Atorvastatin tablet preparation for treating hyperlipidemia and preparation process thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and discloses an atorvastatin tablet preparation for treating hyperlipidemia and a preparation process of the atorvastatin tablet preparation. The preparation process comprises the following steps: (1) pretreating raw materials; (2) pretreating auxiliary materials; (3) preparing quick-release layer particles: stabilizing atorvastatin calcium nanocrystals by adopting an anti-solvent precipitation method and combining with a surfactant; (4) preparing sustained-release layer particles: preparing amorphous sustained-release layer particles of atorvastatin calcium by adopting a hot-melt extrusion method, and realizing targeted sustained release of intestinal tracts in combination with a pH-dependent polymer Eudragit L100-55; (5) performing double-layer tabletting: performing filling twice to obtain a high-hardness double-layer tablet; and (6) coating. According to the invention, the hot melt extrusion is creatively combined with the nanocrystal technology, the problems of low solubility and photothermal sensitivity are solved, the process continuity is realized, the effective content time of the blood fat reducing medicine in the body is prolonged, the balance blood concentration of the medicine in the body is favorably kept, and the medicine taking compliance of a patient is improved.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to an atorvastatin tablet preparation for treating hyperlipidemia and a preparation process thereof. Background Art

[0002] Abnormal fat metabolism or function can cause elevated levels of one or more plasma lipids, a condition known as hyperlipidemia. Hyperlipidemia is a major risk factor for atherosclerosis and coronary heart disease. Coronary heart disease, caused by coronary atherosclerosis, often presents with angina pectoris and myocardial infarction due to insufficient blood supply to the myocardium. Since the beginning of the new century, with the continuous improvement of living standards and changes in dietary patterns, the incidence of hyperlipidemia in my country has been on the rise, becoming a common disease that seriously affects people's quality of life and threatens human health.

[0003] Hyperlipidemia is extremely harmful to the human body, so it is crucial to take effective measures to treat it promptly. Treatment for dyslipidemia includes both non-drug and pharmacological approaches, namely, dietary adjustments, lifestyle modifications, and medication. There are many types of lipid-lowering medications, primarily including the following four categories: reductase inhibitors (statins), fibrates, niacin, and bile acid sequestrants. Generally speaking, lipid-lowering therapy should be based on non-drug treatments and selected based on the type and severity of dyslipidemia, the patient's disease risk factors, the drug's mechanism of action and side effects, and the goals of lipid-lowering therapy.

[0004] 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.

[0005] Atorvastatin is one of the most widely used cholesterol-lowering drugs in clinical practice. It significantly lowers low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C). It has clear efficacy, hepatocyte selectivity, low toxicity, and a good safety profile. It has anti-atherosclerotic, pro-angiogenic, and anti-inflammatory effects. Due to its favorable safety and tolerability profile, it is widely used for lipid-lowering treatment in patients with type 2 diabetes, chronic kidney disease, coronary heart disease, and elderly patients with hypercholesterolemia. Studies have shown that atorvastatin can significantly reduce the morbidity and mortality of coronary heart disease in patients with hyperlipidemia and type 2 diabetes, as well as the incidence of acute coronary syndromes (ACS) in patients with stable coronary heart disease. These effects are not directly related to patients' plasma cholesterol levels. This suggests that the significant role of atorvastatin in the primary and secondary prevention of adverse cardiovascular events may be related to its pleiotropic effects.

[0006] Atorvastatin calcium, as an HMG-CoA reductase inhibitor, is widely used in the treatment of hypercholesterolemia. However, its low solubility (BCS class II) leads to limited bioavailability. Traditional processes such as wet granulation are prone to drug degradation (such as high-temperature wet granulation leading to changes in crystal form), and single-layer tablets are difficult to balance the requirements of rapid release and sustained release, requiring multiple doses. In the existing technology, the sustained-release layer mostly relies on pH-independent excipients (such as HPMC), which cannot accurately achieve intestinal targeting; the rapid-release layer uses a direct pulverization method, and the uneven particle size leads to dissolution fluctuations. In addition, the traditional granule mixing process has low mixing efficiency and is prone to producing fine powder or agglomerates, affecting the tablet hardness and content uniformity.

