technologies have been developed to address the issue of slow dissolution of lercadipine hydrochloride tablets during storage, as detailed below: CN115590833A discloses a lercanidipine hydrochloride tablet composition with high dissolution stability and its preparation method, comprising the following components by weight percentage: 9-16% lercanidipine hydrochloride core, 4-11% hardening disintegrant, 3-7% binder, 70-78% filler, and 0.9-5% lubricant; the coating material accounts for 2.0-4.0% of the total weight of the core. This invention mainly improves the dissolution stability of lercanidipine hydrochloride tablets by hardening the disintegrant to ensure that it does not encapsulate the drug during long-term storage and high-temperature conditions. However, this method requires the preparation of a hardened disintegrant, which necessitates mixing the disintegrant with anhydrous lactose, followed by dry granulation and then pulverization. This combined dry and wet process requires more equipment, complicating the process, increasing production costs, and hindering large-scale industrial production.

[0006] To solve the above problems, the inventors of this invention cleverly added povidone K30 in two forms and adopted a two-step granulation method. While ensuring stable drug dissolution, no special production steps were added, simplifying the process and making it more conducive to large-scale industrial production. Summary of the Invention

[0007] Based on the problems existing in the prior art, the purpose of this invention is to provide a method for preparing lercanidipine hydrochloride tablets. The lercanidipine hydrochloride tablets prepared by this method have the following characteristics: (1) high dissolution rate; (2) stable dissolution during storage without slowing down; (3) simple production process, low cost, and suitable for large-scale industrial production.

[0008] To achieve the objectives of this invention, the following implementation scheme is provided.

[0009] In one embodiment, the present invention provides a method for preparing lercanidipine hydrochloride tablets, wherein the tablets comprise lercanidipine hydrochloride, microcrystalline cellulose, lactose, sodium carboxymethyl starch, povidone, and magnesium stearate. The povidone is divided into two parts. The first part of the povidone is mixed in powder form with lercanidipine hydrochloride, microcrystalline cellulose, lactose, and sodium carboxymethyl starch. Water is added as a wetting agent, and wet granulation is performed. The second part of the povidone is dissolved in water to form a solution, which is added as a binder. Granulation is then performed, and magnesium stearate is added and the mixture is compressed into tablets. Preferably, in the preparation method of the present invention described above, the polyvinyl ketone is polyvinyl ketone K30.

[0010] Preferably, in the preparation method of the present invention described above, the weight ratio of the first part of polyvinyl ketone to the second part of polyvinyl ketone is 1:2 to 2:1.

[0011] Preferably, in the preparation method of the present invention described above, the particle size d (0.9) of lercanidipine hydrochloride is ≤20μm.

[0012] Preferably, in the above-described method for preparing lercanidipine hydrochloride tablets of the present invention, the weight percentage of the components of the tablet is as follows: Lecanidipine hydrochloride 10% Microcrystalline cellulose 39% 30% lactose Sodium carboxymethyl starch 15.5% Povidone 4.5% Magnesium stearate 1.0%.

[0013] In one specific embodiment, the preparation method of the present invention includes the following steps: 1) Add lercanidipine hydrochloride, microcrystalline cellulose, lactose, sodium carboxymethyl starch and the first part of povidone K30 in powder form to a wet granulator and stir to form a mixture; 2) Add the wetting agent purified water to the mixture and perform wet granulation; 3) Dissolve the second part of the povidone K30 in purified water to prepare a binder, and add it to the mixture in step 2) for granulation; 4) Dry the obtained granules, control the moisture content to below 5%, and granulate them to obtain granules; 5) Add magnesium stearate to the granules obtained in the previous step, mix, and compress into tablets.

[0014] Furthermore, the preparation method of the present invention further includes coating the tablets obtained by compression with a gastrointestinal coating premix to increase the weight by 2% to 4%, thereby obtaining coated tablets.

[0015] In another embodiment, the present invention provides a lercanidipine hydrochloride tablet, the weight percentage of its components being: Lecanidipine hydrochloride 10% Microcrystalline cellulose 39% 30% lactose Sodium carboxymethyl starch 15.5% Povidone 4.5% Magnesium stearate 1.0%.

[0016] Povidone was divided into two parts. The first part of povidone was mixed in powder form with lercanidipine hydrochloride, microcrystalline cellulose, lactose, and sodium carboxymethyl starch. Wetting agent water was added, and wet granulation was performed. The second part of povidone was dissolved in water to form a solution, which was added as a binder and granulated. Magnesium stearate was added and mixed to form tablets.

