Rosuvastatin calcium quick release-slow release double-layer tablet preparation and preparation process thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and discloses a rosuvastatin calcium quick release-slow release double-layer tablet preparation and a preparation process thereof. The preparation process comprises the following steps: (1) pretreating raw materials; (2) pretreating auxiliary materials; (3) preparing quick-release layer particles by adopting a supercritical nanocrystallization and carrier adsorption process; (4) preparing sustained-release layer particles: preparing amorphous quick-release layer particles of rosuvastatin calcium by adopting a hot-melt extrusion method in the preparation of the sustained-release layer particles; (5) total mixing of quick-release layer particles; (6) total mixing of sustained-release layer particles; (7) tabletting; and (8) coating with a film. According to the rosuvastatin calcium double-layer tablet prepared by creatively combining hot melt extrusion with a nanocrystal technology, the solubility and bioavailability are improved, the problems of low solubility and photo-thermal sensitivity of an existing preparation are effectively solved, and the preparation method is stable and suitable for large-scale preparation.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a rosuvastatin calcium rapid-release-sustained-release double-layer tablet preparation and a preparation process thereof. Background Art

[0002] Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors developed in the past two decades. By inhibiting a key enzyme in cholesterol synthesis, they can significantly lower plasma cholesterol levels and have become a first-line treatment for hypercholesterolemia. Numerous studies in recent years have demonstrated that statins not only enhance lipid-lowering effects but also have multiple effects, including regulating endothelial function, inhibiting foam cell production, providing anti-inflammatory and antioxidant benefits, stabilizing plaques, and acting as antiplatelet and antithrombotic agents—referred to as statins' pleiotropic effects. Furthermore, studies have shown that statins significantly reduce the incidence of adverse cardiovascular events in both patients with hypercholesterolemia and those with normal blood lipids. This suggests that, in addition to their lipid-lowering effects, statins may exert their cardiovascular protective effects through multiple mechanisms.

[0003] Rosuvastatin calcium tablets are suitable for primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb) whose dyslipidemia cannot be properly controlled by diet control and other non-drug treatments. It is also suitable for patients with homozygous familial hypercholesterolemia. The main blood lipids in the human body are TC and TG, and also contain a small amount of free fatty acids, phospholipids and other components. Clinically, hyperlipidemia is determined when the fasting serum TG level in adults is >1.70mmol / L and the TC level is >5.72mmol / L. Numerous clinical trials have shown that one of the important risk factors for atherosclerosis (AS) is hyperlipidemia, and AS can lead to insufficient blood supply to tissues, thereby inducing serious cardiovascular diseases such as coronary heart disease and stroke, posing a huge threat to people's health [1]. Rosuvastatin is a fully synthetic single enantiomer compound. Although it has the dihydroxyheptanoic acid part that other statins have, the rest of the molecular structure is different from other statins. Compared to similar drugs, it has a stronger hydrophilicity, similar to pravastatin. Numerous clinical trials have demonstrated that compared to pravastatin, simvastatin, and atorvastatin, it significantly increases HDL-C levels and reduces TG, TC, and non-TG levels, enabling patients to achieve target TC levels more quickly. It is more effective than atorvastatin in raising HDL-C and lowers LDL cholesterol by 15%. It is commonly used to treat mixed dyslipidemia or primary hypercholesterolemia. Combining it with birth control pills can increase blood concentrations, and enhanced treatment can even lead to regression of AS lesions.

[0004] Existing rosuvastatin calcium tablets suffer from low solubility, crystal form changes easily caused by high-temperature wet granulation during production, and the need for patients to take the drug multiple times. Traditional processes use a single-layer tablet design, resulting in a dissolution rate of only 60% and poor storage stability. In existing technologies, sustained-release layers often rely on a single pH response mechanism, making it impossible to dynamically adjust the release rate, and the single function of the excipients leads to complex processes. Therefore, it is necessary to develop a suitable formulation and preparation process to ensure that rosuvastatin calcium tablets have good bioavailability and drug stability. Summary of the Invention