[0007] In recent years, HME technology has enabled the preparation of amorphous sustained-release layer particles through a solvent-free process, while nanocrystal technology can further enhance dissolution rates. This invention innovatively combines these two approaches and introduces a bilayer tablet design to optimize efficacy. Based on existing excipients and production conditions, it is necessary to develop a suitable formulation and preparation process to ensure that atorvastatin calcium tablets have good bioavailability and stability, while ensuring low production costs and a simple and feasible preparation process suitable for large-scale industrial production. Summary of the Invention

[0008] The present invention optimizes the dissolution rate of the immediate-release layer through nanocrystal technology, combines the hot-melt extrusion method to prepare the amorphous sustained-release layer, and uses a particle mixing process to improve uniformity. It proposes an atorvastatin tablet preparation for the treatment of hyperlipidemia and its preparation process, aiming to achieve rapid onset and long-term maintenance of the drug's effect in the body.

[0009] To achieve the above object, the present invention adopts the following technical solutions:

[0010] The first aspect of the present invention is to provide a preparation process of an atorvastatin tablet preparation for treating hyperlipidemia, comprising the following steps:

[0011] (1) Raw material pretreatment: Atorvastatin calcium was micronized to a particle size of ≤10 μm by a jet mill and set aside;

[0012] (2) Excipient pretreatment: Lactose and magnesium stearate were sieved through 80 mesh sieves respectively and set aside;

[0013] (3) Preparation of immediate-release layer granules:

[0014] a. Drug dissolution: Dissolve the prescribed amount of atorvastatin calcium in ethanol to a concentration of 10-20 mg / mL and stir magnetically at 500 rpm at 25±2°C until completely dissolved to prepare a good solvent solution;

[0015] b. Preparation of antisolvent: Adding surfactant poloxamer 188 (0.5-1.5% w / v) and stabilizer DSPE-PEG2000 to ultrapure water, stirring and dissolving to obtain an antisolvent solution;

[0016] c. High-pressure mixing: The good solvent solution and the antisolvent solution were mixed by a high-pressure microfluidizer (pressure 15,000 to 20,000 psi, flow rate 100 to 200 mL / min, volume ratio 1:5 to 1:10, cycle 3 to 5 times) to perform an antisolvent precipitation reaction to obtain a primary suspension;

[0017] d. Post-processing: The primary suspension after high-pressure mixing was then subjected to ultrasonic dispersion → centrifugal purification → spray drying to obtain nanocrystalline particles with a particle size of 80 ± 15 nm;

[0018] e. Immediate-release layer mixing: The nanocrystalline particles are granulated by a granulator, a colorant and magnesium stearate (additional 0.5%) are added, and mixed using a square cone mixer for 20 minutes to obtain an immediate-release layer granule intermediate;

[0019] (4) Preparation of sustained-release layer granules:

[0020] a. Premix: The prescribed amount of atorvastatin calcium, lactose, PEG-8000, Eudragit L100-55, and triethyl citrate were added to a wet granulator and stirred at 80 rpm and sheared at 300 rpm for 20 minutes.

[0021] b. Hot melt extrusion: The mixture is fed into a hot melt extruder, set at a temperature of 70-80°C, a screw speed of 150-250 rpm, an extrusion speed of 100-200 rpm, a feed rate of 1-2 kg / h, and a discharge screen of 1.0 mm;

[0022] c. Sustained-release layer mixing: The extruded granules were granulated by a granulator, magnesium stearate (external 1%) was added, and mixed using a ribbon mixer for 15 minutes to obtain a sustained-release layer granule intermediate;

[0023] (5) Double-layer tableting:

[0024] a. Pre-compression of the immediate-release layer: Fill the immediate-release layer granules into a modular tableting mold and pre-compress to form a plain tablet;

[0025] b. Secondary compression of sustained-release layer: Cover the plain tablets with the sustained-release layer granules and perform secondary compression, controlling the tablet weight difference to ±5% and the hardness to >80N;

[0026] (6) Coating: A moisture-proof film containing 2% titanium dioxide and polyvinyl alcohol was used for coating, with a film thickness of 30 to 50 μm to prepare atorvastatin tablet preparations.