[0017] Preferably, in the above-mentioned lecanidipine hydrochloride tablets of the present invention, the weight ratio of the first part of povidone to the second part of povidone is 1:2 to 2:1.

[0018] Technical effects: This preparation method employs a two-step granulation process, which modifies the compact internal structure of the particles, making them more porous and facilitating drug dissolution and its stability. The first step involves adding povidone in powder form and using purified water as a wetting agent for granulation. The second step involves preparing a solution of povidone as a binder and performing a second granulation based on the first granulation. After the first granulation, small particles are initially formed. During the second granulation, these small particles aggregate into larger particles under the action of the binder. The particles obtained through this two-step granulation method have a different degree of internal compactness compared to single-step granulation, exhibiting greater porosity, a more porous structure, and a lower particle density, thus ensuring drug dissolution and its stability. Studies have found that when lercanidipine hydrochloride tablets are granulated using this method, the finished product not only has high dissolution rate, but also, surprisingly, maintains stable dissolution rate during storage without significant changes. In addition, the preparation method of the present invention simply divides wet granulation into two steps without adding other production processes, which has the advantages of simple process, low cost and easy industrial production. Detailed Implementation

[0019] The following embodiments are provided to describe the present invention in more detail. However, these embodiments are provided only to help further understand the present invention and are not intended to limit the present invention. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the content of the present invention still fall within the protection scope of the present invention.

[0020] The following examples are implemented using the 10mg specification, and the 20mg specification is implemented using the same formulation ratio, with the same production process.

[0021] The following examples are for illustrative purposes only and do not limit the scope of the invention in any way.

[0022] Example 1: Lercadipine Hydrochloride Tablets The prescription for lercanidipine hydrochloride tablets is shown in Table 1.

[0023] Table 1. Prescription for Lercadipine Hydrochloride Tablets

[0024] Preparation method: Taking a laboratory scale of 1500 pieces as an example, using a 1-liter pan, the following steps are included: 1) Material mixing Add the prescribed amounts of lercanidipine hydrochloride, microcrystalline cellulose, lactose, and sodium carboxymethyl starch, along with povidone K30 in powder form, to a wet granulator. Start the stirring at 300 rpm and shear at 1100 rpm, and mix for 4 minutes to obtain the mixture.

[0025] 2) Step 1 Wet granulation: Using purified water as a wetting agent, add 30% of the prescribed amount of wetting agent while stirring at 300 rpm and shearing at 1100 rpm. Then stir at 400 rpm and shear at 1400 rpm for 3 minutes. 3) Step 2 Wet granulation: Weigh 30% of the prescribed amount of purified water, dissolve the povidone K30 (added in solution form) in purified water to prepare a binder. Start stirring at 300 rpm and shearing at 1100 rpm, add the prepared binder, then start stirring again at 400 rpm and shearing at 1400 rpm, granulate for 3 minutes.

[0026] 4) Drying: The granules obtained in the previous step are dried in a fluidized bed, with the moisture content controlled below 5%, and then granulated using a 1.2mm aperture sieve to obtain granules.

[0027] 5) Add magnesium stearate to the granules from the previous step according to the prescription ratio, mix for 10 minutes, and obtain total mixed granules.

[0028] 6) Tableting: The prepared total mixed granules are pressed into tablets using a 6.5mm shallow concave circular die, with the hardness controlled at 3-7.5kg, to obtain bare tablets.

[0029] 7) Coating: The bare tablets prepared in the previous step are coated with a stomach-soluble coating premix to obtain the finished product.

[0030] Example 2: Lercadipine Hydrochloride Tablets The prescription for lercanidipine hydrochloride tablets is shown in Table 2.

[0031] Table 2. Prescription for Lercanidipine Hydrochloride Tablets

[0032] Preparation method: Taking a laboratory scale of 1500 pieces as an example, using a 1-liter pan, the following steps are included: 1) Material mixing Add the prescribed amounts of lecanidipine hydrochloride, lactose, microcrystalline cellulose, sodium carboxymethyl starch, and povidone K30 (added in powder form) to a wet granulator, turn on the stirring at 300 rpm, shear at 1100 rpm, and mix for 4 minutes to obtain a mixture.

[0033] 2) Step 1 Wet granulation: Using purified water as a wetting agent, start stirring at 300 rpm and shear at 1100 rpm. Add 20% of the prescribed amount of wetting agent, then start stirring at 400 rpm and shear at 1400 rpm for 2 minutes. 3) Step 2 Wet granulation: Weigh 40% of the prescribed amount of purified water, dissolve the povidone K30 (added in solution form) in purified water to prepare a binder. Start stirring at 300 rpm and shearing at 1100 rpm, add the prepared binder, then start stirring again at 400 rpm and shearing at 1400 rpm, granulating for 4 minutes.

