Ezetimibe and rosuvastatin calcium tablet and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses an ezetimibe and rosuvastatin calcium tablet and a preparation method thereof. According to the ezetimibe and rosuvastatin calcium tablet and the preparation method thereof, the ultrasonic modified microcrystalline cellulose with high specific surface area and high relative water retention value is added into the ezetimibe and rosuvastatin calcium tablet, ezetimibe can be well coated, in addition, the ultrasonic modified microcrystalline cellulose has more hydroxyl groups, and can form hydrogen bonds with the hydroxyl groups in the ezetimibe, so that the ezetimibe and rosuvastatin calcium tablet can be used for preparing the ezetimibe and rosuvastatin calcium tablet. The ezetimibe stably exists in the pore diameter of the ultrasonic modified microcrystalline cellulose, and the solubility of the ezetimibe can be effectively improved in the drug release process.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and specifically discloses an ezetimibe and rosuvastatin calcium tablet and a preparation method thereof. Background Art

[0002] Ezetimibe rosuvastatin calcium tablets are a lipid-lowering drug with dual effects, which can be used to treat chronic diseases caused by excessive blood lipids (such as fat, cholesterol, and triglycerides). Its main components are ezetimibe and rosuvastatin calcium. Ezetimibe is a cholesterol absorption inhibitor, which can effectively reduce intestinal cholesterol absorption, lower plasma cholesterol levels and liver cholesterol reserves by selectively inhibiting intestinal cholesterol transporters. Rosuvastatin calcium is a selective HMG-CoA reductase inhibitor, which is used in combination with ezetimibe to treat primary hypercholesterolemia and can reduce total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B.

[0003] However, ezetimibe is a poorly soluble drug with extremely poor solubility in the aqueous phase environment, which greatly limits the dissolution and absorption of the drug in the body and reduces the bioavailability of the drug. At present, micronization is mostly used to crush ezetimibe. By reducing its particle size and increasing its specific surface area, the solubility of the drug in the aqueous phase environment can be improved. However, although ezetimibe is micronized, its dissolution is still difficult to reach the same level as the reference preparation, and the fluidity of micronized ezetimibe is extremely poor, making it difficult to mix evenly with rosuvastatin calcium and other excipients.

[0004] Therefore, there are problems with the dissolution rate and mixing uniformity of ezetimibe in the clinical application of ezetimibe and rosuvastatin calcium tablets. Summary of the Invention

[0005] In order to solve the problems of poor dissolution rate and mixing uniformity of ezetimibe in the prior art, the present invention provides an ezetimibe and rosuvastatin calcium tablet and a preparation method thereof.

[0006] The ezetimibe and rosuvastatin calcium tablet provided by the present invention adopts the following technical solution:

[0007] An ezetimibe and rosuvastatin calcium tablet, the ezetimibe and rosuvastatin calcium tablet comprises a core layer and a coating layer, and the core layer comprises ezetimibe, a disintegrant, a binder, a solubilizer, rosuvastatin calcium, a filler, a glidant, a lubricant, and ultrasonic modified microcrystalline cellulose;

[0008] Wherein, the specific surface area of the ultrasonic modified microcrystalline cellulose is 1.340 m 2 / g - 1.350 m 2 / g, and the relative water retention value is 157.0% - 168.4%.

[0009] Compared with the prior art, the present invention adds ultrasonically modified microcrystalline cellulose with a high specific surface area and a high relative water retention value to the ezetimibe and rosuvastatin calcium tablets. This ultrasonically modified microcrystalline cellulose can better coat ezetimibe. At the same time, it has more hydroxyl groups, which can form hydrogen bonds with the hydroxyl groups in ezetimibe, enabling ezetimibe to stably exist in the pores of the ultrasonically modified microcrystalline cellulose, and improving the solubility of ezetimibe during the drug release process.

[0010] Preferably, the preparation method of the ultrasonically modified microcrystalline cellulose comprises the following steps:

[0011] Step S1, heating and treating microcrystalline cellulose in an acid solution to obtain a mixture;

[0012] Step S2, placing the mixture in pure water. After mixing and standing, performing solid-liquid separation on the upper slurry, washing the obtained solid with water until the pH value of the washing liquid is 5.7 - 5.9, and drying to obtain primary modified microcrystalline cellulose;

[0013] Step S3, adding the primary modified microcrystalline cellulose to an aqueous ethanol solution, ultrasonicating and then standing, ultrasonicating continuously, performing solid-liquid separation, and drying the obtained solid to obtain ultrasonically modified microcrystalline cellulose.

[0014] In the present invention, an aqueous ethanol solution is used as the solvent during the ultrasonic process. The aqueous ethanol solution can absorb the heat generated when the ultrasonic cavitation bubbles collapse, which can reduce the damage to the structure of microcrystalline cellulose caused by local high temperature, and thus avoid the problem of the decrease in the specific surface area of the ultrasonically modified microcrystalline cellulose. In addition, the present invention uses an intermittent ultrasonic method to treat microcrystalline cellulose, which also reduces the generation amount of ultrasonic cavitation bubbles, enabling the ultrasonically modified microcrystalline cellulose to generate more hydroxyl groups under the action of ultrasonic waves while avoiding the problem of the decrease in the specific surface area of the ultrasonically modified microcrystalline cellulose.

[0015] Preferably, the volume concentration of the aqueous ethanol solution is 40% - 60%.