[0027] Preferably, in step (3), the atorvastatin calcium immediate-release layer granules are formulated according to the following components in parts by weight:

[0028]

[0029]

[0030] Preferably, in step (3), the atorvastatin calcium immediate-release layer granules are formulated according to the following components in parts by weight:

[0031]

[0032] Preferably, in step (4), the atorvastatin calcium sustained-release layer granules are prepared according to the following components in parts by weight:

[0033]

[0034] Preferably, in step (4), the atorvastatin calcium sustained-release layer granules are prepared according to the following components in parts by weight:

[0035]

[0036]

[0037] Preferably, in the post-treatment process of step (3), the ultrasonic dispersion parameters are: power: 300 W (probe diameter 6 mm), time: 5 to 10 minutes (pulse mode, on / off cycle 2s / 1s), ice bath temperature control (to avoid local overheating leading to crystal growth);

[0038] The centrifugal purification parameters are as follows: speed: 15000 rpm, time: 20 minutes, discard the supernatant, resuspend with an aqueous solution containing 0.1% poloxamer 188, repeat twice to remove residual ethanol;

[0039] The spray drying parameters are: inlet temperature 80-90° C., outlet temperature 45-60° C., and atomizing air pressure 0.3-0.6 MPa.

[0040] Preferably, the rotation speed of the square cone mixer in the quick-release layer mixing process of step (3) is 15 to 25 rpm, and the rotation speed of the ribbon mixer in the sustained-release layer mixing process of step (4) is 30 to 50 rpm.

[0041] Preferably, in the double-layer tableting process of step (5), the weight ratio of the immediate-release layer to the sustained-release layer is 1:2 to 1:3.

[0042] A second aspect of the present invention is to provide an atorvastatin tablet preparation for treating hyperlipidemia prepared by the process described above, wherein the release rate of the immediate-release layer is ≥85% in 30 minutes, and the release rate of the sustained-release layer is ≥95% in 18 hours in a pH 6.8 medium; and the nanocrystal particle size of the immediate-release layer is 80±15nm and the PDI is ≤0.2.

[0043] Preferably, the atorvastatin tablet preparation for treating hyperlipidemia has a storage stability of ≤2% content decrease under the conditions of 40°C / 75% RH for 6 months.

[0044] Preferably, the atorvastatin tablet preparation for treating hyperlipidemia has a tablet hardness of 80-120N and a friability of ≤0.5%.

[0045] Preferably, in the atorvastatin tablet preparation for treating hyperlipidemia, the moisture-proof film coating layer has an ultraviolet light blocking rate of ≥95%.

[0046] The present invention adopts the above technical solution, which has the following technical effects compared with the prior art:

[0047] (1) The antisolvent precipitation method is based on the difference between the high solubility of the drug in the good solvent and the low solubility in the antisolvent. The supersaturated precipitation of nanocrystals (80±15 nm) is induced by rapid high-pressure microfluidic mixing, which can significantly improve the dissolution rate. Poloxamer 188 is used as a surfactant to adsorb on the crystal surface, inhibiting particle aggregation through the steric hindrance effect, and effectively stabilizing the nanosuspension.

[0048] (2) The amorphous solid dispersion prepared by hot melt extrusion 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, and combining with Eudragit L100-55 to achieve pH-dependent sustained release; this method can make the drug into an amorphous state, increase 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.

[0049] (3) 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 treatment. At the same time, the quick-release layer uses a square cone mixer combined with an external lubricant, and the sustained-release layer uses a spiral ribbon mixer to ensure the fluidity of the particles and the stability of the tablet.

[0050] (4) The atorvastatin tablet preparation for treating hyperlipidemia prepared by the process of the present invention is in accordance with the State Drug Administration's imported drug registration standard (standard number: JX20070073): the content of atorvastatin (C33H34FN2O5) should be 95.0-105.0% of the labeled amount, and the solubility limit of atorvastatin calcium is 85% of the labeled amount.