[0005] In order to solve the above-mentioned problems in the prior art, the present invention provides a rosuvastatin calcium rapid-release and sustained-release double-layer tablet preparation and a preparation process thereof. The solubility and bioavailability of the rosuvastatin calcium tablets prepared by the present invention are improved, and the preparation method thereof is stable and suitable for large-scale preparation.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] The first aspect of the present invention is to provide a process for preparing a rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation, comprising the following steps:

[0008] (1) Raw material pretreatment: The main drug rosuvastatin calcium is micronized using a jet mill and set aside;

[0009] (2) Excipient pretreatment: Pass the prescribed amount of crospovidone, sodium carboxymethyl starch, lactose, magnesium stearate, and colloidal silicon dioxide through an 80-mesh sieve and set aside;

[0010] (3) Preparation of immediate-release layer granules: After mixing the main drug with a super disintegrant and a lubricant, suvastatin immediate-release granules were prepared using a supercritical nano-crystallization and carrier adsorption process;

[0011] (4) Preparation of sustained-release layer granules: Suvastatin sustained-release granules were prepared by hot melt extrusion combined with pH-dependent polymer Eudragit L100-55;

[0012] (5) Blending of immediate-release layer granules: The suvastatin immediate-release granules were granulated using a granulator, and the granules and magnesium stearate (1% added) were added to a square-cone mixer to prepare immediate-release granule intermediate 1;

[0013] (6) Total mixing of sustained-release layer granules: The sustained-release layer granules were granulated using a granulator, and the granules and magnesium stearate (1% added) were added to a ribbon mixer to prepare a sustained-release granule intermediate 2;

[0014] (7) Tabletting: The tablet weight is calculated based on the content of the granular intermediate, and the tablet weight difference is controlled to be ±5%. The hardness is 5-12 kg, and the tablets are compressed using a Fette tablet press. In the first compression, intermediate 1 is compressed to obtain plain tablet 1. In the second compression, intermediate 2 and plain tablet 1 are compressed together to form a double-layer tablet.

[0015] (8) Coating: A moisture-proof film containing titanium dioxide (2%) and polyvinyl alcohol is used to coat the prepared compressed tablets to obtain a rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation.

[0016] Preferably, in step (1), the pressure of the air flow mill is 0.8 MPa, the feed rate is 5 g / min; the average particle size is controlled to be ≤2 μm, and the specific surface area is ≥15 m 2 / g.

[0017] Preferably, in step (3), the rosuvastatin calcium immediate-release layer granules are formulated according to the following components in parts by weight:

[0018]

[0019] Preferably, in step (3), the rosuvastatin calcium immediate-release layer granules are formulated according to the following components in parts by weight:

[0020]

[0021] Preferably, in step (3), the preparation process of the rosuvastatin calcium rapid-release layer granules is as follows:

[0022] Rosuvastatin calcium, super disintegrant, and lubricant were dissolved in ethanol (concentration 4-10 mg / mL) and rapidly mixed with supercritical CO2 (pressure 12-18 MPa, temperature 35-45°C) at a volume ratio of 1:4-6 through a microchannel mixer. Nanoparticles were precipitated using the antisolvent effect and simultaneously collected on the surface of a porous mannitol carrier pre-dispersed in a fluidized bed to form a drug-loaded complex (particle yield ≥95%).

[0023] Among them, the supercritical equipment uses the supercritical fluid preparation system (with a 0.1mm pore size micro-mixer) of Thar Technologies, USA, and the fluidized bed uses the Glatt fluidized bed adsorption device from Germany.

[0024] Preferably, step (3) further comprises forming a silicon dioxide nanocrystal coating layer on the surface of the quick-release layer particles by a supercritical CO2 process, wherein the nanocrystal particle size is 20-50 nm and the coating thickness is 100-200 nm.

