Lacidipine tablets and preparation method thereof

Abstract

The invention relates to the field of medical technology, and discloses a lacidipine tablet and a preparation method thereof. The weight ratio of raw materials of the lacidipine tablet is: 2%-4% lacidipine; 1%-1.9% surfactant; 8%-10% cellulose polymer; 1.1%-1.6% acrylic resin polymer material; 0.8%-1.2% triglyceride; 1.3%-1.7% carbomer; and the remainder is lactose. The raw material formula is weighed, the prepared raw materials are melt-mixed in sequence, the mixture is added into an extruder, and the process parameters of the extruder are adjusted to finally obtain an initial lacidipine tablet, and then the initial lacidipine tablet is further subjected to a devolatilization operation, and a cellulose polymer is used for coating treatment. After the coating is completed, the lacidipine tablet is prepared, and the lacidipine tablet is subjected to evaluation tests of dissolution rate and cumulative dissolution rate. Finally, according to the test results, the formula and process parameters are adjusted. The preparation according to the above raw material formula combined with a hot melt extrusion process can effectively overcome the problem of low dissolution rate and low cumulative dissolution rate in the existing preparation method.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, in particular to lacidipine tablets and a preparation method thereof. Background Art

[0002] Lacidipine is a third-generation long-acting calcium ion antagonist belonging to the dihydropyridine class of compounds. The drug was first developed by GlaxoSmithKline (GSK) in the UK and was first launched in Italy in 1991 under the trade names Lacipil and Motens. Lacidipine is a white or off-white crystalline powder, odorless and tasteless, unstable to light, easily soluble in ethyl acetate, soluble in acetone, slightly soluble in methanol and ethanol, and almost insoluble in water, with a melting point of 175-179°C.

[0003] Due to the extremely poor solubility of lacidipine, in the existing method for preparing lacidipine tablets, the dissolution rate and the cumulative dissolution rate cannot be improved simultaneously in actual production, resulting in low bioavailability. Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides lacidipine tablets and a preparation method thereof, which have the advantages of fast dissolution speed and high solubility, and solve the problem that the dissolution rate and cumulative dissolution rate cannot be improved simultaneously in actual production in the existing method for preparing lacidipine tablets.

[0005] To achieve the above object, the present invention provides the following technical solution: Lacidipine tablets, whose raw materials include lacidipine, lactose, surfactant, cellulose polymer, acrylic resin polymer material, triglyceride, and carbomer; The weight percentages of the raw materials of the lacidipine tablets are: lacidipine 2%-4%; surfactant 1%-1.9%; cellulose polymer 8%-10%; acrylic resin polymer material 1.1%-1.6%; triglyceride 0.8%-1.2%; carbomer 1.3%-1.7%, and the remainder is lactose.

[0006] Preferably, the lacidipine is micronized before use, and the process of micronization is as follows: S1.1, coarse grinding and fine grinding: lacidipine is subjected to coarse grinding and fine grinding; S1.2, operating equipment and parameter settings: select air flow mill as the crushing equipment, and set the crushing pressure to 0.8MPa, the feed pressure to 0.5MPa, and the spiral feed speed to 230 r / min; S1.3, crushing process: preheat the airflow mill according to the parameters of the above step for 30 minutes, feed the coarsely crushed and finely crushed lacidipine into the airflow mill, set the crushing time to 30 minutes, start the button, and the final particle size is controlled between D90=11-12um; S1.4, Particle size detection: Use a laser particle size analyzer to detect the particle size and distribution of the crushed powder; S1.5 Drying and packaging: Use a freeze dryer to dry the powder and keep the dried powder for later use.

[0007] Preferably, the surfactant comprises sorbitan monooleate and vitamin ETPGS, and the mass ratio of sorbitan monooleate to vitamin ETPGS is 2:1.

[0008] Preferably, the acrylic resin polymer material includes two types: Eudragit RL and Eudragit RS, and the acrylic resin polymer material is composed of Eudragit RL and Eudragit RS in a mass ratio of 3:5.