[0051] (5) The present invention creatively prepares atorvastatin calcium double-layer tablets by hot melt extrusion combined with nanocrystal technology, aiming to solve the problems of low solubility and photothermal sensitivity, and realize process continuity, so as to prolong the effective content time of lipid-lowering drugs in the body, help to achieve balanced blood drug concentration in the body, and improve patients' compliance with medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 This is a test image (powder X-ray diffraction) of the immediate-release nanocrystals prepared in an embodiment of the present invention;

[0053] Figure 2 This is the dissolution and release curve of the atorvastatin tablet preparation for treating hyperlipidemia prepared in an embodiment of the present invention. DETAILED DESCRIPTION

[0054] The main technical solution of the present invention is to creatively combine HME technology and nanocrystal technology, and introduce a double-layer tablet design to optimize drug efficacy. While ensuring low production costs and a simple and easy preparation process, the prepared atorvastatin calcium tablets have good bioavailability and drug stability, and the preparation process is stable and suitable for large-scale production.

[0055] The antisolvent precipitation method exploits the difference between the high solubility of the drug in a good solvent and its low solubility in an antisolvent. Rapid mixing induces supersaturation to precipitate nanocrystals. Poloxamer 188, acting as a surfactant, adsorbs on the crystal surface, inhibiting particle aggregation through steric hindrance and stabilizing the nanosuspension.

[0056] Eudragit L100-55 forms a dense, insoluble film at the low pH of the stomach (<5.5), preventing drug release. Upon entering the intestine (pH ≥ 5.5), the polymer dissolves, exposing the PEG-drug amorphous matrix and enabling sustained release through the porous lactose structure. High-melting-point PEG 8000, used as a carrier, forms intermolecular hydrogen bonds through hot-melt extrusion, inhibiting atorvastatin calcium crystallization (glass transition temperature Tg ≥ 50°C, above room temperature to ensure long-term stability).

[0057] The present invention has been verified through continuous experiments that the adjustment of different parameters in the immediate-release granulation and sustained-release granulation processes will have a direct impact on the dissolution of the prepared tablets. Through relevant research, the final process scheme was creatively determined, thereby providing an atorvastatin calcium tablet with good stability, high solubility and stable release of the active ingredient.

[0058] 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.

[0059] Example 1

[0060] A process for preparing an atorvastatin tablet preparation for treating hyperlipidemia, characterized by comprising the following steps:

[0061] (1) Raw material pretreatment: Atorvastatin calcium was micronized to a particle size of ≤10 μm by a jet mill and set aside;

[0062] (2) Excipient pretreatment: Lactose and magnesium stearate were sieved through 80 mesh sieves respectively and set aside;

[0063] (3) Preparation of immediate-release layer granules:

[0064] a. Drug dissolution: Dissolve 1 part of atorvastatin calcium in ethanol to a concentration of 15 mg / mL and stir magnetically at 500 rpm at 25 ± 2°C until completely dissolved to prepare a good solvent solution;

[0065] b. Preparation of antisolvent: 0.5 parts of a surfactant, poloxamer 188 (0.5% w / v), and 2 parts of a stabilizer, DSPE-PEG2000, were added to 20 parts of ultrapure water and stirred to dissolve to obtain an antisolvent solution;

[0066] c. High-pressure mixing: The good solvent solution and the antisolvent solution were mixed by a high-pressure microfluidizer (pressure 18,000 psi, flow rate 150 mL / min, volume ratio 1:5, 4 cycles), and the antisolvent precipitation reaction was performed to obtain a primary suspension;

[0067] d. Post-treatment: The primary suspension after high pressure mixing was then sequentially subjected to ultrasonic dispersion (300W, 8 minutes) → centrifugal purification (15000rpm, 20 minutes) → spray drying (inlet 85 ° C, outlet 48 ° C), to obtain Figure 1 The nanocrystalline particles shown have a particle size of 80 ± 15 nm;

[0068] e. Immediate-release layer mixing: The nanocrystalline particles were granulated by a granulator, 0.5 parts of magnesium stearate (externally) and 0.01 parts of a colorant were added, and mixed for 20 minutes using a square cone mixer (speed 20 rpm) to obtain an immediate-release layer granule intermediate;