[0034] 4) Drying: The granules obtained in the previous step are dried in a fluidized bed, with the moisture content controlled below 5%, and then granulated using a 1.2mm aperture sieve to obtain granules.

[0035] 5) Add magnesium stearate to the granules from the previous step according to the prescription ratio, mix for 10 minutes, and obtain total mixed granules.

[0036] 6) Tableting: The prepared total mixed granules are pressed into tablets using a 6.5mm shallow concave circular die, with the hardness controlled at 3-7.5kg, to obtain bare tablets.

[0037] 7) Coating: The bare tablets prepared in the previous step are coated with a stomach-soluble coating premix to obtain the finished product.

[0038] Example 3: Lecanidipine Hydrochloride Tablets Formula The prescription for lercanidipine hydrochloride tablets is shown in Table 3.

[0039] Table 3. Prescription for Lercanidipine Hydrochloride Tablets

[0040] Preparation method: Taking a laboratory scale of 1500 pieces as an example, using a 1-liter pan, the following steps are included: 1) Material mixing Add the prescribed amounts of lecanidipine hydrochloride, microcrystalline cellulose, sodium carboxymethyl starch, and povidone K30 (in powder form) to a wet granulator, turn on the stirring at 300 rpm, shear at 1100 rpm, and mix for 4 minutes to obtain a mixture.

[0041] 2) Step 1 Wet granulation: Using purified water as a wetting agent, turn on the granulator to stir at 300 rpm and shear at 1100 rpm, add 40% of the prescribed amount of wetting agent, then turn on the stirring at 400 rpm and shear at 1400 rpm, and granulate for 4 minutes. 3) Step 2 Wet Granulation: Weigh 20% of the prescribed amount of purified water, dissolve the povidone K30 (added in solution form) in purified water to prepare a binder. Turn on the granulator to stir at 300 rpm and shear at 1100 rpm, add the prepared binder, then turn on the stirrer to stir at 400 rpm and shear at 1400 rpm, granulate for 2 minutes.

[0042] 4) Drying: The granules obtained in the previous step are dried in a fluidized bed, with the moisture content controlled below 5%, and then granulated using a 1.2mm aperture sieve to obtain granules.

[0043] 5) Add magnesium stearate to the granules from the previous step according to the prescription ratio, mix for 10 minutes, and obtain total mixed granules.

[0044] 6) Tableting: The prepared total mixed granules are pressed into tablets using a 6.5mm shallow concave circular die, with the hardness controlled at 3-7.5kg, to obtain bare tablets.

[0045] 7) Coating: The bare tablets prepared in the previous step are coated with a stomach-soluble coating premix to obtain the finished product.

[0046] Comparative Example 1: Lecanidipine Hydrochloride Tablets The prescription for lercanidipine hydrochloride tablets is shown in Table 4, in which povidone K30 is added all at once in powder form.

[0047] Table 4. Comparative Example 1: Lercanidipine Hydrochloride Tablets Formula

[0048] Preparation method: Taking a laboratory scale of 1500 pieces as an example, using a 1-liter pan, the following steps are included: 1) Material mixing Add the prescribed amounts of lercanidipine hydrochloride, lactose, microcrystalline cellulose, sodium carboxymethyl starch, and povidone K30 to a wet granulator, turn on the stirring at 300 rpm, shear at 1100 rpm, and mix for 4 minutes.

[0049] 2) Wet granulation: Using purified water as a wetting agent, turn on the granulator to stir at 300 rpm and shear at 1100 rpm, add 60% of the prescribed amount of wetting agent, then turn on the stirring at 400 rpm and shear at 1400 rpm, and granulate for 6 minutes. 3) Drying: The granules obtained in the previous step are dried in a fluidized bed, with the moisture content controlled below 5%, and then granulated using a 1.2mm aperture sieve to obtain granules.

[0050] 4) Add magnesium stearate to the granules prepared in the previous step according to the prescription ratio, mix for 10 minutes, and obtain total mixed granules.

[0051] 5) Tableting: The prepared total mixed granules are pressed into tablets using a 6.5mm shallow concave circular die, with the hardness controlled at 3-7.5kg, to obtain bare tablets.

