Fluvastatin sodium sustained release tablet and preparation method thereof

Abstract

The invention relates to the technical field of medicines, and discloses a fluvastatin sodium sustained release tablet and a preparation method of the fluvastatin sodium sustained release tablet. 5-9 parts of a polyethylene substance; 20 to 24 parts of fluvastatin sodium; 20 to 25 parts of a filling agent; 1-3 parts of an adhesive; 1-1.2 parts of a disintegrating agent; the preparation method comprises the following steps: weighing all the raw material components according to the ratio of the raw materials, uniformly mixing the components in sequence, carrying out dry granulation on the powder mixed in the previous step to form uniform particles, uniformly coating the surfaces of the particles with a coating material by using fluidized bed coating equipment to form a damp-proof coating layer with a slow-release function, and drying the coating layer. The preparation method comprises the following steps: coating fluvastatin sodium, putting the coated particles into a tablet press, pressing the coated particles into the shape and thickness of tablets preset by manufacturers, controlling pressure and temperature to prepare sustained-release tablets, carrying out quality detection on the prepared fluvastatin sodium sustained-release tablets, finally carrying out aluminum-plastic packaging on the sustained-release tablets qualified in quality detection, and storing the packaged sustained-release tablets in a cool and dry place.

Description

Technical Field

[0001] The invention relates to the field of medical technology, in particular to a fluvastatin sodium sustained-release tablet and a preparation method thereof. Background Art

[0002] Fluvastatin sodium is a drug used to lower cholesterol, mainly by inhibiting HMG-CoA reductase to reduce cholesterol synthesis in the body. However, existing fluvastatin sodium tablets have some problems, such as poor moisture resistance. These problems may affect the efficacy and safety of the drug, so further improvement and optimization are needed. Summary of the invention

[0003] In view of the deficiencies in the prior art, the present invention provides fluvastatin sodium sustained-release tablets and a preparation method thereof, which have the advantages of hygroscopic degradation, less impurities and sustained release, and solve the problem of poor moisture resistance of the existing fluvastatin sodium tablets.

[0004] To achieve the above-mentioned purpose, the present invention provides the following technical solution: Fluvastatin sodium sustained-release tablets are prepared from the following raw materials in parts by weight: 25-29 parts of cellulose derivatives; 5-9 parts of polyethylene substances; 20-24 parts of fluvastatin sodium; 20-25 parts of fillers; 1-3 parts of binders; 1-1.2 parts of disintegrants; and 2-3 parts of lubricants.

[0005] Preferably, the cellulose derivative consists of hydroxypropyl methylcellulose phthalate, carboxymethyl cellulose and ethyl cellulose in a mass ratio of 1:1-1.5:2-2.5.

[0006] Preferably, the polyethylene material consists of polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol in a mass ratio of 3:5-6.

[0007] Preferably, the fluvastatin sodium sustained-release tablets and preparation method are prepared according to the weight ratio of raw materials of the above-mentioned fluvastatin sodium sustained-release tablets, and the preparation steps of the sustained-release tablets are: Step 1, mixing raw materials: weigh fluvastatin sodium and excipients according to the raw material ratio, and mix them evenly; Step 2: preparing the skeleton: dry granulating the powder mixed in step 1 to form uniform particles; Step 3: coating treatment: mixing the cellulose derivative and the polyethylene material, dispersing them in water to obtain a coating material solution, and evenly coating the coating material solution on the surface of the particles to form coated particles; Step 4: Tablet preparation: Place the coated granules into a tablet press to obtain fluvastatin sodium sustained-release tablets.

[0008] Preferably, the order and conditions of mixing the raw materials in step 1 are: S11. Mixing fluvastatin sodium with a filler and a disintegrant and uniformly dispersing the mixture; S12. Add 1 / 2 of the mass of the binder and mix at a temperature of 40 ℃ -45 ℃ at a speed of 50r / min for 25min-30min; S13. Add the lubricant and the remaining 1 / 2 of the adhesive by mass, and mix at a temperature of 20°C-25°C and a speed of 50 r / min for 5 min-8 min.