[0009] Preferably, the preparation method of lacidipine tablets is prepared according to the weight ratio of the raw materials of the above-mentioned lacidipine tablets, and the preparation process is as follows: Step 1. Raw material preparation: weigh the surfactant, cellulose polymer, acrylic resin polymer material, triglyceride, lacidipine, and lactose in the raw material formula ratio; Step 2, melt extrusion: melt lacidipine and acrylic resin polymer material, extrude, and then mix with surfactant, triglyceride, and lactose to obtain lacidipine initial tablets; Step 3, devolatilization operation: further performing a devolatilization operation on the initial lacidipine tablets; Step 4: coating: using a cellulose polymer for coating. After coating, lacidipine tablets are prepared; Step 5. Quality control: Conduct dissolution rate and cumulative dissolution evaluation tests.

[0010] Preferably, the order of melt mixing and the preparation process in step 2 are as follows: S2.1, putting acrylic resin polymer material into an extruder, melting and extruding; S2.2, the extrudate is put into a high shear mixer at a speed of 500r / min for 10min, and the mixture is stirred thoroughly to be evenly dispersed; S2.3, add surfactant again, readjust the speed of high shear mixer to 1000r / min, and the duration is 3min; S2.4. Finally, add triglyceride and carbomer, readjust the speed of the high shear mixer to 1500 r / min, the duration is 15 min, and crush through a 60-mesh sieve.

[0011] Preferably, in the step 3, the extruded initial lacidipine tablets are further subjected to a devolatilization operation to remove degraded small molecules and water from the material, and the operation is as follows; The temperature of the devolatilization operation was set to 70°C; Set the devolatilization time to 2-4h; During the devolatilization process, a reduced pressure method was adopted and the pressure was set to 0.15 MPa.

[0012] Preferably, the coating process in step 4 is: The cellulose polymer and pure water are prepared into a coating solution in a ratio of 0.9:1.3; Set the inlet air temperature of the fluidized bed coating equipment to 55°C, the spray pressure to 0.5MPa, and the spray rate to 80m 3 / s, the total spraying time is 1 min, and then the initial lacidipine tablets to be coated are placed into the fluidized bed coating equipment, and the equipment is turned on; After coating, the coated initial lacidipine tablets were placed in a fluidized bed dryer and solidified at 60° C. for 20 min to prepare lacidipine tablets.

[0013] Preferably, in step five, differential scanning calorimetry is used to determine the dispersion state of the drug in the solid dispersion, and the dissolution rate and cumulative dissolution are evaluated by an in vitro dissolution test.

[0014] Compared with the prior art, the present invention provides lacidipine tablets and a preparation method thereof, which have the following beneficial effects: 1. The raw material acrylic resin polymer material of the present invention is composed of Eudragit RL and Eudragit RS in a ratio of 3:5. The two materials can be mixed in different proportions to adjust the drug release rate. The pore diameter of Eudragit RL is 1-5μm, and the pore diameter of Eudragit RS is 0.1-0.6μm, which allows them to form pores in the coating to control drug release, and dynamically adjust the parameters of the extrusion equipment during the hot melt extrusion process to maximize the drug efficacy. Gradually lowering the temperature helps to protect the activity of the drug, while gradually increasing the extrusion speed, and can also improve the solubility of lacidipine tablets, thereby optimizing the release performance of the drug. Therefore, the raw material formula of the present invention combined with the hot melt extrusion process can effectively overcome the problems of splits and fragments in the existing preparation method, improve the dissolution rate and cumulative solubility of lacidipine tablets, and maintain good mechanical strength and hardness. DETAILED DESCRIPTION

[0015] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Example 1

[0016] Lacidipine tablets, the raw materials of which include lacidipine, lactose, surfactant, cellulose polymer, acrylic resin polymer material, triglyceride, and carbomer; The cellulose-based polymer is specifically ethyl cellulose.