[0069] (4) Preparation of sustained-release layer granules:

[0070] a premix: 10 parts of atorvastatin calcium, 20 parts of lactose, 15 parts of PEG-8000, 30 parts of Eudragit L100-55, 2.5 parts of triethyl citrate were added to a wet granulator, stirred at 80 rpm, sheared at 300 rpm and mixed for 20 minutes;

[0071] b. Hot melt extrusion: The mixture was fed into a hot melt extruder, with the temperature set at 75°C, the screw speed at 200 rpm, the extrusion speed at 150 rpm, the feed rate at 1 to 2 kg / h, and the discharge screen at 1.0 mm.

[0072] c. Sustained-release layer mixing: extruded granules were granulated by a granulator, 1 part of magnesium stearate (externally added) was added, and mixed for 15 minutes using a ribbon mixer (speed 40 rpm) to obtain a sustained-release layer granule intermediate;

[0073] (5) Double-layer tableting:

[0074] a. Pre-compression of the immediate-release layer: Fill the immediate-release layer granules into a modular tableting mold and pre-compress to form a plain tablet;

[0075] b. Sustained-release layer secondary tableting: Cover the sustained-release layer granules on the plain tablets and perform secondary tableting. The weight ratio of the immediate-release layer to the sustained-release layer is 1:2. The tablet weight difference is controlled to ±5%. The hardness is 95N.

[0076] (6) Coating: A moisture-proof film containing 2% titanium dioxide and polyvinyl alcohol was used for coating, with a film thickness of 40 μm, to prepare an atorvastatin tablet preparation for treating hyperlipidemia.

[0077] Experimental results: After testing, Figure 2 As shown, the dissolution rate of the immediate-release layer (30 minutes): 89%; the release of the sustained-release layer (pH 6.8, 18 hours): 98%; the friability of the tablets: 0.3%; and the decrease in content after 6 months of storage: 1.2%.

[0078] Example 2

[0079] The difference from Example 1 is that the concentration of Poloxamer 188 in the immediate-release layer is increased to 1.5% w / v. The rest is the same as Example 1.

[0080] Experimental results: Nanocrystal particle size: 75±10 nm (PDI=0.12); Dissolution rate (30 minutes): 95% (increased by 6%).

[0081] Result analysis: High concentration of poloxamer 188 enhanced the steric hindrance effect, inhibited crystal aggregation, made the particle size smaller and the distribution narrower, and significantly improved the dissolution rate.

[0082] Example 3

[0083] The difference from Example 1 is that the hot melt extrusion temperature of the sustained-release layer is reduced to 70° C. and the screw speed is 150 rpm. The rest is the same as Example 1.

[0084] Experimental results: Drug release curve: 96% was released in 18 hours, and the release rate was more gradual (RSD = 2.1% vs. RSD = 3.5% of Example 1).

[0085] Result analysis: Low temperature extrusion reduces thermal stress, maintains the stability of amorphous dispersion, and improves release uniformity.

[0086] Example 4

[0087] The difference from Example 1 is that the weight ratio of the immediate-release layer to the sustained-release layer is adjusted to 1:3, and the rest is the same as Example 1.

[0088] Experimental results: dissolution rate of the immediate-release layer: 85% (30 minutes); extended sustained-release time: 99% released in 14 hours.

[0089] Result analysis: Increasing the proportion of the sustained-release layer prolongs the drug release time and is suitable for patients who require long-term treatment.

[0090] Example 5

[0091] The difference from Example 1 is that the titanium dioxide content of the coating layer is increased to 3% and the film thickness is 50 μm. The rest is the same as Example 1.

[0092] Experimental results: UV blocking rate: 98% (vs. 95% in Example 1); dissolution rate: 87% (30 minutes); stability: content decreased by 0.8% in 6 months (better than 1.2% in Example 1).

[0093] Result analysis: Thickening the coating layer enhances moisture and light resistance and reduces drug degradation.