[0025] Preferably, in step (4), the sustained-release layer granules are prepared according to the following components:

[0026]

[0027]

[0028] Preferably, in step (4), the sustained-release layer particles are prepared according to the following components:

[0029]

[0030] Preferably, in step (4), the preparation process of the suvastatin sustained-release granules is as follows:

[0031] The prescribed amount of rosuvastatin calcium, / Put the HPMCAS into a three-dimensional mixer at a speed of 20 rpm and mix for 15-20 minutes to obtain a mixed material;

[0032] The mixed material was put into a twin-screw hot melt extruder, and the setting temperature was 80-120°C, the screw speed was 150-200 rpm, the extrusion speed was 100-200 rpm, the feeding rate was 1-2 kg / h, and the discharge screen was 1.0 mm to obtain mixed particles;

[0033] The prepared mixed granules are placed in a high-efficiency fluidized granulation coating machine, the inlet air temperature is set to 40-45°C, the exhaust air temperature is set to 35-40°C, and the ethanol coating liquid of lactose and microcrystalline cellulose is sprayed by bottom spraying or side spraying. After drying, suvastatin sustained-release granules are obtained.

[0034] More preferably, the preparation process of the sustained-release layer granules in (4) is as follows:

[0035] Material pretreatment: Rosuvastatin calcium, / HPMCAS is thoroughly mixed in a ratio of 1:3. A three-dimensional mixer can be used for mixing. The mixing time is 15-20 minutes and the speed is set to 20-30 rpm to ensure that the materials are mixed evenly and avoid local concentration differences that affect the quality of the solid dispersion;

[0036] Temperature setting: The barrel of the hot melt extruder is divided into multiple heating zones. The temperature of zone 1 is set at 80-90℃, which is mainly used for preheating and conveying the material; the temperature of zone 2 is 100-110℃, which makes the material begin to soften; the temperature of zone 3 is 120-130℃, which realizes the full plasticization and mixing of the material; the temperature of the die head is controlled at 110-120℃ to ensure the smooth extrusion of the material without degradation. The temperature of each heating zone needs to be fine-tuned according to the actual melting characteristics of the material to ensure that the material maintains good fluidity and uniformity during the extrusion process.

[0037] Hot melt extrusion granulation: A twin-screw hot melt extruder (such as the Coperion ZSK series) is used. The screw diameter is usually 25-35mm, the aspect ratio (L / D) is 30-40:1, and the screw speed is controlled at 150-200rpm. Too high a speed may cause the material to stay in the barrel for too short a time and uneven mixing; too low a speed will cause insufficient plasticization of the material, affecting the quality of the extrudate. The feeding speed is controlled by a loss-in-weight feeder and is set to 1-2kg / h to match the screw speed to ensure that the material can enter the extruder continuously and stably.

[0038] Granulation: A water-cooled pelletizer is used to cut the extruded strips into uniform pellets. The particle size can be adjusted according to the subsequent tableting requirements. The general particle size is controlled at 1-3mm.

[0039] Controlled-release coating: Place the prepared granules into a high-efficiency fluidized bed granulator, set the inlet air temperature to 40-45°C and the exhaust air temperature to 35-40°C. Apply the coating solution using a bottom or side spray method, controlling the spray rate at 5-8 mL / min and the coating weight gain to 5-8%. Continuously monitor the material temperature and coating film formation during the coating process to avoid granule sticking or coating film cracking due to uneven coating or excessive temperatures. After coating, continue forced air drying for 30-40 minutes to fully cure the coating film.

[0040] Preferably, in step (4), the sustained-release layer particles further comprise a temperature-sensitive polymer poly N-isopropylacrylamide (PNIPAM) in an amount of 5-15 parts by weight. The sustained-release layer is released under the intestinal pH environment and accelerates the drug release rate as the body temperature rises (above 37°C).

[0041] Preferably, the rotation speed of the square cone mixer in the quick-release layer mixing process of step (5) is 15-25 rpm, and the rotation speed of the ribbon mixer in the sustained-release layer mixing process of step (6) is 30-50 rpm.

[0042] Preferably, in the tableting process of step (7), the weight ratio of the quick-release layer to the sustained-release layer is 1:2 to 1:3.

[0043] Preferably, in step (7), an isolation layer is further included between the first tableting and the second tableting, and the isolation layer is composed of hydroxypropyl methylcellulose (HPMC) and has a thickness of 0.1-0.3 mm.

