Preparation method of ezetimibe atorvastatin calcium tablet

Abstract

The invention discloses a preparation method of ezetimibe atorvastatin calcium tablets. The ezetimibe atorvastatin calcium tablets are prepared from atorvastatin calcium, ezetimibe, microcrystalline cellulose, lactose, polyvinylpolypyrrolidone, hydroxypropyl cellulose, magnesium stearate and colloidal silicon dioxide through a specific process. Comprising the following steps: sieving micronized atorvastatin calcium, ezetimibe, a filler, a disintegrating agent and other auxiliary materials, and carrying out first-step mixing in an environment in which the temperature and humidity are strictly controlled to prepare total mixed powder; then adding a lubricant and carrying out second-step short-time low-speed mixing to obtain final mixed particles; and finally, carrying out high-speed tabletting under the condition of controlling the temperature of a punch of a tabletting machine, and optionally carrying out film coating. The core technical problems that the content uniformity of low-dose ezetimibe in a compound preparation is poor and the stability of atorvastatin calcium is poor are effectively solved, and the prepared tablet is high in content uniformity, good in dissolution behavior, excellent in stability and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of pharmaceutical preparations, and specifically discloses a preparation method of ezetimibe atorvastatin calcium tablets. BACKGROUND

[0002] Ezetimibe atorvastatin calcium tablets, as a kind of powerful compound lipid-lowering drug, exhibit significant synergistic effect in the treatment of hypercholesterolemia through double inhibition of cholesterol absorption and synthesis, and thus are widely used in clinical practice. However, the development and production of the compound preparation face many technical challenges, mainly due to the significant differences in physical and chemical properties of the two active pharmaceutical ingredients (APIs), ezetimibe and atorvastatin calcium.

[0003] The existing production technology generally has problems such as poor content uniformity, poor stability and unsatisfactory dissolution behavior. First, ezetimibe belongs to BCSII class drugs, which has extremely poor water solubility, while atorvastatin calcium is sensitive to moisture, heat and light, and is prone to hydrolytic degradation in a wet environment, which greatly limits the traditional wet granulation process. Although the direct powder compression or dry granulation process can avoid the introduction of water, the differences in density, particle size and flowability between the two APIs and various excipients can easily cause separation during mixing and transportation, resulting in large fluctuations in the content uniformity (CU) of the main drugs in the tablets, which is difficult to meet the strict pharmacopoeia standards, affecting the safety and effectiveness of drug administration.

[0004] The current mainstream preparation method has obvious technical limitations: first, simple mechanical mixing cannot ensure the micro-uniform distribution of low-dose ezetimibe in high-load excipients, which poses a quality risk of uneven content; second, if the mixing time or shear force is not properly controlled in the production process, it can damage the crystal form of atorvastatin calcium or induce its degradation, leading to an increase in the content of related substances; third, the introduction of excessive excipients or improper lubrication process to improve compressibility or flowability often delays the dissolution of the hydrophobic drug ezetimibe, affecting its in vivo bioavailability; fourth, the existing process does not strictly control the production environment (such as temperature and humidity), or does not perform necessary micronization pretreatment on the raw drug, which leads to stability problems of the finished product during storage, such as an increase in related substances or a decrease in dissolution.

[0005] In addition, the existing technology often extends the mixing time or adds a premixing step to improve uniformity, which not only reduces production efficiency, but also exacerbates the degradation of APIs and changes the physical properties of the powder, resulting in poor flowability. The tabletting process generally relies on empirical control, making it difficult to accurately quantify key process parameters, resulting in large batch-to-batch quality differences. Therefore, it is urgent to develop a green and efficient new preparation process that takes into account content uniformity, drug stability, excellent dissolution behavior and production reproducibility. SUMMARY

[0006] To address the above problems, this invention discloses a method for preparing ezetimibe atorvastatin calcium tablets.

[0007] The objective of this invention is achieved through the following technical solution.