[0009] Preferably, the process of dry granulation in step 2 is: S2. Put the powder mixed in step 1 into a granulator with a pressure of 5 MPa, collect the particles, and granulation is completed.

[0010] Preferably, the coating process in step 3 is: S31, preparing a coating solution: mixing hydroxypropyl methylcellulose phthalate, carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol and other coating materials according to the raw material ratio, and adding pure water in the raw material ratio to prepare a uniform coating solution; S32, setting parameters of fluidized bed coating equipment: first turn on the equipment, heat the fluidized bed coating equipment to 50°C, preheat for 30 minutes, set the air inlet temperature of the fluidized bed coating equipment to 50°C, the spray pressure to 0.5MPa, and the spray rate to 50-100g / min, and then put the particles to be coated into the fluidized bed coating equipment; S33, spray coating: the prepared coating liquid is sprayed evenly onto the particle surface through the spray system of the fluidized bed coating equipment to form a continuous coating layer. When the spray volume reaches 1 / 4, the spray rate is increased from 60m / s to 1 / 4. 3 / s is adjusted to 50m 3 / s, when the spray volume reaches 1 / 2, the spray rate is increased from 50m / s to 3 / s is adjusted to 30m 3 / s, by continuously adjusting the spray parameters; S34, curing: After coating, the coated particles are placed in a fluidized bed dryer for curing at 60°C for 1 hour.

[0011] Preferably, the tableting preparation conditions in step 4 are: adjusting the pressure of the tablet press between 15 MPa-20 MPa, and adjusting the temperature between 35° C.-40° C.

[0012] Preferably, the preparation method further comprises: Step 5, quality inspection: conducting quality inspection on the prepared fluvastatin sodium sustained-release tablets; Step 6. Packaging and storage: The sustained-release tablets that have passed the quality inspection are packaged in aluminum-plastic packaging.

[0013] Compared with the prior art, the present invention provides a fluvastatin sodium sustained-release tablet and a preparation method thereof, which have the following beneficial effects: 1. In the present invention, the particle size distribution, shape and hardness of the skeleton are improved by reasonably matching the proportions of fluvastatin sodium, filler and binder. This step not only enhances the stability of the drug, but also lays the foundation for the subsequent coating process. In the aggregate preparation step, the raw materials are added in different orders, and the temperature, stirring speed and stirring time are adjusted at the same time. The improvement of this step makes the coated particles smoother and crack-free in appearance, and the film thickness is more uniform, which also helps to improve the release rate. By applying the mixture of the combined proportion in the cellulose derivative, the outer layer quality and moisture-proof performance of the coating layer are further improved. Combining the above-mentioned preparation process and improvement steps, the method of the present invention not only improves the overall quality of the fluvastatin sodium sustained-release tablets, but also ensures its stability and effectiveness during storage and use, thereby solving the problem of poor moisture-proof ability of the existing fluvastatin sodium tablets. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 It is a preparation step diagram of the present invention; DETAILED DESCRIPTION

[0015] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. 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] See also Figure 1 The weight percentages of the following raw materials are: 250 g of cellulose derivative, 50 g of polyethylene material, 200 g of fluvastatin sodium, 200 g of filler, 10 g of binder, 10 g of disintegrant, 20 g of lubricant, and 1000 g of water.

[0017] The filler is specifically corn starch, the binder is specifically povidone, the disintegrant is specifically sodium carboxymethyl starch, and the lubricant is specifically magnesium stearate.

[0018] The cellulose derivative consists of hydroxypropyl methylcellulose phthalate, carboxymethyl cellulose and ethyl cellulose in a mass ratio of 1:1:2.