[0094] Comparative Example 1

[0095] The difference from Example 1 is that the immediate-release layer is prepared using a traditional wet granulation method (without nanocrystals), and the rest is the same as Example 1.

[0096] Experimental results: Dissolution rate (30 minutes): 65%; Bioavailability: decreased by 32% compared with Example 1.

[0097] Result analysis: The traditional wet granulation process cannot form nanocrystals, and the dissolution rate and absorption rate are significantly reduced.

[0098] Comparative Example 2

[0099] The difference from Example 1 is that Eudragit L100-55 in the sustained-release layer is replaced by an equal amount of HPMC, and the rest is the same as Example 1.

[0100] Experimental results: Gastric juice release (pH 1.2): 45% released in 2 hours; total release (18 hours): 82%.

[0101] Result analysis: HPMC has no pH dependence, is released prematurely in the stomach, and cannot achieve intestinal targeting.

[0102] Comparative Example 3

[0103] The difference from Example 1 is that the hot melt extrusion temperature of the sustained-release layer is increased to 90° C., and the rest is the same as Example 1.

[0104] Experimental results: Drug degradation rate: content decreased by 5% (1.2% in Example 1); abnormal release curve: 88% released in 18 hours, RSD = 8.7%.

[0105] Result analysis: High temperature caused partial degradation of the drug, destruction of the sustained-release layer structure, and uneven release.

[0106] Comparative Example 4

[0107] The difference from Example 1 is that poloxamer 188 is not added to the immediate-release layer. The rest is the same as Example 1.

[0108] Experimental results: Nanocrystal particle size: 220±30 nm (PDI=0.35); Dissolution rate (30 minutes): 52%.

[0109] Result analysis: The lack of surfactant led to crystal aggregation, increased particle size, and a sharp drop in dissolution rate.

[0110] Comparative Example 5

[0111] The difference from Example 1 is that a single filling tableting method (non-modular mold) is adopted, and the rest is the same as Example 1.

[0112] Experimental results: Tablet delamination rate: 18%; hardness: 70N (not up to standard).

[0113] Result analysis: Single tableting resulted in insufficient interlayer bonding, easy delamination of the tablets and low hardness.

[0114] The experimental data are summarized in Table 1 below:

[0115]

[0116]

[0117] Conclusion: From the data analysis in Table 1 above, it can be seen that the present invention adopts nanocrystal technology (Example 2, Comparative Example 1 and Comparative Example 4), which can significantly increase the poloxamer concentration and optimize the particle size and solubility. The absence of a surfactant will lead to aggregation. Through the hot melt extrusion temperature control technology (Example 3, Comparative Example 3), low-temperature extrusion is achieved to maintain an amorphous state, avoiding high temperature-induced degradation. And through pH-dependent sustained-release technology (Example 1, Comparative Example 2), Eudragit L100-55 is used to ensure intestinal targeting, overcoming the existing use of HPMC to cause premature release in the stomach. The present invention systematically solves the dissolution, sustained-release and stability problems of atorvastatin tablet preparations through multi-dimensional technological innovation, and has significant industrial application value.