[0008] A method for preparing ezetimibe / atorvastatin calcium tablets, wherein the tablets are made from components comprising the following parts by weight:

[0009] Atorvastatin calcium 5-20 parts;

[0010] 5-20 portions of Ezekiel;

[0011] 30-60 parts of microcrystalline cellulose;

[0012] Lactose 10-30 parts;

[0013] 3-8 parts of crospovidone;

[0014] 2-5 parts hydroxypropyl cellulose;

[0015] Magnesium stearate 0.5-1.5 parts;

[0016] 0.1-0.5 parts of colloidal silica;

[0017] The method includes the following steps:

[0018] (1) Pretreatment of raw materials and auxiliary materials: Atorvastatin calcium, ezetimibe, microcrystalline cellulose and lactose are passed through an 80-100 mesh sieve for later use;

[0019] (2) Mixing: Add the sieved atorvastatin calcium, ezetimibe, microcrystalline cellulose, lactose, crospovidone, and hydroxypropyl cellulose into a mixer and mix at a speed of 15-25 r / min for 20-30 minutes to obtain a total powder.

[0020] (3) Lubrication: Add magnesium stearate and colloidal silica to the total powder mixture and mix at a speed of 10-15 r / min for 3-5 minutes to obtain the final powder mixture.

[0021] (4) Tableting: The final mixed particles are compressed into tablets using a high-speed tablet press, with the weight difference controlled within ±3% and the hardness 70-100N, to obtain the tablet core.

[0022] Furthermore, in the above preparation method, the particle size D90 of the atorvastatin calcium is ≤25μm, and the particle size D90 of the ezetimibe is ≤30μm.

[0023] Furthermore, in the above preparation method, the mixer mentioned in step (2) is a three-dimensional motion mixer or a hopper mixer, and the mixing environment is controlled with relative humidity ≤40%RH and temperature below 25℃.

[0024] Further, the preparation method, the tabletting speed of the tablet press in step (4) is controlled at 10-30 million tablets / hour, and the temperature of the punch and the die ring of the tablet press is controlled at 25-30 DEG C during the tabletting process.

[0025] Further, the preparation method further comprises step (5) film coating: using Opadry coating premix to form a film coating layer on the surface of the tablet core, the film coating layer accounting for 2%-4% of the weight of the tablet core.

[0026] Further, the preparation method, the step (5) uses a high-efficiency coating pot, the air inlet temperature is controlled at 50-65 DEG C, the rotation speed of the pot body is 5-10 r / min, and the spraying speed of the coating liquid is 10-20 mL / min.

[0027] The application further discloses an ezetimibe atorvastatin calcium tablet, wherein the dissolution rate of ezetimibe is not less than 85% in 15 minutes, the dissolution rate of atorvastatin is not less than 80% in 30 minutes in a phosphate buffer with pH 6.8, and the dissolution determination method accords with the method in the Chinese Pharmacopoeia with a rotation speed of 50 r / min.

[0028] Further, the ezetimibe atorvastatin calcium tablet has the following characteristics: the related substance single impurity content of ezetimibe and atorvastatin is not more than 0.5%, and the total impurity content is not more than 1.5% when the tablet is placed under accelerated conditions of 40 DEG C + / - 2 DEG C / 75% RH + / - 5% RH for 6 months.

[0029] Further, the ezetimibe atorvastatin calcium tablet is packaged by using double-aluminum blister packaging or high-density polyethylene bottle packaging.

[0030] The application further discloses a use of the ezetimibe atorvastatin calcium tablet in preparation of a medicine for treating hypercholesterolemia or familial hypercholesterolemia.

[0031] Compared with the prior art, the application has the following advantages and beneficial effects:

[0032] 1. Excellent content uniformity: through micronization pretreatment of low-dose medicine ezetimibe and combination of a scientific step-by-step mixing process, the high uniform dispersion of medicine particles in excipients is ensured, and the quality risk of uneven content of low-dose components is fundamentally solved.

[0033] 2. High medicine stability: through strict control of the temperature and humidity of the production environment and the punch temperature in the tabletting process, the influence of moisture and heat effect on the stability of atorvastatin calcium is maximally reduced, and the increase of related substances in the production and storage processes is effectively inhibited.

[0034] 3. Ideal dissolution behavior: optimized formulation system (containing super-disintegrant) and process ensure the rapid disintegration of the tablet, so that both of the poorly water-soluble ezetimibe and the easily degradable atorvastatin calcium can achieve high-efficiency and synchronous dissolution, which is beneficial to the in-vivo absorption.