[0019] The polyethylene material is composed of a polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol in a mass ratio of 3:5. The mass proportion of the polyvinyl alcohol unit in the polyvinyl alcohol-polyethylene glycol copolymer is 75%, the mass proportion of the polyethylene glycol unit is 25%, and the molecular weight is 30,000.

[0020] Step 1, mixing raw materials: mixing fluvastatin sodium, filler, binder, disintegrant and lubricant evenly; Step 2: Prepare the skeleton: dry granulate the powder mixed in step 1 to form uniform particles. The above particles will be used as the skeleton material of the sustained-release tablet to help control the drug release rate; Step 3: Mix the cellulose derivative and the polyethylene substance, disperse them in water to obtain a coating material solution, and evenly coat the coating material solution on the surface of the particles to form coated particles; Step 4: Tablet preparation: Place the coated granules into a tablet press and press them into the shape and thickness of tablets preset by the manufacturer, while controlling the pressure and temperature to produce sustained-release tablets to ensure that the quality of each tablet is consistent; Step 5, quality inspection: conducting quality inspection on the prepared fluvastatin sodium sustained-release tablets; Step 6. Packaging and storage: The sustained-release tablets that have passed the quality inspection should be packaged in aluminum-plastic packaging to ensure their stability and moisture resistance, and stored in a cool and dry place to prevent moisture and light.

[0021] Specifically, the order and conditions for mixing the raw materials in step 1 are: S11. Mixing fluvastatin sodium with a filler and a disintegrant and uniformly dispersing the mixture; S12. Add 1 / 2 of the mass of the binder and mix at a temperature of 40°C at a speed of 50r / min for 25min; S13. Add the lubricant and the remaining 1 / 2 of the adhesive by mass, and mix at a temperature of 20° C. and a speed of 50 r / min for 5 minutes.

[0022] The advantage is that through the above steps, it can be ensured that the raw materials of the fluvastatin sodium sustained-release tablets are mixed in the correct proportion and order, thereby ensuring that the quality of the final product is uniform.

[0023] Specifically, the process of dry granulation in step 2 is: S2. Put the powder mixed in step 1 into a granulator with a pressure of 5 MPa, collect the particles, and granulation is completed.

[0024] Specifically, the coating process in step 3 is as follows: S31, preparing a coating solution: mixing hydroxypropyl methylcellulose phthalate, carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol and other coating materials according to the raw material ratio, and adding pure water in the raw material ratio to prepare a uniform coating solution; S32, setting parameters of fluidized bed coating equipment: first turn on the equipment, heat the fluidized bed coating equipment to 50°C, preheat for 30 minutes, set the air inlet temperature of the fluidized bed coating equipment to 50°C, the spray pressure to 0.5MPa, and the spray rate to 50g / min, and then put the particles to be coated into the fluidized bed coating equipment; S33, spray coating: the prepared coating liquid is sprayed evenly onto the particle surface through the spray system of the fluidized bed coating equipment to form a continuous coating layer. When the spray volume reaches 1 / 4, the spray rate is increased from 60m / s to 1 / 4. 3 / s is adjusted to 50m 3 / s, when the spray volume reaches 1 / 2, the spray rate is increased from 50m / s to 3 / s is adjusted to 30m 3 / s, by constantly adjusting the spray parameters to ensure the uniformity and quality of the coating layer; S34, solidification: After coating, the coated particles are placed in a fluidized bed dryer and solidified at 60°C for 1 hour to enhance the moisture-proof performance and sustained-release function of the coating layer.

[0025] Specifically, the conditions for tablet preparation in step 4 are: select a rotary tablet press, select the tablet press shape and set the thickness parameters of the tablet press according to the shape and thickness of the tablets preset by the manufacturer, adjust the pressure of the tablet press between 15 MPa, and adjust the temperature between 35°C.