[0052] 6) Coating: The bare tablets are coated with a stomach-soluble coating premix to obtain the finished product.

[0053] Comparative Example 2: Lecanidipine Hydrochloride Tablets Formula The prescription for lercanidipine hydrochloride tablets is shown in Table 5. In this prescription, all of the povidone K30 is prepared as a solution and added as a binder.

[0054] Table 5. Comparative Example 2: Lercanidipine Hydrochloride Tablets Formula

[0055] Preparation method: Taking a laboratory scale of 1500 pieces as an example, using a 1-liter pan, the following steps are included: 1) Material mixing Add the prescribed amounts of lercanidipine hydrochloride, lactose, microcrystalline cellulose, and sodium carboxymethyl starch to a wet granulator, turn on the stirring at 300 rpm, shear at 1100 rpm, and mix for 4 minutes.

[0056] 2) Wet granulation: Add the prescribed amount of povidone K30 to 60% of the prescribed amount of purified water, stir to dissolve, and prepare the binder. Turn on the granulator to stir at 300 rpm and shear at 1100 rpm, add the prepared binder, then turn on the stirring at 400 rpm and shear at 1400 rpm, and granulate for 6 minutes. 3) Drying: The granules obtained in the previous step are dried in a fluidized bed, with the moisture content controlled below 5%, and then granulated using a 1.2mm aperture sieve to obtain granules.

[0057] 4) Add magnesium stearate to the granules from the previous step according to the prescription ratio, mix for 10 minutes, and obtain total mixed granules.

[0058] 5) Tableting: The prepared total mixed granules are pressed into tablets using a 6.5mm shallow concave circular die, with the hardness controlled at 3-7.5kg, to obtain bare tablets.

[0059] 6) Coating: The bare tablets are coated with a stomach-soluble coating premix to obtain the finished product.

[0060] Comparative Example 3 Example 1 disclosed in document CN115590833A is used as comparative example 3, and the prescription is shown in Table 6.

[0061] Table 6. Comparative Example 3: Lercanidipine Hydrochloride Tablets Formula

[0062] Preparation method: 1) Hardening treatment of disintegrant: Sodium carboxymethyl starch disintegrant is mixed evenly with anhydrous lactose and placed in a dry granulator. The granulation parameters are set as follows: feeding speed 10-20 rpm, roller speed 12-15 rpm, roller pressure 40-50 MPa. Granules are prepared and the obtained granules are crushed. The particle size is controlled to be 150um-200um to obtain hardened disintegrant.

[0063] 2) Mixing and granulation: Mix the prescribed amount of lecanidipine hydrochloride tablets, filler microcrystalline cellulose, binder povidone K30, and hardening disintegrant evenly, stir at 400 rpm, cut at 1000 rpm, add an appropriate amount of purified water while stirring, granulate for 2 minutes, wet granulate through a 20-mesh sieve, and then dry granulate with the moisture content controlled below 2% through a 1.2 mm aperture sieve to obtain granules.

[0064] 3) Total Mixing: Add the prescribed amount of lubricant to the granules, mix evenly, and obtain total mixed granules.

[0065] 4) Tableting: The total mixed particles are compressed into tablets to obtain tablet cores with a hardness of 3-6Kg.

[0066] 5) Coating: Coating the tablet core with the prescribed amount of coating material.

[0067] Comparative Example 4 The commercially available original reagent (manufacturer: Recordati S.PA) was used as a comparative example 4.

[0068] Effect Experiment Experiment 1: Determination of Powder Properties The powder properties of the total mixed particles of Examples 1-3, and Comparative Examples 1, 2, and 3 were determined, and the results are shown in Table 7 below.

[0069] Table 7. Results of Powder Properties Determination

[0070] Results evaluation: As can be seen from the above results, the loose density and tapped density of the samples in Examples 1-3 are significantly smaller than those of the comparative samples. This indicates that the samples prepared by this method have a looser internal structure and greater porosity, which is beneficial for particle disintegration and dissolution of the active ingredient.

[0071] Experiment 2: Determination of Dissolution Curve Dissolution curves were measured for each example and comparative sample (tablet).

[0072] The dissolution and release were determined according to the guidelines of the 2025 edition of the Chinese Pharmacopoeia 0931. The specific method was determined with reference to the import registration standard of this product. The slurry method was used, the rotation speed was 50 rpm, the dissolution medium was pH 1.0 hydrochloric acid solution (containing 0.3% Tween 80) in a volume of 900 mL, and the detection method was HPLC.

[0073] The dissolution results of each embodiment and comparative example are shown in Table 8 below.