[0035] 4. Good process reproducibility: the key process parameters (such as mixing speed and time, tabletting temperature) are quantitatively controlled, which reduces the human and environmental influences, ensures the consistency of batch quality, has high production efficiency, and is very suitable for large-scale production. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 Ezetimibe content uniformity test results (standard deviation (S));

[0037] Figure 2 Ezetimibe content uniformity test results (A+2.2S value);

[0038] Figure 3 Comparison of 30-minute cumulative dissolution of double API (Active Pharmaceutical Ingredient). DETAILED DESCRIPTION

[0039] In order to make the objectives, technical solutions and advantages of the present application clearer and more comprehensible, the present application will be further described in detail below. However, it should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the scope of the present application. In addition, in the following description, the description of well-known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present application. All raw materials in the embodiments of the present application can be obtained through commercial channels.

[0040] It should be noted that the embodiments in the present application and the features in the embodiments can be combined with each other without conflict. The present application will be described in detail below with reference to the embodiments.

[0041] Table 1 is a raw material parameter table in the embodiments of the present application

[0042] Example 1

[0043] An ezetimibe atorvastatin calcium tablet is made from components containing the following weight parts:

[0044] Atorvastatin calcium (D90=20μm) 10 parts;

[0045] Ezetimibe (D90=25μm) 10 parts;

[0046] Microcrystalline cellulose (PH-101) 45 parts;

[0047] Lactose (spray-dried) 20 parts;

[0048] Crospovidone (XL-10) 5 parts;

[0049] Hydroxypropyl cellulose (HPC-L) 3 parts;

[0050] Magnesium stearate 1 part;

[0051] Colloidal silicon dioxide 0.5 parts;

[0052] The preparation method comprises the following steps:

[0053] (1) Pre-treatment of raw materials: atorvastatin calcium, ezetimibe, microcrystalline cellulose, lactose are respectively passed through an 80-mesh sieve for use;

[0054] (2) Mixing: the sieved atorvastatin calcium, ezetimibe, microcrystalline cellulose, lactose and crospovidone, hydroxypropyl cellulose are put into a three-dimensional motion mixer, the environmental temperature is controlled at 23℃, the relative humidity is controlled at 35% RH, and the speed is controlled at 20 r / min for mixing for 25 minutes to obtain total mixed powder;

[0055] (3) Lubrication: magnesium stearate and colloidal silicon dioxide are added to the total mixed powder, and the speed is controlled at 12 r / min for mixing for 4 minutes to obtain final mixed granules;

[0056] (4) Tabletting: the final mixed granules are tabletted by using a high-speed tabletting machine, the tabletting speed is controlled at 200,000 tablets / hour, the punch temperature is controlled at 28℃, the tablet weight is controlled at 500 mg / tablet, the tablet weight difference is within ±2.5%, and the hardness is 85 N, so that the tablet core is obtained.

[0057] (5) Coating: the obtained tablet core is coated by using Opadry II (85F340004) to obtain a coating weight of 3% of the weight of the tablet core.

[0058] Example 2

[0059] An ezetimibe atorvastatin calcium tablet is made from components comprising the following parts by weight:

[0060] Atorvastatin calcium (D90=18 μm) 20 parts;

[0061] Ezetimibe (D90=22 μm) 5 parts;

[0062] Microcrystalline cellulose (PH-102) 50 parts;

[0063] Lactose (monohydrate) 15 parts;

[0064] Crospovidone (XL-10) 8 parts;

[0065] Hydroxypropyl cellulose (HPC-SSL) 2.5 parts;

[0066] magnesium stearate 0.8 parts;

[0067] colloidal silicon dioxide 0.3 parts;

[0068] The preparation method comprises the following steps:

[0069] (1) Pre-treatment of raw materials: atorvastatin calcium, ezetimibe, microcrystalline cellulose, lactose are respectively passed through a 100-mesh sieve for use;

[0070] (2) Mixing: the sieved atorvastatin calcium, ezetimibe, microcrystalline cellulose, lactose, cross-linked povidone and hydroxypropyl cellulose are put into a hopper mixer, the environmental temperature is controlled at 20℃, the relative humidity is controlled at 30% RH, and the speed is controlled at 18 r / min for mixing for 30 minutes to obtain total mixed powder;

[0071] (3) Lubrication: magnesium stearate and colloidal silicon dioxide are added to the total mixed powder, and the speed is controlled at 10 r / min for mixing for 5 minutes to obtain final mixed granules;

[0072] (4) Tabletting: the final mixed granules are tabletted by using a high-speed tabletting machine, the tabletting speed is controlled at 1.5 million tablets / hour, the punch temperature is controlled at 25℃, the tablet weight is controlled at 500 mg / tablet, the tablet weight difference is within ±2%, and the hardness is 90 N, so that the tablet core is obtained.