[0026] Specifically, the quality inspection items in step five are: content determination, impurity inspection, release test, property inspection and identification test, and moisture resistance test. Example 2

[0027] The weight percentages of the following raw materials are respectively: cellulose derivative 290 g, polyethylene material 90 g, fluvastatin sodium 240 g, filler 250 g, binder 30 g, disintegrant 12 g, lubricant 30 g, water 1000 g.

[0028] The filler is specifically corn starch, the binder is specifically povidone, the disintegrant is specifically sodium carboxymethyl starch, and the lubricant is specifically magnesium stearate.

[0029] The cellulose derivative consists of hydroxypropyl methylcellulose phthalate, carboxymethyl cellulose and ethyl cellulose in a mass ratio of 1:1:2.

[0030] The polyethylene material is composed of a polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol in a mass ratio of 3:5. The mass proportion of the polyvinyl alcohol unit in the polyvinyl alcohol-polyethylene glycol copolymer is 75%, the mass proportion of the polyethylene glycol unit is 25%, and the molecular weight is 30,000.

[0031] Step 1, mixing raw materials: mixing fluvastatin sodium, filler, binder, disintegrant and lubricant evenly; Step 2: Prepare the skeleton: dry granulate the powder mixed in step 1 to form uniform particles. The above particles will be used as the skeleton material of the sustained-release tablet to help control the drug release rate; Step 3: Mix the cellulose derivative and the polyethylene substance, disperse them in water to obtain a coating material solution, and evenly coat the coating material solution on the surface of the particles to form coated particles; Step 4: Tablet preparation: Place the coated granules into a tablet press and press them into the shape and thickness of tablets preset by the manufacturer, while controlling the pressure and temperature to produce sustained-release tablets to ensure that the quality of each tablet is consistent; Step 5, quality inspection: conducting quality inspection on the prepared fluvastatin sodium sustained-release tablets; Step 6. Packaging and storage: The sustained-release tablets that have passed the quality inspection should be packaged in aluminum-plastic packaging to ensure their stability and moisture resistance, and stored in a cool and dry place to prevent moisture and light.

[0032] Specifically, the order and conditions for mixing the raw materials in step 1 are: S11. Mixing fluvastatin sodium with a filler and a disintegrant and uniformly dispersing the mixture; S12. Add 1 / 2 of the mass of the binder and mix at a temperature of 45°C at a speed of 50r / min for 25min; S13. Add the lubricant and the remaining 1 / 2 of the adhesive by mass, and mix at a temperature of 25° C. and a speed of 50 r / min for 8 minutes.

[0033] The advantage is that through the above steps, it can be ensured that the raw materials of the fluvastatin sodium sustained-release tablets are mixed in the correct proportion and order, thereby ensuring that the quality of the final product is uniform.

[0034] Specifically, the process of dry granulation in step 2 is: S2. Put the powder mixed in step 1 into a granulator with a pressure of 5 MPa, collect the particles, and granulation is completed.

[0035] Specifically, the coating process in step 3 is as follows: S31, preparing a coating solution: mixing hydroxypropyl methylcellulose phthalate, carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol and other coating materials according to the raw material ratio, and adding pure water in the raw material ratio to prepare a uniform coating solution; S32, setting parameters of the fluidized bed coating equipment: first turn on the equipment, heat the fluidized bed coating equipment to 50°C, preheat for 30 minutes, set the air inlet temperature of the fluidized bed coating equipment to 50°C, the spray pressure to 0.5MPa, and the spray rate to 100g / min, and then put the particles to be coated into the fluidized bed coating equipment; S33, spray coating: the prepared coating liquid is sprayed evenly onto the particle surface through the spray system of the fluidized bed coating equipment to form a continuous coating layer. When the spray volume reaches 1 / 4, the spray rate is increased from 60m / s to 1 / 4. 3 / s is adjusted to 50m 3 / s, when the spray volume reaches 1 / 2, the spray rate is increased from 50m / s to 3 / s is adjusted to 30m 3 / s, by constantly adjusting the spray parameters to ensure the uniformity and quality of the coating layer; S34, solidification: After coating, the coated particles are placed in a fluidized bed dryer and solidified at 60°C for 1 hour to enhance the moisture-proof performance and sustained-release function of the coating layer.