[0016] The present invention selects an ethanol aqueous solution with a volume concentration of 40%-60% as the solvent. Because of its relatively high thermal conductivity, relatively high specific heat capacity, and high volatility, it can combine heat absorption and volatile heat dissipation, ensuring that the heat generated when ultrasonic cavitation bubbles collapse is completely absorbed and dissipated through volatilization. For an ethanol aqueous solution with a volume concentration less than 40%, due to the low content of the ethanol aqueous solution, although its specific heat capacity and thermal conductivity are relatively high and can effectively absorb heat, the effect of heat transfer by volatilization is limited. After the ethanol aqueous solution absorbs the heat generated when ultrasonic cavitation bubbles collapse, it will cause the solvent to heat up and cannot play a role in protecting the structure of microcrystalline cellulose. For an ethanol aqueous solution with a volume concentration greater than 60%, due to the high content of the ethanol aqueous solution, although its volatility is strong and the effect of heat transfer by volatilization is strong, its specific heat capacity and thermal conductivity are low, and its heat absorption capacity is poor. It cannot completely absorb the heat generated when ultrasonic cavitation bubbles collapse, which will cause the local temperature of microcrystalline cellulose to rise and then damage the structure of microcrystalline cellulose.

[0017] Preferably, in step S1, the particle size of the microcrystalline cellulose is 0.1 μm - 10 μm.

[0018] Preferably, in step S1, the acid solution is selected from hydrochloric acid aqueous solution or carbonic acid aqueous solution, the mass-volume ratio of the microcrystalline cellulose to the acid solution is 1 g:(10 - 15) mL, and the volume concentration of the acid solution is 30% - 40%.

[0019] Preferably, in step S1, the temperature of the heat treatment is 70°C - 80°C, and the time is 2.5 h - 3.5 h. By limiting the type and dosage of the acid solution and the temperature and time of the heat treatment, the present invention is conducive to promoting the full progress of the reaction.

[0020] Preferably, in step S3, the power of the ultrasonic wave is 600 W - 800 W, the frequency is 25 kHz - 35 kHz, and the time is 5 - 10 min.

[0021] Preferably, in step S3, the temperature of the static state is 25°C - 30°C, and the time is 10 - 20 min.

[0022] By modifying microcrystalline cellulose with ultrasonic waves, the present invention can increase the number of active hydroxyl groups in microcrystalline cellulose. In addition, the present invention limits the ultrasonic wave to be carried out at a relatively high ultrasonic power, which can partially destroy the structure of the primary modified microcrystalline cellulose, reduce the particle size of the preliminarily modified microcrystalline cellulose to the nanometer level, improve the coating effect of the ultrasonic-modified microcrystalline cellulose on ezetimibe, and at the same time, the present invention cooperates with a relatively high frequency to reduce the generation amount of ultrasonic cavitation bubbles and avoid the generation of larger cavitation bubbles, thereby avoiding the problem of excessive damage to the structure of the preliminarily modified microcrystalline cellulose.

[0023] Preferably, the core layer comprises components in the following parts by mass: 5-20 parts of ezetimibe, 50-200 parts of ultrasonically modified microcrystalline cellulose, 2-20 parts of disintegrant, 1-10 parts of binder, 1-10 parts of solubilizer, 5-40 parts of rosuvastatin calcium, 20-100 parts of filler, 0.1-5 parts of glidant, and 0.1-5 parts of lubricant.

[0024] Preferably, the coating layer is 2%-4% of the mass of the core layer.

[0025] Preferably, the filler is selected from one or more of lactose, corn starch, or calcium hydrogen phosphate.

[0026] Preferably, the disintegrant is selected from one or more of croscarmellose sodium, crospovidone, or sodium carboxymethyl starch.

[0027] Preferably, the binder is selected from one or more of povidone, hypromellose, or hydroxypropyl cellulose.

[0028] Preferably, the solubilizer is sodium dodecyl sulfate, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate.

[0029] The present invention also provides a method for preparing the ezetimibe and rosuvastatin calcium tablets according to the foregoing scheme, which comprises the following steps:

[0030] Step 1: Mix ezetimibe, lubricant, ultrasonically modified microcrystalline cellulose, part of the disintegrant, and solubilizer, granulate, and dry to obtain ezetimibe granules.

[0031] Step 2: Mix rosuvastatin calcium, filler, the remaining disintegrant, stabilizer, and binder to obtain rosuvastatin calcium granules.

[0032] Step 3: Mix the ezetimibe granules and rosuvastatin calcium granules, press tablets, and coat to obtain ezetimibe and rosuvastatin calcium tablets.

[0033] Compared with the prior art, the present invention granulates ezetimibe and rosuvastatin calcium separately and then mixes and tablets them, ensuring that the solubility of ezetimibe in the ezetimibe granules is relatively high, and at the same time, ensuring that rosuvastatin calcium has relatively high stability.

[0034] Preferably, in Step 1, the device used for mixing is a wet granulator, the stirring speed for mixing is 100 rpm - 120 rpm, the chopping speed is 800 rpm - 1000 rpm, and the time is 5 min - 15 min.

[0035] Preferably, in step one, the device used for granulation is a wet granulator, the solvent used for granulation is purified water, the stirring speed for granulation is 100 rpm - 120 rpm, the chopping speed is 1000 rpm - 1200 rpm, and the time is 1 min - 5 min.

[0036] Preferably, in step one, the drying temperature is 50°C - 60°C, and the time is 10 min - 20 min.

[0037] Preferably, in step two, the mixing speed is 5 rpm - 15 rpm, and the time is 10 min - 20 min.