[0074] Table 8. Results of dissolution curve measurements for each example and comparative example.

[0075] Summary: Based on the results at day 0, all examples and comparative examples showed good dissolution. Examples 1, 2, 3, and comparative examples 1, 2, and 3, along with the original formulation, showed similarity factors (f2) to the original formulation at sampling times of 5 min, 10 min, 15 min, and 30 min, with f2 values ​​all greater than 50, indicating similar dissolution.

[0076] Experiment 3 Acceleration Stability Experiment The samples prepared in each example and comparative example were investigated under accelerated conditions (40°C, 75%), and the dissolution curves were determined according to the above method. The results are shown in Table 9 below.

[0077] Table 9. Results of accelerated stability dissolution curves for each example and comparative example.

[0078] In summary, the accelerated stability results show that the dissolution curve of the sample in this embodiment did not change significantly after accelerated stability testing, indicating that the dissolution rate and extent of the sample prepared by this invention can remain stable. In contrast, the samples in the comparative examples showed slower in vitro dissolution. This demonstrates that the lercanidipine hydrochloride tablets prepared by this invention not only have high dissolution rate but also better dissolution stability during storage.

[0079] The present invention relates to lercanidipine hydrochloride tablets and their preparation method, which innovatively incorporates povidone K30 in two forms and employs a two-step granulation process. This results in high dissolution rate, solves the dissolution stability problem, and is characterized by simple process, low cost, and suitability for large-scale industrial production. The lercanidipine hydrochloride tablets and their preparation method of the present invention possess outstanding substantive features and significant technological advancements, which are of great importance to the development of this product.

Claims

1. A process for the preparation of a tablet of lercanidipine hydrochloride comprising lercanidipine hydrochloride, microcrystalline cellulose, lactose, sodium carboxymethyl starch, povidone and magnesium stearate, characterized in that: The povidone is divided into two parts, the first part of the povidone is mixed with lercanidipine hydrochloride, microcrystalline cellulose, lactose, sodium carboxymethyl starch in powder form, purified water is added as a wetting agent, wet granulation is performed, the second part of the povidone is dissolved in water to form a solution, which is added as a binder, granulation is performed, and magnesium stearate is added and mixed to form tablets.

2. The preparation method of claim 1, wherein the povidone is povidone K30.

3. The preparation method of claim 1, wherein the weight ratio of the first part of the povidone to the second part of the povidone is 1:2 to 2:

1.

4. The preparation method of claim 1, wherein the particle size d(0.9) of the lercanidipine hydrochloride is ≤20 μm.

5. The tablet of claim 1, wherein the components are present in the following weight proportions: Lercanidipine hydrochloride 10% Microcrystalline cellulose 39% Lactose 30% Sodium carboxymethyl starch 15.5% Povidone 4.5% Magnesium stearate 1.0%.

6. The preparation method of any one of claims 1-5, comprising the following steps: 1) adding lercanidipine hydrochloride, microcrystalline cellulose, lactose, sodium carboxymethyl starch, and the first part of povidone K30 in powder form into a wet granulator, stirring and mixing to form a mixture; 2) adding purified water as a wetting agent to the mixture, wet granulation; 3) dissolving the second part of povidone K30 in purified water to prepare a binder, which is added to the mixture of step 2) for granulation; 4) drying the prepared granules to control the moisture content to be less than 5%, sizing the granules to obtain granules; 5) adding magnesium stearate to the granules prepared in the previous step, mixing, and tabletting.

7. The preparation method of claim 6, further comprising coating the tablets prepared by tabletting with a stomach-soluble coating premix to obtain coated tablets.

8. The preparation method of claim 7, wherein the coated tablets have an increase in weight of 2% to 4%.

9. A lercanidipine hydrochloride tablet, wherein the components are present in the following weight proportions: Lercanidipine hydrochloride 10% Microcrystalline cellulose 39% Lactose 30% Sodium carboxymethyl starch 15.5% Povidone 4.5% Magnesium stearate 1.0%, characterized in that The povidone is divided into two parts, the first part of the povidone is mixed with lercanidipine hydrochloride, microcrystalline cellulose, lactose, sodium carboxymethyl starch in powder form, purified water is added as a wetting agent, wet granulation is performed, the second part of the povidone is dissolved in water to form a solution, which is added as a binder, granulation is performed, and magnesium stearate is added and mixed to form tablets.

10. The tablet of claim 9, wherein the weight ratio of the first part of the povidone to the second part of the povidone is 1:2 to 2:1.

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