[0044] The second aspect of the present invention is to improve a rosuvastatin calcium fast-release-sustained-release bilayer tablet preparation prepared by the process described in any of the above items, wherein the dissolution rate of the fast-release layer is ≥85% within 30 minutes, the sustained-release layer is continuously released within 12 hours, and the release rate is increased by 20-30% at 37°C.

[0045] Preferably, in an accelerated stability test (40°C / 75% RH), the tablet shows an increase in related substances of ≤0.5% after 6 months.

[0046] Preferably, the bioavailability of the tablet is increased by 40-50% compared with ordinary tablets, and the tablet hardness uniformity (RSD) is ≤5%.

[0047] The present invention adopts the above technical solution, which has the following technical effects compared with the prior art:

[0048] (1) Significantly improved dissolution rate: Through supercritical CO2 nano-crystallization technology, the specific surface area of ​​the immediate-release layer particles is increased by 4 times compared to the original crystalline form, and the dissolution rate in 15 minutes is ≥98% (the traditional process is only 80%);

[0049] (2) Dynamic release regulation: Combining the pH-dependent polymer Eudragit L100-55 and the temperature-sensitive polymer PNIPAM to construct a pH-temperature dual-responsive sustained-release system, achieving intestinal targeted release and accelerated release in response to body temperature (release rate increased by 20-30% at 37°C);

[0050] (3) Enhanced stability: The nanocrystal-coated immediate-release layer (silicon dioxide thickness 100-200 nm) and composite excipients (crospovidone / magnesium stearate) resulted in a degradation rate of ≤0.5% in an accelerated test (40°C / 75% RH) (compared to ≥1.5% in conventional processes);

[0051] (4) Process simplification and industrial production: hot melt extrusion combined with supercritical CO2 technology reduces the use of organic solvents, shortens the production cycle by 30%, and achieves tablet hardness uniformity (RSD) ≤ 5%;

[0052] (5) Optimization of treatment convenience: The two-layer or three-layer tablet design (immediate-release layer, isolation layer, and sustained-release layer) achieves delayed sustained-release after immediate release. Patients only need to take the medicine once a day, and compliance is significantly improved. DETAILED DESCRIPTION

[0053] The invention adopts supercritical nano-crystallization and carrier adsorption technology to prepare suvastatin rapid-release particles. The specific surface area of ​​the nanoparticles is increased by 4 times compared with the original crystal form. The solubility in 15 minutes is ≥98%, which is significantly improved compared with the traditional process (80%).

[0054] The amorphous solid dispersion prepared by the hot melt extrusion method of the present invention can fully mix the drug and the carrier under the action of high temperature and high shear force, so that the drug can be evenly dispersed in the carrier in a molecular state, thereby improving the dispersion and stability of the drug. This method can make the drug into an amorphous state, increasing the solubility and dissolution rate of the drug. At the same time, the carrier material can inhibit the crystallization of the drug and maintain the amorphous state of the drug, which is conducive to the rapid release and absorption of the drug in the body and improves the bioavailability of the drug; the hot melt extrusion method is suitable for large-scale continuous production, has high production efficiency, and can reduce production costs. Compared with other preparation methods, such as the solvent method, the hot melt extrusion method does not require the use of a large amount of organic solvents, reducing the cost and risk of solvent recovery and environmental protection treatment.

[0055] The rosuvastatin calcium rapid-release and sustained-release bilayer tablets prepared by the process of the present invention have the following characteristics: according to the State Food and Drug Administration's imported drug registration standard (standard number: JX20030283): the content of rosuvastatin (C22H28FN3O6S) should be 95.0-105.0% of the labeled amount, and the solubility limit of rosuvastatin calcium is 80% of the labeled amount.

[0056] The present invention will be described in detail and specifically below through specific examples to provide a better understanding of the present invention, but the following examples do not limit the scope of the present invention.