[0017] The weight percentages of the raw materials of lacidipine tablets are: lacidipine 2%; surfactant 1%; cellulose polymer 8%; acrylic resin polymer material 1.1%; triglyceride 0.8%; carbomer 1.3%; and the remainder is lactose.

[0018] Specifically, lacidipine is micronized before use, and the process of micronization is as follows: S1.1, coarse pulverization and fine pulverization: Lacidipine is subjected to two steps of coarse pulverization and fine pulverization before entering the next stage. This step is to reduce the particle size of the material and lay the foundation for subsequent ultrafine pulverization; S1.2, operating equipment and parameter settings: Select airflow mill as the pulverizing equipment, and set the pulverizing pressure to 0.8MPa, the feed pressure to 0.5MPa, and the spiral feed speed to 230 r / min. The airflow mill uses high-speed gas (such as compressed air, high-pressure superheated steam or inert gas) to cause strong collision, impact and friction between particles and between particles and the wall of the device, thereby achieving ultra-fine pulverization; S1.3, crushing process: after preheating the airflow mill according to the parameters of the above step for 30 minutes, feed the coarsely crushed and finely crushed lacidipine into the airflow mill, set the crushing time to 30 minutes, press the start button, and through the feed injector, the compressed gas brings the material into the crushing chamber, and driven by the high-speed airflow sprayed by multiple nozzles, it is sprayed onto the crushing wall in a tangential manner to achieve a friction crushing effect, and obtain micronized lacidipine. The final particle size is controlled between D90=11-12um. During the airflow crushing process, the coarse powder will be continuously crushed to reduce its particle size. At the same time, the powder that meets the particle size requirements is separated and collected by a grading device to ensure that the particle size distribution of the final product is narrower and more uniform; S1.4, Particle size detection: Use a laser particle size analyzer to detect the particle size and distribution of the crushed powder to ensure that it meets the submicron requirements; S1.5. Drying and packaging: Use a freeze dryer to dry the powder. Since a certain amount of moisture will be generated during the airflow crushing process, the powder needs to be dried and the dried powder is ready for use.

[0019] Specifically, the surfactant includes sorbitan monooleate and vitamin ETPGS, and the mass ratio of sorbitan monooleate to vitamin ETPGS is 2:1.

[0020] Specifically, the acrylic resin polymer material includes two types: Eudragit RL and Eudragit RS. Eudragit RL is a high permeability polymer, while Eudragit RS is a low permeability polymer. The acrylic resin polymer material is composed of Eudragit RL and Eudragit RS in a mass ratio of 3:5. These two materials can be mixed in different proportions to adjust the drug release rate. The pore diameter of Eudragit RL is 1-5μm, while the pore diameter of Eudragit RS is 0.1-0.6μm, which allows them to form pores in the coating to control drug release.

[0021] Specifically, the preparation method of lacidipine tablets is prepared according to the weight ratio of the raw materials of the above-mentioned lacidipine tablets, and the preparation process is as follows: Step 1. Raw material preparation: weigh the surfactant, cellulose polymer, acrylic resin polymer material, triglyceride, lacidipine, and lactose in the raw material formula ratio; Step 2, melt extrusion: melt lacidipine and acrylic resin polymer material, extrude, and then mix with surfactant, triglyceride, and lactose to obtain lacidipine initial tablets; Step 3, devolatilization operation: further performing a devolatilization operation on the initial lacidipine tablets; Step 4: coating: using a cellulose polymer for coating. After coating, lacidipine tablets are prepared; Step 5. Quality control: Conduct dissolution rate and cumulative dissolution evaluation tests.

[0022] The advantages are: through the above steps, the problems of splitting and fragmentation in the existing preparation method can be overcome, the dissolution rate and cumulative dissolution rate of lacidipine tablets can be improved, and good mechanical strength and hardness can be maintained.