[0118] 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 of atorvastatin tablet preparation for treating hyperlipidemia, characterized in that: The steps include: (1) Raw material pretreatment: Atorvastatin calcium was micronized to a particle size of ≤10 μm by a jet mill and set aside; (2) Excipient pretreatment: Lactose and magnesium stearate were sieved through 80 mesh sieves respectively and set aside; (3) Preparation of immediate-release layer granules: a. Drug dissolution: Dissolve the prescribed amount of atorvastatin calcium in ethanol to a concentration of 10-20 mg / mL and stir magnetically at 500 rpm at 25±2°C until completely dissolved to prepare a good solvent solution; b. Preparation of antisolvent: Adding surfactant poloxamer 188 (0.5-1.5% w / v) and stabilizer DSPE-PEG2000 to ultrapure water, stirring and dissolving to obtain an antisolvent solution; c. High-pressure mixing: The good solvent solution and the antisolvent solution were mixed by a high-pressure microfluidizer (pressure 15,000 to 20,000 psi, flow rate 100 to 200 mL / min, volume ratio 1:5 to 1:10, cycle 3 to 5 times) to perform an antisolvent precipitation reaction to obtain a primary suspension; d. Post-processing: The primary suspension after high-pressure mixing was then subjected to ultrasonic dispersion → centrifugal purification → spray drying to obtain nanocrystalline particles with a particle size of 80 ± 15 nm; e. Immediate-release layer mixing: The nanocrystalline particles are granulated by a granulator, a colorant and magnesium stearate (additional 0.5%) are added, and mixed using a square cone mixer for 20 minutes to obtain an immediate-release layer granule intermediate; (4) Preparation of sustained-release layer granules: a. Premix: The prescribed amount of atorvastatin calcium, lactose, PEG-8000, Eudragit L100-55, and triethyl citrate were added to a wet granulator and stirred at 80 rpm and sheared at 300 rpm for 20 minutes. b. Hot melt extrusion: put the mixed material into the hot melt extruder, set the temperature to 70-80 ° C, screw speed 150-250 rpm, extrusion speed 100-200 rpm, feeding rate 1-2 kg / h, discharge screen 1.0 mm; c. Sustained-release layer mixing: The extruded granules were granulated by a granulator, magnesium stearate (external 1%) was added, and mixed using a ribbon mixer for 15 minutes to obtain a sustained-release layer granule intermediate; (5) Double-layer tableting: a. Pre-compression of the immediate-release layer: Fill the immediate-release layer granules into a modular tableting mold and pre-compress to form a plain tablet; b. Secondary compression of sustained-release layer: Cover the sustained-release layer granules on the plain tablets and perform secondary compression, controlling the tablet weight difference to ±5% and the hardness to >80N; (6) Coating: A moisture-proof film containing 2% titanium dioxide and polyvinyl alcohol is used for coating, with a film thickness of 30 to 50 μm, to prepare an atorvastatin tablet preparation for treating hyperlipidemia.

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

3. The preparation process according to claim 2, characterized in that In step (3), the atorvastatin calcium rapid-release layer granules are prepared according to the following components in parts by weight:

4. The preparation process according to claim 1, characterized in that In step (4), the atorvastatin calcium sustained-release layer granules are prepared according to the following components in parts by weight:

5. The preparation process according to claim 4, characterized in that: In step (4), the atorvastatin calcium sustained-release layer granules are prepared according to the following components in parts by weight:

6. The preparation process according to claim 1, characterized in that In the post-treatment process of step (3), the ultrasonic dispersion parameters are: power: 300 W (probe diameter 6 mm), time: 5 to 10 minutes (pulse mode, on / off cycle 2 s / 1 s), ice bath temperature control (to avoid local overheating leading to crystal growth); The centrifugal purification parameters are as follows: speed: 15000 rpm, time: 20 minutes, discard the supernatant, resuspend with an aqueous solution containing 0.1% poloxamer 188, repeat twice to remove residual ethanol; The spray drying parameters are: inlet temperature 80-90° C., outlet temperature 45-60° C., and atomizing air pressure 0.3-0.6 MPa.

7. The preparation process according to claim 1, characterized in that The rotation speed of the square cone mixer in the quick-release layer mixing process of step (3) is 15 to 25 rpm, and the rotation speed of the ribbon mixer in the sustained-release layer mixing process of step (4) is 30 to 50 rpm.

8. The preparation process according to claim 1, characterized in that In the double-layer tableting process of step (5), the weight ratio of the quick-release layer to the sustained-release layer is 1:2 to 1:

3.

9. An atorvastatin tablet preparation for treating hyperlipidemia prepared by the process according to any one of claims 1 to 8, characterized in that: The release amount of the immediate-release layer is ≥85% in 30 minutes, and the release amount of the sustained-release layer is ≥95% in 18 hours in a pH 6.8 medium; and the particle size of the nanocrystals in the immediate-release layer is 80±15nm, and the PDI is ≤0.

2.

10. The atorvastatin tablet preparation for treating hyperlipidemia according to claim 9, characterized in that: Storage stability is 40℃ / 75%RH for 6 months with a decrease of ≤2%.

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