[0057] Example 1

[0058] A preparation process of a rosuvastatin calcium rapid-release and sustained-release double-layer tablet preparation comprises the following steps:

[0059] (1) Raw material pretreatment: The main drug rosuvastatin calcium was micronized using a jet mill (model: QYF-200, pressure 0.8 MPa, feed rate 5 g / min) to an average particle size of ≤2 μm and a specific surface area of ​​≥15 m 2 / g, spare;

[0060] (2) Excipient pretreatment: Cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, lactose, magnesium stearate, and colloidal silicon dioxide were sieved through an 80-mesh sieve and set aside;

[0061] (3) Preparation of immediate-release layer granules:

[0062] According to the formula, weigh the following: 5 parts of rosuvastatin calcium (50-200 nm), 100 parts of porous mannitol carrier (porosity ≥ 60%), 12 parts of super disintegrant (pre-prepared, cross-linked polyvinylpyrrolidone: sodium carboxymethyl starch = 2:1), and 2 parts of lubricant (pre-prepared, magnesium stearate: micro-powdered silica gel = 3:1);

[0063] The drug, disintegrant, and lubricant were dissolved in ethanol (8 mg / mL) and mixed with supercritical CO2 (15 MPa, 40°C) at a volume ratio of 1:5 in a microchannel mixer. Nanoparticles were precipitated by antisolvent effect and collected simultaneously on the surface of a porous mannitol carrier pre-dispersed in a fluidized bed to form a drug-loaded complex (yield ≥ 95%).

[0064] (4) Preparation of sustained-release layer granules:

[0065] Weigh according to the formula: 10 parts of rosuvastatin calcium, / 30 parts of HPMCAS, 20 parts of lactose, 15 parts of microcrystalline cellulose;

[0066] The main drug and HPMCAS was put into a three-dimensional mixer (rotating speed 20 rpm, mixing for 20 minutes), and then extruded through a twin-screw hot melt extruder (temperature 100°C, screw speed 180 rpm, feeding rate 1.5 kg / h) to produce sustained-release granules;

[0067] (5) Blending of immediate-release layer granules: The suvastatin immediate-release granules were granulated using a granulator, and the granules and magnesium stearate (1% added) were added to a square-cone mixer (20 rpm) to prepare immediate-release granule intermediate 1;

[0068] (6) Sustained-release layer granule mixing: The sustained-release layer granules were granulated using a granulator, and the granules and magnesium stearate (1% added) were added to a ribbon mixer (rotating speed 40 rpm) to prepare the sustained-release granule intermediate 2;

[0069] (7) Tabletting: The tablet weight was calculated based on the content of the granular intermediate, and the tablet weight difference was controlled to be ±5%. The hardness was 10 kg, and tablets were pressed using a Fette tablet press. In the first tableting, intermediate 1 was compressed to produce plain tablet 1 (plain tablet 1, hardness 8 kg). In the second tableting, intermediate 2 and plain tablet 1 were compressed together to form a double-layer tablet (immediate-release layer: sustained-release layer = 1:2, tablet weight difference ±3%).

[0070] (8) Coating: A bottom spray coating machine (inlet air temperature 45°C) was used to spray a moisture-proof coating solution containing 2% titanium dioxide and polyvinyl alcohol, with a weight gain of 4%, to prepare a rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation.

[0071] Example 2

[0072] The difference from Example 1 is that the super disintegrant in the immediate-release layer in step (3) is increased to 15 parts (cross-linked polyvinylpyrrolidone: sodium carboxymethyl starch = 2:1). The remaining steps are the same as in Example 1.

[0073] Example 3

[0074] The difference from Example 1 is that the weight ratio of the immediate-release layer to the sustained-release layer in the tableting process in step (7) was adjusted from 1:2 to 1:3; and an isolation layer was directly added to the first and second tableting processes to form a three-layer tableting structure of immediate-release layer + isolation layer (HPMC 0.2 mm) + sustained-release layer. The remaining steps were the same as in Example 1.

[0075] Example 4

[0076] The differences from Example 1 were that the supercritical CO2 pressure in step (3) was adjusted to 12 MPa and the temperature to 45°C with a volume ratio of 1:6; and that the hot melt extrusion temperature in step (4) was adjusted to 120°C, the screw speed to 200 rpm, the extrusion speed to 150 rpm, and the feed rate to 1.8 kg / h, with high-temperature extrusion. The remaining steps were the same as in Example 1.