[0036] Specifically, the conditions for tablet preparation in step 4 are: select a rotary tablet press, select the tablet press shape and set the thickness parameters of the tablet press according to the shape and thickness of the tablets preset by the manufacturer, adjust the pressure of the tablet press between 15 MPa, and adjust the temperature between 35°C.

[0037] Specifically, the quality inspection items in step five are: content determination, impurity inspection, release test, property inspection and identification test, and moisture resistance test.

[0038] Comparative Example 1 Comparative Example 1: The polyethylene material in Example 1 consists only of polyvinyl alcohol and is prepared according to the preparation steps of Example 1.

[0039] Comparative Example 2 Comparative Example 2: The cellulose derivative in Example 1 consists only of ethyl cellulose and is prepared according to the preparation steps of Example 1.

[0040] Comparative Example 3 Changing the preparation steps: Comparative Example 3 uses the raw material formula of Example 1, and the method of mixing the raw materials in Step 1 of Example 1 is changed. All the raw materials are mixed in the same beaker at a temperature of 40°C and a speed of 100 r / min, and the other steps remain unchanged.

[0041] Finished product testing The finished products of fluvastatin sodium sustained-release tablets prepared in Examples 1-2 and Comparative Examples 1-3 were tested, and the test items included hardness, solubility, and impurity content.

[0042] The hardness test was carried out using a tablet hardness tester, and the results are shown in Table 1.

[0043] Table 1 Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 28N 27N 26N 26N 20N By comparing the test data in Table 1 of Examples 1-2 and Comparative Examples 1-3, it can be seen that appropriate preparation steps can effectively prepare fluvastatin sodium sustained-release tablets with hardness meeting the standard.

[0044] The dissolution test used water containing 1 wt% Tween as the release medium to test the dissolution after 60 minutes of release. The results are shown in Table 2.

[0045] Table 2 Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 101.03% 100.48% 92.52% 93.49% 97.20% By comparing the test data of Examples 1-2 with Comparative Examples 1-3, it can be seen that suitable coating materials such as polyethylene substances and cellulose derivatives can achieve higher dissolution rates.

[0046] The test results of impurity content are shown in Table 3.

[0047] Table 3 Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 0.49% 0.53% 0.88% 0.74% 0.96% By comparing the test data in Table 1 of Examples 1-2 and Comparative Examples 1-3, it can be seen that appropriate preparation steps can effectively prepare fluvastatin sodium sustained-release tablets with impurity content meeting the standards.

[0048] In addition, in order to test the moisture resistance of fluvastatin sodium sustained-release tablets, the fluvastatin sodium sustained-release tablets were subjected to a long-term test and then a dissolution test. The long-term test conditions were a temperature of 40°C and a relative humidity of 75% RH for 6 months. The dissolution results after the long-term test are shown in Table 4.

[0049] Table 4 Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 100.53% 100.02% 87.33% 88.25% 94.37%

[0050] It can be seen that after long-term testing, the moisture-proof performance of fluvastatin sodium sustained-release tablets is excellent, so that the dissolution rate can still be maintained at a high level.

[0051] 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. A fluvastatin sodium sustained-release tablet, characterized in that: The invention is prepared from the following raw materials in parts by weight: 25-29 parts of cellulose derivatives; 5-9 parts of polyethylene substances; 20-24 parts of fluvastatin sodium; 20-25 parts of fillers; 1-3 parts of binders; and 1-1.2 parts of disintegrants. 2-3 parts of lubricant.