[0038] Preferably, in step three, the hardness of the tablets after tableting is 40 N - 60 N.

[0039] In summary, the present invention includes at least one of the following beneficial technical effects.

[0040] 1. The present invention adds ultrasonically modified microcrystalline cellulose with a high specific surface area and a high relative water retention value to the ezetimibe and rosuvastatin calcium tablets. This ultrasonically modified microcrystalline cellulose can better coat ezetimibe. At the same time, it has more hydroxyl groups, which can form hydrogen bonds with the hydroxyl groups in ezetimibe, enabling ezetimibe to stably exist in the pores of the ultrasonically modified microcrystalline cellulose and improving the solubility of ezetimibe during the drug release process.

[0041] 2. The present invention granulates ezetimibe and rosuvastatin calcium separately and then mixes and tablets them, ensuring that the solubility of ezetimibe in the ezetimibe particles is relatively high, and at the same time ensuring that rosuvastatin calcium has relatively high stability. Specific Embodiments

[0042] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only one embodiment of the present invention, rather than all embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention. Example 1

[0043] A preparation method of ultrasonically modified microcrystalline cellulose includes the following steps:

[0044] Step S1, weigh 80 g of microcrystalline cellulose with a particle size of 5 μm, put it into a reaction kettle containing 800 mL of hydrochloric acid aqueous solution with a volume concentration of 30%, increase the temperature of the reaction kettle, raise the temperature in the reaction kettle to 70°C, and react for 2.5 h to obtain a mixture.

[0045] Step S2: Feed the mixture into a mixing tank, inject 1600 mL of pure water into the mixing tank. After mixing and standing, extract the upper-layer slurry in the mixing tank into a centrifuge, centrifuge at a speed of 1000 rpm for 0.5 h, take the precipitate and wash it with pure water until the pH value of the washing liquid is 5.7, and dry the precipitate at 50 °C for 2 h to obtain primary modified microcrystalline cellulose;

[0046] Step S3: Mix the primary modified microcrystalline cellulose evenly with 1600 mL of an ethanol aqueous solution with a volume concentration of 40%. After ultrasonic treatment at parameters of 600 W and 25 kHz for 5 min, let the ultrasonic mixed solution stand at 25 °C for 10 min, then continue to perform ultrasonic treatment at parameters of 600 W and 25 kHz for 5 min, filter to obtain the precipitate and dry it at 50 °C for 2 h to obtain ultrasonically modified microcrystalline cellulose. Example 2

[0047] A preparation method of ultrasonically modified microcrystalline cellulose includes the following steps:

[0048] Step S1: Weigh 80 g of microcrystalline cellulose with a particle size of 0.1 μm, put it into a reaction kettle containing 1200 mL of a carbonic acid aqueous solution with a volume concentration of 40%, raise the temperature of the reaction kettle to make the temperature in the reaction kettle rise to 80 °C, and react for 3.5 h to obtain a mixture;

[0049] Step S2: Feed the mixture into a mixing tank, inject 2000 mL of pure water into the mixing tank. After mixing and standing, extract the upper-layer slurry in the mixing tank into a centrifuge, centrifuge at a speed of 1000 rpm for 0.5 h, take the precipitate and wash it with pure water until the pH value of the washing liquid is 5.8, and dry the precipitate at 50 °C for 2 h to obtain primary modified microcrystalline cellulose;

[0050] Step S3: Mix the primary modified microcrystalline cellulose evenly with 3200 mL of an ethanol aqueous solution with a volume concentration of 60%. After ultrasonic treatment at parameters of 600 W and 25 kHz for 5 min, let the ultrasonic mixed solution stand at 30 °C for 20 min, then continue to perform ultrasonic treatment at parameters of 600 W and 25 kHz for 5 min, filter to obtain the precipitate and dry it at 50 °C for 2 h to obtain ultrasonically modified microcrystalline cellulose. Example 3

[0051] A preparation method of ultrasonically modified microcrystalline cellulose includes the following steps:

[0052] Step S1: Weigh 80 g of microcrystalline cellulose with a particle size of 0.1 μm, put it into a reaction kettle containing 1000 mL of a carbonic acid aqueous solution with a volume concentration of 30%, raise the temperature of the reaction kettle to make the temperature in the reaction kettle rise to 75 °C, and react for 3 h to obtain a mixture;

[0053] Step S2: Feed the mixture into a mixing tank, inject 1600 mL of pure water into the mixing tank. After mixing and standing, extract the upper-layer slurry in the mixing tank into a centrifuge, centrifuge at a speed of 1000 rpm for 0.5 h, take the precipitate and wash it with pure water until the pH value of the washing liquid is 5.9, and dry the precipitate at 50 °C for 2 h to obtain primary modified microcrystalline cellulose;

[0054] Step S3: Mix the primary modified microcrystalline cellulose evenly with 2400 mL of an ethanol aqueous solution with a volume concentration of 50%. After ultrasonic treatment at parameters of 600 W and 25 kHz for 5 min, let the ultrasonic mixed solution stand at 27 °C for 15 min, then continue to perform ultrasonic treatment at parameters of 600 W and 25 kHz for 5 min, filter, take the precipitate and dry it at 50 °C for 2 h to obtain ultrasonically modified microcrystalline cellulose. Comparative Example 1

[0055] A preparation method of ultrasonically modified microcrystalline cellulose comprises the following steps:

[0056] Step S1: Weigh 80 g of microcrystalline cellulose with a particle size of 0.1 μm and put it into a reaction kettle containing 1000 mL of a carbonic acid aqueous solution with a volume concentration of 30%. Raise the temperature of the reaction kettle to make the temperature in the reaction kettle rise to 75 °C and react for 3 h to obtain a mixture;