[0077] Example 5

[0078] The difference from Example 1 is that 6 parts of temperature-sensitive polymer poly N-isopropylacrylamide (PNIPAM) are added in the preparation of sustained-release layer particles in step (4). The remaining steps are the same as those in Example 1.

[0079] Comparative Example 1

[0080] The difference from Example 1 is that in step (3), conventional wet granulation is used instead of supercritical CO2 technology and carrier adsorption process to prepare suvastatin rapid-release granules. The remaining steps are the same as in Example 1.

[0081] Comparative Example 2

[0082] The difference from Example 1 is that in step (4), conventional wet granulation is used instead of hot melt extrusion combined with pH-dependent polymer Eudragit L100-55 to prepare suvastatin sustained-release granules. The remaining steps are the same as in Example 1.

[0083] Comparative Example 3

[0084] The difference from Example 1 is that the formula of the super disintegrant in the immediate-release layer in step (3) is adjusted to crospovidone: sodium carboxymethyl starch = 1:2. The remaining steps are the same as in Example 1.

[0085] Comparative Example 4

[0086] The difference from Example 1 is that the sustained-release layer in step (3) is adjusted The remaining steps were the same as in Example 1.

[0087] Example 5

[0088] The difference from Example 1 is that the formula of the lubricant in the immediate-release layer in step (3) is adjusted to magnesium stearate: micro-powder silica gel = 1:3. The remaining steps are the same as in Example 1.

[0089] Performance Testing

[0090] The rosuvastatin calcium rapid-release and sustained-release bilayer tablets prepared in Examples 1-5 and Comparative Examples 1-5 were tested for dissolution, stability and other performance. The test results are shown in Table 1 below.

[0091] Table 1 Test data of each embodiment and comparative example preparation

[0092]

[0093] Note: Test indicators not involved are indicated by “-”.

[0094] The test results in Table 1 above demonstrate that the dissolution rates of the rosuvastatin calcium rapid-release / sustained-release bilayer tablets prepared using the present invention all exceeded 95%, while those of Comparative Examples 1-2, prepared using conventional processes, were only 65-85%. In terms of release rate, Example 5, due to the use of PNIPAM for dynamic regulation, achieved a 25% increase in release rate at 37°C, surpassing Example 1, which lacked PNIPAM. In terms of stability, the degradation rates of Examples 1-5 were ≤0.3%, while those of Comparative Examples 1-3 were as high as 1.8%.

[0095] Furthermore, the test results in Table 1 clearly show that Example 2 exhibited a disintegration time of ≤1 minute, demonstrating the advantage of a high disintegrant ratio. Example 3 achieved a delayed onset of sustained release through a three-layer design, requiring patients to take the drug only once daily, significantly improving compliance. Example 4 employed a 120°C high-temperature extrusion process, which inhibited drug crystallization to a certain extent, counteracting the effect.

[0096] In summary, the preparation process of the rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation of the present invention improves and innovates the existing process. The prepared rosuvastatin calcium preparation is significantly superior to the comparative example in terms of dissolution, sustained-release regulation, stability and industrial production, which fully verifies the innovation and practicality of the solution of the present invention.

[0097] While the specific embodiments of the present invention have been described in detail above, these are merely exemplary and the present invention is not limited thereto. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, any equivalent changes and modifications made without departing from the spirit and scope of the present invention are intended to be encompassed within the scope of the present invention.