[0023] Specifically, the sequence and preparation process of melt extrusion in step 2 are as follows: S2.1, putting acrylic resin polymer material into an extruder, melting and extruding; S2.2, the extrudate is put into a high shear mixer at a speed of 500r / min for 10min, and the mixture is stirred thoroughly to be evenly dispersed; S2.3, add surfactant again, readjust the speed of high shear mixer to 1000r / min, and the duration is 3min; S2.4. Finally, add triglyceride and carbomer, readjust the speed of the high shear mixer to 1500 r / min, the duration is 15 min, and crush through a 60-mesh sieve.

[0024] Specifically, in step 3, the extruded initial lacidipine tablets are further subjected to a devolatilization operation to remove degraded small molecules and water from the material, and the operation is as follows; The temperature of the devolatilization operation was set to 70°C; Set the devolatilization time to 2h; During the devolatilization process, the decompression method is used and the pressure is set to 0.15MPa. This pressure can promote the volatilization of impurities. At the same time, the temperature and time must be controlled to maintain the stability and efficacy of the drug.

[0025] Specifically, the coating process in step 4 is as follows: The cellulose polymer and pure water are prepared into a coating solution in a ratio of 0.9:1.3; Set the inlet air temperature of the fluidized bed coating equipment to 55°C, the spray pressure to 0.5MPa, and the spray rate to 80m 3 / s, the total spraying time is 1 min, and then the initial lacidipine tablets to be coated are placed into the fluidized bed coating equipment, and the equipment is turned on; After coating, the coated initial lacidipine tablets were placed in a fluidized bed dryer and solidified at 60° C. for 20 min to prepare lacidipine tablets.

[0026] Specifically, in step five, differential scanning calorimetry (DSC) is used to determine the dispersion state of the drug in the solid dispersion, and its dissolution rate and cumulative dissolution are evaluated by in vitro dissolution testing. Example 2

[0027] This embodiment differs from Embodiment 1 in that: The weight percentage of the raw materials of lacidipine tablets was adjusted as follows, and the other preparation steps remained unchanged.

[0028] The weight percentages of the raw materials of lacidipine tablets are: lacidipine 4%; surfactant 1.9%; cellulose polymer 10%; acrylic resin polymer material 1.6%; triglyceride 1.2%; carbomer 1.7%; and the remainder is lactose.

[0029] Comparative Example 1 This comparative example differs from Example 1 in that: The composition of the acrylic resin polymer material is changed to a single Eudragit RS, the preparation steps remain unchanged, and other raw materials remain unchanged.

[0030] Comparative Example 2 This comparative example differs from Example 1 in that: The composition of the acrylic resin polymer material is changed to a single Eudragit RL, the preparation steps remain unchanged, and other raw materials remain unchanged.

[0031] The finished products prepared in Example 1-2 and Comparative Example 1-2 were subjected to evaluation tests of dissolution rate and 60 min cumulative dissolution.

[0032] The dissolution rate and cumulative dissolution of Examples 1-2 are better than those of Comparative Examples 1 and 2, indicating that the present invention can improve the dissolution performance of lacidipine tablets by using acrylic resin polymer materials in different proportions. The finished products prepared in Example 1-2 and Comparative Example 1-2 were tested for impurity content. The present invention can reduce the impurity level of lacidipine tablets by using acrylic resin polymer materials in different proportions.

[0033] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. Lacidipine tablets, characterized in that: Its raw materials include lacidipine, lactose, surfactant, cellulose polymer, acrylic resin polymer material, triglyceride, and carbomer; The weight percentages of the raw materials of the lacidipine tablets are: lacidipine 2%-4%; surfactant 1%-1.9%; cellulose polymer 8%-10%; acrylic resin polymer material 1.1%-1.6%; triglyceride 0.8%-1.2%; carbomer 1.3%-1.7%, and the remainder is lactose.