[0057] Step S2: Feed the mixture into a mixing tank, inject 1600 mL of pure water into the mixing tank. After mixing and standing, extract the upper-layer slurry in the mixing tank into a centrifuge, centrifuge at a speed of 1000 rpm for 0.5 h, take the precipitate and wash it with pure water until the pH value of the washing liquid is 5.9, and dry the precipitate at 50 °C for 2 h to obtain primary modified microcrystalline cellulose;

[0058] Step S3: Mix the primary modified microcrystalline cellulose evenly with 2400 mL of an ethanol aqueous solution with a volume concentration of 20%. Perform ultrasonic treatment at parameters of 1000 W and 60 kHz for 5 min, filter, take the precipitate and dry it at 50 °C for 2 h to obtain ultrasonically modified microcrystalline cellulose. Comparative Example 2

[0059] A preparation method of ultrasonically modified microcrystalline cellulose comprises the following steps:

[0060] Step S1: Weigh 80 g of microcrystalline cellulose with a particle size of 0.1 μm and put it into a reaction kettle containing 1000 mL of a carbonic acid aqueous solution with a volume concentration of 30%. Raise the temperature of the reaction kettle to make the temperature in the reaction kettle rise to 75 °C and react for 3 h to obtain a mixture;

[0061] Step S2: Feed the mixture into a mixing tank, inject 1600 mL of pure water into the mixing tank. After mixing and standing, extract the upper-layer slurry in the mixing tank into a centrifuge, centrifuge at a speed of 1000 rpm for 0.5 h, take the precipitate and wash it with pure water until the pH value of the washing liquid is 5.9, and dry the precipitate at 50 °C for 2 h to obtain primary modified microcrystalline cellulose;

[0062] Step S3: Mix the primary modified microcrystalline cellulose evenly with 2400 mL of ethanol aqueous solution with a volume concentration of 80%. After ultrasonic treatment at the parameters of 300 W and 15 kHz for 20 min, filter to obtain the precipitate and dry it at 50 °C for 2 h to obtain ultrasonic modified microcrystalline cellulose. Comparative Example 3

[0063] A preparation method of ultrasonic modified microcrystalline cellulose comprises the following steps:

[0064] Step S1: Weigh 80 g of microcrystalline cellulose with a particle size of 0.1 μm and put it into a reaction kettle containing 1000 mL of carbonic acid aqueous solution with a volume concentration of 30%. Raise the temperature of the reaction kettle to make the temperature in the reaction kettle rise to 75 °C and react for 3 h to obtain a mixture;

[0065] Step S2: Feed the mixture into a mixing tank, inject 1600 mL of pure water into the mixing tank. After mixing and standing, extract the upper-layer slurry in the mixing tank into a centrifuge, centrifuge at a speed of 1000 rpm for 0.5 h, take the precipitate and wash it with pure water until the pH value of the washing liquid is 5.9, and dry the precipitate at 50 °C for 2 h to obtain primary modified microcrystalline cellulose;

[0066] Step S3: Mix the primary modified microcrystalline cellulose evenly with 2400 mL of ethanol aqueous solution with a volume concentration of 40%. After ultrasonic treatment at the parameters of 300 W and 15 kHz for 5 min, filter to obtain the precipitate and dry it at 50 °C for 2 h to obtain ultrasonic modified microcrystalline cellulose.

[0067] Measure the relative water retention value and specific surface area of the microcrystalline cellulose in Example 1 and the ultrasonic modified microcrystalline cellulose obtained in Examples 1-3 and Comparative Examples 1-3.

[0068] The method for measuring the relative water retention value includes the following steps: Weigh 0.5 g of ultrasonically modified microcrystalline cellulose and stir it to disperse in 50 mL of deionized water; Transfer the dispersed ultrasonically modified microcrystalline cellulose suspension to a centrifuge tube, set the rotation speed of the centrifuge to 4000 rpm for 15 min; After centrifugation, transfer the precipitate to a pre-weighed filter paper, and repeatedly wash it with deionized water to remove residual suspended substances or impurities. Put the filter paper together with the ultrasonically modified microcrystalline cellulose into an oven, dry it to a constant weight at 60 °C, weigh the mass of the filter paper and the ultrasonically modified microcrystalline cellulose, and calculate the relative water retention quality according to the formula: Relative water retention quality = (mass of the filter paper and the ultrasonically modified microcrystalline cellulose after drying - mass of the filter paper) / initial mass of MCC × 100%.

[0069] The method for measuring the specific surface area includes the following steps: Degas the ultrasonically modified microcrystalline cellulose in a vacuum drying oven. Use a specific surface area analyzer, with hydrogen as the carrier gas and nitrogen as the adsorption gas, measure the adsorption amount of nitrogen, fit the data using the BET formula, and calculate the specific surface area. The BET calculation formula is 1 / V = C / Vm + 1 / Vm, where V is the adsorption amount per unit mass of the sample; C is the BET constant, and Vm is the monolayer adsorption amount.