2. The fluvastatin sodium sustained-release tablet according to claim 1, characterized in that: The cellulose derivative consists of hydroxypropyl methylcellulose phthalate, carboxymethyl cellulose and ethyl cellulose in a mass ratio of 1:1-1.5:2-2.

5.

3. The fluvastatin sodium sustained-release tablet according to claim 1, characterized in that: The polyethylene material is composed of a polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol in a mass ratio of 3:5-6.

4. A method for preparing a fluvastatin sodium sustained-release tablet, characterized in that: The fluvastatin sodium sustained-release tablets according to claim 1 are prepared according to the weight ratio of raw materials, and the preparation steps of the sustained-release tablets are: Step 1, mixing raw materials: weigh fluvastatin sodium and excipients according to the raw material ratio, and mix them evenly; Step 2: preparing the skeleton: dry granulating the powder mixed in step 1 to form uniform particles; Step 3: coating treatment: mixing the cellulose derivative and the polyethylene material, dispersing them in water to obtain a coating material solution, and evenly coating the coating material solution on the surface of the particles to form coated particles; Step 4: Tablet preparation: Place the coated granules into a tablet press to obtain fluvastatin sodium sustained-release tablets.

5. The method for preparing the fluvastatin sodium sustained-release tablets according to claim 4, characterized in that: The order and conditions for mixing the raw materials in step 1 are as follows: S11. Mixing fluvastatin sodium with a filler and a disintegrant and uniformly dispersing the mixture; S12. Add 1 / 2 of the mass of the binder and mix at a temperature of 40 ℃ -45 ℃ at a speed of 50r / min for 25min-30min; S13. Add the lubricant and the remaining 1 / 2 of the adhesive by mass, and mix at a temperature of 20°C-25°C and a speed of 50 r / min for 5 min-8 min.

6. The method for preparing the fluvastatin sodium sustained-release tablets according to claim 5, characterized in that: The process of dry granulation in step 2 is as follows: S2. Put the powder mixed in step 1 into a granulator with a pressure of 5 MPa, collect the particles, and granulation is completed.

7. The method for preparing the fluvastatin sodium sustained-release tablets according to claim 4, characterized in that: The coating process in step 3 is as follows: S31, preparing a coating solution: mixing hydroxypropyl methylcellulose phthalate, carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol and other coating materials according to the raw material ratio, and adding pure water in the raw material ratio to prepare a uniform coating solution; S32, setting parameters of fluidized bed coating equipment: first turn on the equipment, heat the fluidized bed coating equipment to 50°C, preheat for 30 minutes, set the air inlet temperature of the fluidized bed coating equipment to 50°C, the spray pressure to 0.5MPa, and the spray rate to 50-100g / min, and then put the particles to be coated into the fluidized bed coating equipment; S33, spray coating: the prepared coating liquid is sprayed evenly onto the particle surface through the spray system of the fluidized bed coating equipment to form a continuous coating layer. When the spray volume reaches 1 / 4, the spray rate is increased from 60m / s to 1 / 4. 3 / s is adjusted to 50m 3 / s, when the spray volume reaches 1 / 2, the spray rate is increased from 50m / s to 3 / s is adjusted to 30m 3 / s, by continuously adjusting the spray parameters; S34, solidification: After coating, the coated particles are placed in a fluidized bed dryer for solidification at a temperature of 60° C. for 1 hour.

8. The method for preparing the fluvastatin sodium sustained-release tablets according to claim 4, characterized in that: The conditions for tableting in step 4 are as follows: adjusting the pressure of the tablet press between 15 MPa and 20 MPa, and adjusting the temperature between 35° C. and 40° C.

9. The method for preparing the fluvastatin sodium sustained-release tablets according to claim 4, characterized in that: The preparation method also includes: Step 5, quality inspection: conducting quality inspection on the prepared fluvastatin sodium sustained-release tablets; Step 6. Packaging and storage: The sustained-release tablets that have passed the quality inspection are packaged in aluminum-plastic packaging.

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