Claims

1. A preparation process for a rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation, characterized in that: The steps include: (1) Raw material pretreatment: The main drug rosuvastatin calcium is micronized using a jet mill and set aside; (2) Excipient pretreatment: Pass the prescribed amount of crospovidone, sodium carboxymethyl starch, lactose, magnesium stearate, and colloidal silicon dioxide through an 80-mesh sieve and set aside; (3) Preparation of immediate-release layer granules: After mixing the main drug with a super disintegrant and a lubricant, suvastatin immediate-release granules were prepared using a supercritical nano-crystallization and carrier adsorption process; (4) Preparation of sustained-release layer granules: Suvastatin sustained-release granules were prepared by hot melt extrusion combined with pH-dependent polymer Eudragit L100-55; (5) Blending of immediate-release layer granules: The suvastatin immediate-release granules were granulated using a granulator, and the granules and magnesium stearate (1% added) were added to a square-cone mixer to prepare immediate-release granule intermediate 1; (6) Total mixing of sustained-release layer granules: The sustained-release layer granules were granulated using a granulator, and the granules and magnesium stearate (1% added) were added to a ribbon mixer to prepare a sustained-release granule intermediate 2; (7) Tabletting: The tablet weight is calculated based on the content of the granular intermediate, and the tablet weight difference is controlled to be ±5%. The hardness is 5-12 kg, and the tablets are compressed using a Fette tablet press. In the first compression, intermediate 1 is compressed to obtain plain tablet 1. In the second compression, intermediate 2 and plain tablet 1 are compressed together to form a double-layer tablet. (8) Coating: A moisture-proof film containing titanium dioxide (2%) and polyvinyl alcohol is used to coat the prepared compressed tablets to obtain a rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation.

2. The preparation process of the rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation according to claim 1, characterized in that: In step (1), the pressure of the air flow mill is 0.8 MPa, the feed rate is 5 g / min, and the average particle size is controlled to be ≤2 μm and the specific surface area is ≥15 m 2 / g.

3. The preparation process of the rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation according to claim 1, characterized in that: In step (3), the rosuvastatin calcium rapid-release layer granules are prepared according to the following components in parts by weight:

4. The preparation process of the rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation according to claim 3, characterized in that: In step (3), the preparation process of the rosuvastatin calcium rapid-release layer granules is as follows: Rosuvastatin calcium, super disintegrant, and lubricant were dissolved in ethanol (concentration 4-10 mg / mL) and rapidly mixed with supercritical CO2 (pressure 12-18 MPa, temperature 35-45°C) at a volume ratio of 1:4-6 through a microchannel mixer. Nanoparticles were precipitated using the antisolvent effect and simultaneously collected on the surface of a porous mannitol carrier pre-dispersed in a fluidized bed to form a drug-loaded complex (particle yield ≥95%).

5. The preparation process of the rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation according to claim 1, characterized in that: In step (4), the sustained-release layer granules are prepared according to the following components:

6. The preparation process of the rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation according to claim 1, characterized in that: In step (4), the preparation process of the suvastatin sustained-release granules is as follows: The prescribed amount of rosuvastatin calcium, Put it into a three-dimensional mixer at a speed of 20 rpm and mix for 15-20 minutes to obtain a mixed material; The mixed material was put into a twin-screw hot melt extruder, and the setting temperature was 80-120°C, the screw speed was 150-200 rpm, the extrusion speed was 100-200 rpm, the feeding rate was 1-2 kg / h, and the discharge screen was 1.0 mm to obtain mixed particles; The prepared mixed granules are placed in a high-efficiency fluidized granulation coating machine, the inlet air temperature is set to 40-45°C, the exhaust air temperature is set to 35-40°C, and the ethanol coating liquid of lactose and microcrystalline cellulose is sprayed by bottom spraying or side spraying. After drying, suvastatin sustained-release granules are obtained.

7. The preparation process of the rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation according to claim 1, characterized in that: The rotation speed of the square cone mixer in the quick-release layer mixing process of step (5) is 15-25 rpm, and the rotation speed of the ribbon mixer in the sustained-release layer mixing process of step (6) is 30-50 rpm.

8. The preparation process of the rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation according to claim 1, characterized in that: In the tableting process of step (7), the weight ratio of the quick-release layer to the sustained-release layer is 1:2 to 1:

3.

9. A rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation prepared according to the process of any one of claims 1 to 8, wherein the rapid-release layer has a dissolution rate of ≥85% within 30 minutes, the sustained-release layer has a sustained release rate within 12 hours, and the release rate is increased by 20-30% at 37°C.

10. The rosuvastatin calcium rapid-release and sustained-release bilayer tablet preparation according to claim 9, characterized in that: In an accelerated stability test (40° C. / 75% RH) of the tablets, the increase in related substances was ≤0.5% after 6 months.

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