[0070] The measurement results of the relative water retention value and the specific surface area of the microcrystalline cellulose in Example 1 and the ultrasonically modified microcrystalline cellulose in Examples 1 - 3 and Comparative Examples 1 - 3 are shown in Table 1. Table 1 Measurement results of relative water retention value and specific surface area Project Relative water retention value (%) <![CDATA[Specific surface area (m 2 / g) <!-- 5 -->]]> Microcrystalline cellulose 130.5 0.251 Example 1 157.0 1.350 Example 2 168.4 1.340 Example 3 164.7 1.343 Comparative Example 1 144.6 1.157 Comparative Example 2 135.7 0.795 Comparative Example 3 132.1 0.552

[0071] As can be seen from Table 1, the ultrasonically modified microcrystalline cellulose provided in Examples 1 - 3 of the present invention has a higher specific surface area and relative water retention value compared with the unmodified microcrystalline cellulose. The specific surface area of the ultrasonically modified microcrystalline cellulose prepared in the examples of the present invention is 1.340 m2 / g - 1.350 m2 / g, and the relative water retention value is 157.0% - 168.4%. And it can be seen from Table 1 that the specific surface area of Example 2 is less than that of Example 3, and at the same time, the specific surface areas of Examples 2 and 3 are both less than that of Example 1. At the same time, the relative water retention value of Example 1 is less than that of Example 3, and at the same time, the relative water retention values of Examples 1 and 3 are both less than that of Example 2. In addition, by comparing Examples 1 - 3 and Comparative Examples 1 - 3, it can be seen that with the increase of the power and time of ultrasound, although the specific surface area decreases to some extent, its relative water retention value gradually increases. This is because in Examples 1 - 3 of the present invention, intermittent ultrasound is used, and an ethanol aqueous solution with a volume concentration of 40% - 60% is used as the solvent, which avoids the generation of large cavitation bubbles during the ultrasound process, thereby avoiding the problem of obvious damage to the structure of microcrystalline cellulose, and at the same time increasing the number of active hydroxyl groups of microcrystalline cellulose. Example 4

[0072] This example provides an ezetimibe and rosuvastatin calcium tablet, and the dosage for the prescription (1000 tablets) is shown in the following table:

[0073] The preparation process of the above ezetimibe and rosuvastatin calcium tablets includes the following steps:

[0074] Step 1: Put 6 g of ezetimibe, 55 g of ultrasonically modified microcrystalline cellulose, 30 g of lactose, 5 g of cross-linked carboxymethylcellulose sodium, 5 g of sodium lauryl sulfate, and 5 g of polyvinylpyrrolidone into a wet granulator for premixing. The stirring speed is 100 rpm, the chopping speed is 800 rpm. After premixing for 10 min, pass through a sieving machine with a sieve mesh size of 0.8 mm. After sieving, continue to put the material into the wet granulator for mixing for 10 min, add purified water for wet granulation. The stirring speed is 100 rpm, the chopping speed is 1000 rpm. After granulating for 3 min, add it to a fluidized bed for drying at a drying temperature of 50 °C, and then perform sizing to obtain ezetimibe granules; among them, the ultrasonically modified microcrystalline cellulose is prepared by the preparation method of Example 1;

[0075] Step 2: Mix 20 g of rosuvastatin, 30 g of corn starch, 3 g of colloidal silicon dioxide, 6 g of cross-linked carboxymethylcellulose sodium, and 3 g of magnesium stearate for 10 - 20 min at a mixing speed of 10 rpm to obtain rosuvastatin granules;

[0076] Step 3: After mixing the ezetimibe granules and rosuvastatin granules, press tablets, adjust the tablet hardness to 40 N, and take 20.0 g of Eudragit RL30D aqueous dispersion (solid content 30%, dried to 6 g) for coating to obtain ezetimibe and rosuvastatin calcium tablets. Example 5

[0077] This example provides an ezetimibe and rosuvastatin calcium tablet, and the dosage for the prescription (1000 tablets) is shown in the following table:

[0078] The preparation process of the above ezetimibe and rosuvastatin calcium tablets includes the following steps:

[0079] Step 1: Put 20 g of ezetimibe, 180 g of ultrasonically modified microcrystalline cellulose, 40 g of lactose, 5 g of croscarmellose sodium, 4 g of sodium lauryl sulfate, and 4 g of povidone into a wet granulator for premixing. The stirring speed is 120 rpm, and the chopping speed is 1000 rpm. After premixing for 10 min, pass through a sieve using a granulator, with the sieve mesh size of 0.8 mm. After sieving, continue to put the material into the wet granulator for mixing for 15 min, add purified water for wet granulation, with the stirring speed of 120 rpm and the chopping speed of 1200 rpm. After granulating for 3 min, add it to a fluidized bed for drying at a drying temperature of 60°C, and then perform screening to obtain ezetimibe granules; among them, the ultrasonically modified microcrystalline cellulose is prepared by the preparation method of Example 2;

[0080] Step 2: Mix 10.4 g of rosuvastatin, 44 g of corn starch, 0.6 g of colloidal silicon dioxide, 3 g of croscarmellose sodium, and 3 g of magnesium stearate for 10 min at a mixing speed of 10 rpm to obtain rosuvastatin granules;

[0081] Step 3: After mixing the ezetimibe granules and rosuvastatin granules, press tablets and adjust the tablet hardness to 60 N. Take 30.0 g of Eudragit RL30D aqueous dispersion (solid content 30%, dried to 9 g) for coating to obtain ezetimibe and rosuvastatin calcium tablets. Example 6

[0082] This example provides an ezetimibe and rosuvastatin calcium tablet, and the dosage for the prescription (1000 tablets) is shown in the following table:

[0083] The preparation process of the above ezetimibe and rosuvastatin calcium tablets includes the following steps:

[0084] Step 1: Put 15 g of ezetimibe, 100 g of ultrasonically modified microcrystalline cellulose, 35 g of lactose, 5 g of croscarmellose sodium, 5 g of sodium lauryl sulfate, and 5 g of povidone into a wet granulator for premixing. The stirring speed is 100 rpm, and the chopping speed is 800 rpm. After premixing for 10 min, pass through a sieve using a granulator, with the sieve mesh size of 0.8 mm. After sieving, continue to put the material into the wet granulator for mixing for 10 min, add purified water for wet granulation, with the stirring speed of 100 rpm and the chopping speed of 1000 rpm. After granulating for 3 min, add it to a fluidized bed for drying at a drying temperature of 50°C, and then perform screening to obtain ezetimibe granules; among them, the ultrasonically modified microcrystalline cellulose is prepared by the preparation method of Example 3;

[0085] Step 2: Mix 15 g of rosuvastatin calcium, 35 g of corn starch, 2 g of colloidal silicon dioxide, 4.5 g of croscarmellose sodium and 3 g of magnesium stearate for 10 - 20 min at a mixing speed of 10 rpm to obtain rosuvastatin granules;

[0086] Step 3: Mix the ezetimibe granules and rosuvastatin granules, then press tablets, adjust the tablet hardness to 40 N, and take 30.0 g of Eudragit RL30D aqueous dispersion (solid content 30%, dried to 9 g) for coating to obtain ezetimibe and rosuvastatin calcium tablets. Comparative Example 4

[0087] This comparative example provides an ezetimibe and rosuvastatin calcium tablet, and the dosage for the prescription (1000 tablets) is shown in the following table:

[0088] The preparation process of the above ezetimibe and rosuvastatin calcium tablets includes the following steps:

[0089] Step 1: Put 10 g of ezetimibe, 90 g of lactose, 5 g of croscarmellose sodium, 4 g of sodium lauryl sulfate, and 4 g of polyvinylpyrrolidone into a wet granulator for mixing for 10 min, add purified water for wet granulation, stir at a speed of 100 rpm, chop at a speed of 1000 rpm for granulation for 3 min, then add to a fluidized bed for drying at a drying temperature of 50 °C, and size the granules to obtain ezetimibe granules;

[0090] Step 2: Mix 10.4 g of rosuvastatin, 44 g of corn starch, 0.6 g of colloidal silicon dioxide, 3 g of croscarmellose sodium and 2 g of magnesium stearate for 10 min at a mixing speed of 10 rpm to obtain rosuvastatin granules;

[0091] Step 3: Mix the ezetimibe granules and rosuvastatin granules, then press tablets, adjust the tablet hardness to 60 N, and take 33.3 g of Eudragit RL30D aqueous dispersion (solid content 30%, dried to 10 g) for coating to obtain ezetimibe and rosuvastatin calcium tablets. Comparative Example 5

[0092] This comparative example provides an ezetimibe and rosuvastatin calcium tablet. The dosage for the prescription (1000 tablets) is the same as that in Example 5. The preparation process of the ezetimibe and rosuvastatin calcium tablet includes the following steps: Put 20 g of ezetimibe, 180 g of ultrasonically modified microcrystalline cellulose, 40 g of lactose, 5 g of cross-linked carboxymethylcellulose sodium, 4 g of sodium lauryl sulfate, 4 g of polyvinylpyrrolidone, 10.4 g of rosuvastatin, 44 g of corn starch, 0.6 g of colloidal silicon dioxide, 3 g of cross-linked carboxymethylcellulose sodium, and 2 g of magnesium stearate into a wet granulator for premixing. The stirring speed is 120 rpm, the chopping speed is 1000 rpm. After premixing for 10 min, pass through a granulating machine with a screen mesh of 0.8 mm. After sieving, continue to put the materials into the wet granulator for mixing for 15 min, add purified water for wet granulation. The stirring speed is 120 rpm, the chopping speed is 1200 rpm, granulate for 3 min, then add to a fluidized bed for drying at a drying temperature of 60°C, size the granules, press tablets, adjust the tablet hardness to 60 N, take 30.0 g of Eudragit RL30D aqueous dispersion (solid content 30%, dried to 9 g) for coating to obtain the ezetimibe and rosuvastatin calcium tablets; among them, the ultrasonically modified microcrystalline cellulose is prepared by the preparation method in Example 2. Comparative Example 6

[0093] This comparative example provides an ezetimibe and rosuvastatin calcium tablet. The dosage for the prescription (1000 tablets) is the same as that in Example 5. The preparation process of the ezetimibe and rosuvastatin calcium tablet includes the following steps:

[0094] Step 1: Put 20 g of ezetimibe, 180 g of ultrasonically modified microcrystalline cellulose, 40 g of lactose, 5 g of cross-linked carboxymethylcellulose sodium, 4 g of sodium lauryl sulfate, 4 g of polyvinylpyrrolidone into a wet granulator for mixing for 10 min, add purified water for wet granulation. The stirring speed is 100 rpm, the chopping speed is 1000 rpm, granulate for 3 min, then add to a fluidized bed for drying at a drying temperature of 50°C, size the granules to obtain ezetimibe granules.