2. The lacidipine tablet according to claim 1, characterized in that: The lacidipine is micronized before use, and the process of micronization is as follows: S1.1, coarse grinding and fine grinding: lacidipine is subjected to coarse grinding and fine grinding; S1.2, operating equipment and parameter settings: select air flow mill as the crushing equipment, and set the crushing pressure to 0.8MPa, the feed pressure to 0.5MPa, and the spiral feed speed to 230 r / min; S1.3, crushing process: preheat the airflow mill according to the parameters of the above step for 30 minutes, feed the coarsely crushed and finely crushed lacidipine into the airflow mill, set the crushing time to 30 minutes, start the button, and the final particle size is controlled between D90=11-12um; S1.4, Particle size detection: Use a laser particle size analyzer to detect the particle size and distribution of the crushed powder; S1.5 Drying and packaging: Use a freeze dryer to dry the powder and keep the dried powder for later use.

3. The lacidipine tablet according to claim 1, characterized in that: The surfactant comprises sorbitan monooleate and vitamin ETPGS, and the mass ratio of the sorbitan monooleate to vitamin ETPGS is 2:

1.

4. The lacidipine tablet according to claim 1, characterized in that: The acrylic resin polymer material includes two types: Eudragit RL and Eudragit RS. The acrylic resin polymer material is composed of Eudragit RL and Eudragit RS in a mass ratio of 3:

5.

5. A method for preparing lacidipine tablets, characterized in that: The lacidipine tablets according to claim 1 are prepared according to the weight ratio of raw materials, and the preparation process is as follows: Step 1. Raw material preparation: weigh the surfactant, cellulose polymer, acrylic resin polymer material, triglyceride, lacidipine, and lactose in the raw material formula ratio; Step 2, melt extrusion: melt lacidipine and acrylic resin polymer material, extrude, and then mix with surfactant, triglyceride, and lactose to obtain lacidipine initial tablets; Step 3, devolatilization operation: further performing a devolatilization operation on the initial lacidipine tablets; Step 4: coating: using a cellulose polymer for coating. After coating, lacidipine tablets are prepared; Step 5. Quality control: Conduct dissolution rate and cumulative dissolution evaluation tests.

6. The method for preparing lacidipine tablets according to claim 5, characterized in that: The sequence and preparation process of melt extrusion in step 2 are as follows: S2.1, putting acrylic resin polymer material into an extruder, melting and extruding; S2.2, the extrudate is put into a high shear mixer at a speed of 500r / min for 10min, and the mixture is stirred thoroughly to be evenly dispersed; S2.3, add surfactant again, readjust the speed of high shear mixer to 1000r / min, and the duration is 3min; S2.

4. Finally, add triglyceride and carbomer, readjust the speed of the high shear mixer to 1500 r / min, the duration is 15 min, and crush through a 60-mesh sieve.

7. The method for preparing lacidipine tablets according to claim 5, characterized in that: In the step 3, the extruded initial lacidipine tablets are further subjected to a devolatilization operation to remove degraded small molecules and water from the material, and the operation is as follows; The temperature of the devolatilization operation was set to 70°C; Set the devolatilization time to 2-4h; During the devolatilization process, a reduced pressure method was adopted and the pressure was set to 0.15 MPa.

8. The method for preparing lacidipine tablets according to claim 5, characterized in that: The coating process in step 4 is as follows: The cellulose polymer and pure water are prepared into a coating solution in a ratio of 0.9:1.3; Set the inlet air temperature of the fluidized bed coating equipment to 55°C, the spray pressure to 0.5MPa, and the spray rate to 80m 3 / s, the total spraying time is 1 min, and then the initial lacidipine tablets to be coated are placed into the fluidized bed coating equipment, and the equipment is turned on; After coating, the coated initial lacidipine tablets were placed in a fluidized bed dryer and solidified at 60° C. for 20 min to prepare lacidipine tablets.

9. The method for preparing lacidipine tablets according to claim 5, characterized in that: In the step 5, differential scanning calorimetry is used to determine the dispersion state of the drug in the solid dispersion, and the dissolution rate and cumulative dissolution are evaluated by an in vitro dissolution test.