[0095] Step 2: Mix 10.4 g of rosuvastatin, 44 g of corn starch, 0.6 g of colloidal silicon dioxide, 3 g of cross-linked carboxymethylcellulose sodium, and 2 g of magnesium stearate for 10 min at a mixing speed of 10 rpm to obtain rosuvastatin granules;

[0096] Step 3: After mixing the ezetimibe granules and rosuvastatin granules, press tablets, adjust the tablet hardness to 60 N, take 30.0 g of Eudragit RL30D aqueous dispersion (solid content 30%, dried to 9 g) for coating to obtain the ezetimibe and rosuvastatin calcium tablets. Mixing uniformity test

[0097] The mixing uniformity of Examples 4 and 5 and Comparative Examples 4-6 was detected respectively. The detection method was an in vitro dissolution detection method, including the following steps: 6 tablets were taken from each group for parallel experiments. The detection parameters were paddle method at 100 rpm, pH 1.0 acetate medium of 1000 mL, and the sampling time point was 1 min. The dissolution degree of ezetimibe was detected by HPLC. The detection results are shown in Table 2 below. Table 2 Test Results of Mixing Uniformity

[0098] As can be seen from Table 2, after the raw materials of ezetimibe granules were stirred and premixed by the preparation method provided by the present invention and then mixed, and combined with ultrasonic modified microcrystalline cellulose, the mixing uniformity of ezetimibe could be significantly improved, enabling it to be released stably and uniformly. In Comparative Examples 4-6, ezetimibe was directly mixed with other raw materials, and the ultrasonic modified microcrystalline cellulose was not used, resulting in the inability to mix ezetimibe evenly. Cumulative Dissolution Test

[0099] The dissolution curves of ezetimibe in Examples 4 and 5, Comparative Example 4, and commercial products (trade name: Zenon, single-layer tablet) (specification 10 mg / 10 mg) and commercial products (trade name: Zenon Neo, double-layer tablet) (specification 10 mg / 10 mg) were detected in a medium of pH 4.5 acetate buffer solution. The paddle method was used at 75 rpm, and the sampling times were 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min. 10 mL was sampled each time, and 10 mL of pH 4.5 acetate buffer solution was added after sampling. Detection was carried out by HPLC. The detection results are shown in Table 3 below. Table 3 Test Results of Cumulative Dissolution

[0100] As can be seen from Table 3, the ezetimibe and rosuvastatin calcium tablets provided by the present invention have good dissolution performance and can achieve a dissolution curve consistent with that of the commercial product (trade name: Zenon). Stability Detection

[0101] Examples 4-5, Comparative Example 4, and commercial products (trade name: Zenon, single-layer tablets) (specification: 10 mg / 10 mg) and commercial products (trade name: Zenon Neo, double-layer tablets) (specification: 10 mg / 10 mg) were subjected to stability tests in an environment with a temperature of 28°C - 42°C and a relative humidity of 70% - 80%. The dissolution, related substances, and active ingredient content of Example 1, Example 2, the comparative example, the commercial product (trade name: Zenon), and the commercial product (trade name: Zenon Neo) were detected respectively. The test results are shown in Tables 4-8.

[0102] Among them, the dissolution detection specifically includes the following steps: Detect the dissolution curves of ezetimibe and rosuvastatin calcium in a medium of pH 6.5 acetate buffer solution, paddle method, 75 rpm, sampling time is 60 min, 10 mL is sampled each time, and 10 mL of pH 6.5 acetate buffer solution is added after sampling, and HPLC is used for detection.

[0103] Among them, the related substances and the content of the active ingredient are detected by high performance liquid chromatography, and the detection conditions are as follows:

[0104] (1) Sample preparation: Take 5 tablets of ezetimibe rosuvastatin calcium tablets, place them in a 50 ml volumetric flask, add 12 ml of water - acetonitrile - acetic acid (40:60:0.1), ultrasonicate for 30 min, then cool to room temperature, add water - acetonitrile - acetic acid (40:60:0.1) to volume to the mark, centrifuge for 5 min (10,000 revolutions), take the supernatant, filter with a 0.45 μm PP filter head, and discard 1 ml of the subsequent filtrate to obtain the sample solution;

[0105] (2) Reference solution: Take about 10 mg of ezetimibe reference substance and about 10 mg of rosuvastatin calcium reference substance (specification: 10 mg / 10 mg) or 5 mg (specification: 10 mg / 5 mg), accurately weigh and place them in a 100 ml volumetric flask, dilute to the mark with water - acetonitrile - acetic acid (40:60:0.1), and shake well. Accurately measure 1 ml and place it in a 100 ml volumetric flask, dilute to the mark with water - acetonitrile - acetic acid (40:60:0.1), and shake well;

[0106] (3) Brand model of the high performance liquid chromatograph: Thermo Fisher U3000;

[0107] (4) Detector: DAD;

[0108] (5) Chromatographic column: HORIZON Aurashell C18 / PFP (150 mm × 4.6 mm, 2.7 μm);

[0109] (6) Mobile phase A: methanol - water - trifluoroacetic acid (15:85:0.01), mobile phase B: acetonitrile - trifluoroacetic acid (100:0.01), gradient elution is carried out as follows:

[0110] Start elution with 76% of mobile phase A and 24% of mobile phase B, continue elution for 25 minutes, gradually reduce the proportion of mobile phase A and increase the proportion of mobile phase B. By 60 minutes, adjust the proportion of mobile phase A to 74% and the proportion of mobile phase B to 26%. Continue to gradually reduce the proportion of mobile phase A and increase the proportion of mobile phase B. By 85 minutes, adjust mobile phase A to 20% and mobile phase B to 80%. Gradually increase the proportion of mobile phase A and reduce the proportion of mobile phase B. After 0.1 minute, adjust mobile phase A to 76% and mobile phase B to 24%, and maintain this mobile phase ratio to continue elution until 90 minutes;

[0112] (7) The flow rate is 1.2 ml per minute;

[0113] (8) The detection wavelength is 215 nm from 0 to 5 minutes and 242 nm from 5 to 90 minutes;

[0114] (9) The column temperature is 35 °C;

[0115] (10) The injection volume is 10 μl. Table 4 Stability test results of Example 4 Table 5 Stability test results of Example 5 Table 6 Stability test results of Comparative Example 4 Table 7 Stability test results of the marketed product (trade name: Zenon) Table 8 Stability test results of the marketed product (trade name: Zenon Neo)

[0116] It can be seen from Tables 4 - 8 that the preparation method provided by the present invention granulates ezetimibe and rosuvastatin calcium separately, which can make the mixing of ezetimibe and internal excipients more uniform and the combination more compact. At the same time, it reduces the contact with rosuvastatin calcium raw materials, thereby improving the stability of rosuvastatin calcium. The stability is good after 6 months of acceleration. And the present invention uses ultrasonic modified microcrystalline cellulose to improve the dissolution effect and stability of ezetimibe. Therefore, the stability of the ezetimibe and rosuvastatin calcium tablets provided by the present invention is superior to that of Comparative Example 4 and the marketed products.

[0117] The above are all preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby. Therefore, all equivalent changes made according to the structure, shape, and principle of the present invention shall be covered within the protection scope of the present invention.

Claims

1. An ezetimibe and rosuvastatin calcium tablet, characterized in that, The ezetimibe and rosuvastatin calcium tablets comprise a core layer and a coating layer. The core layer comprises ezetimibe, a disintegrant, a binder, a solubilizer, rosuvastatin calcium, a filler, a glidant, a lubricant and ultrasonically modified microcrystalline cellulose; Among them, the specific surface area of the ultrasonically modified microcrystalline cellulose is 1.340 m 2 / g - 1.350 m 2 / g, and the relative water retention value is 157.0% - 168.4%.

2. The ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that, The preparation method of the ultrasonically modified microcrystalline cellulose comprises the following steps: Step S1, heating microcrystalline cellulose in an acid solution to obtain a mixture; Step S2, placing the mixture in pure water. After mixing and standing, subject the upper slurry to solid-liquid separation, and wash the obtained solid with water until the pH value of the washing liquid is 5.7 - 5.9, then dry to obtain primary modified microcrystalline cellulose; Step S3, adding the primary modified microcrystalline cellulose into an aqueous ethanol solution, standing after ultrasonic treatment, then continuing ultrasonic treatment, performing solid-liquid separation, and drying the obtained solid to obtain ultrasonically modified microcrystalline cellulose.

3. The ezetimibe and rosuvastatin calcium tablets according to claim 2, characterized in that, In step S1, the acid solution is selected from hydrochloric acid, carbonic acid or nitric acid, and the mass-volume ratio of the microcrystalline cellulose to the acid solution is 1 g:(10 - 15) mL; and / or In step S1, the temperature of the heating treatment is 70°C - 80°C, and the time is 2.5 h - 3.5 h; and / or In step S1, the particle size of the microcrystalline cellulose is 0.1 μm - 10 μm.

4. The ezetimibe and rosuvastatin calcium tablets according to claim 2, characterized in that, In step S2, the volume-mass ratio of the pure water to the microcrystalline cellulose is (15 - 25) mL:1 g; and / or In step S3, the volume concentration of the aqueous ethanol solution is 40% - 60%, and the volume-mass ratio of the aqueous ethanol solution to the microcrystalline cellulose is (20 - 40) mL:1 g.

5. The ezetimibe and rosuvastatin calcium tablets according to claim 2, characterized in that, In step S3, the power of the ultrasonic treatment is 600 W - 800 W, the frequency is 25 kHz - 35 kHz, and the time is 5 - 10 min; and / or In step S3, the temperature of the standing is 25°C - 30°C, and the time is 10 - 20 min.

6. The ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that, The core layer comprises the following components in parts by mass: 5 - 20 parts of ezetimibe, 50 - 200 parts of ultrasonically modified microcrystalline cellulose, 2 - 20 parts of disintegrant, 1 - 10 parts of binder, 1 - 10 parts of solubilizer, 5 - 40 parts of rosuvastatin calcium, 20 - 100 parts of filler, 0.1 - 5 parts of glidant and 0.1 - 5 parts of lubricant.

7. The ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that, The coating layer is 2% - 4% of the mass of the core layer.

8. The ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that, The filler is selected from one or more of lactose, corn starch or calcium hydrogen phosphate; and / or The solubilizer is sodium dodecyl sulfate, the glidant is colloidal silica, and the lubricant is magnesium stearate; and / or The binder is selected from one or more of povidone, hypromellose or hydroxypropyl cellulose.

9. The ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that, The disintegrant is selected from one or more of cross-linked carboxymethyl cellulose sodium, cross-linked povidone or sodium carboxymethyl starch.

10. A preparation method of the ezetimibe and rosuvastatin calcium tablets according to any one of claims 1-9, characterized in that, Comprises the following steps: Step one, mixing ezetimibe, a lubricant, ultrasonically modified microcrystalline cellulose, part of the disintegrant and a solubilizer, granulating and drying to obtain ezetimibe granules; Step two, mixing rosuvastatin calcium, a filler, the remaining disintegrant, a stabilizer and a binder to obtain rosuvastatin calcium granules; Step three, mixing the ezetimibe granules and the rosuvastatin calcium granules, tabletting and coating to obtain the ezetimibe and rosuvastatin calcium tablets.

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