[0073] (5) Coating: the obtained tablet core is coated by using Opadry II (85F340004) to obtain a coating weight of 2.5% of the weight of the tablet core.

[0074] Example 3

[0075] An ezetimibe atorvastatin calcium tablet is made from components comprising the following parts by weight:

[0076] atorvastatin calcium (D90=23 μm) 5 parts;

[0077] ezetimibe (D90=28 μm) 20 parts;

[0078] microcrystalline cellulose (PH-200) 35 parts;

[0079] lactose (monohydrate) 30 parts;

[0080] cross-linked povidone (XL-10) 3 parts;

[0081] hydroxypropyl cellulose (HPC-SL) 5 parts;

[0082] magnesium stearate 1.2 parts;

[0083] colloidal silicon dioxide 0.4 parts;

[0084] The preparation method comprises the following steps:

[0085] (1) Raw material pretreatment: atorvastatin calcium, ezetimibe, microcrystalline cellulose, lactose were respectively passed through 80 mesh sieve for use;

[0086] (2) Mixing: the sieved atorvastatin calcium, ezetimibe, microcrystalline cellulose, lactose and crospovidone, hydroxypropyl cellulose were put into a three-dimensional motion mixer, the environmental temperature was controlled at 25℃, the relative humidity was controlled at 38% RH, and the speed was controlled at 22r / min for 20 minutes to obtain total mixed powder;

[0087] (3) Lubrication: magnesium stearate and colloidal silicon dioxide were added to the total mixed powder, and the speed was controlled at 15r / min for 3 minutes to obtain final mixed granules;

[0088] (4) Tabletting: the final mixed granules were tabletted by a high-speed tabletting machine, the tabletting speed was controlled at 2.5 million tablets / hour, the punch temperature was controlled at 30℃, the tablet weight was controlled at 500mg / tablet, the tablet weight difference was within ±2.8%, and the hardness was 75N to obtain the tablet core.

[0089] (5) Coating: the obtained tablet core was coated by Opadry II (85F340004) to obtain a tablet core with a coating weight of 3.5% of the tablet core weight.

[0090] Comparative Example 1

[0091] Process comparison: improper lubricant addition method and mixing time

[0092] A tablet, the raw materials and preparation method of which are basically the same as those of Example 1, the only difference being that in step (3) lubrication, magnesium stearate and colloidal silicon dioxide were put into the mixer together with the total mixed powder, and the speed was controlled at 20r / min for 8 minutes.

[0093] Comparative Example 2

[0094] Process comparison: missing key process parameters

[0095] A tablet, the raw materials and preparation method of which are basically the same as those of Example 1, the only difference being that in step (4) tabletting, the punch temperature was not controlled during the tabletting process, and the punch temperature of the tabletting machine rose to 45℃ under high-speed operation.

[0096] Comparative Example 3

[0097] Raw material comparison: API was not pretreated by micronization

[0098] A tablet, the raw materials and preparation method of which are basically the same as those of Example 1, the only difference being that the atorvastatin calcium raw material particle size D90=85μm, and the ezetimibe raw material particle size D90=90μm.

[0099] Comparative Example 4

[0100] Process comparison: improper mixing environment control

[0101] A tablet, whose raw materials and preparation method are basically the same as those of Example 1, the only difference is that step (2) mixing: mixing is carried out at an ambient temperature of 30°C and a relative humidity of 65% RH.

[0102] Comparative Example 5

[0103] Raw material comparison: lack of key functional excipients

[0104] A tablet, whose raw materials and preparation method are basically the same as those of Example 1, the only difference is that the formulation does not contain cross-linked povidone (XL-10), which is replaced by an equivalent amount of microcrystalline cellulose.

[0105] Test Example 1

[0106] Content uniformity test

[0107] Purpose: to verify the effect of the process of the present application on the improvement of the content uniformity of low-dose ingredient ezetimibe.

[0108] Method:

[0109] Take 10 tablets each of Example 1-3, Comparative Example 1 (over-mixed lubrication), Comparative Example 3 (API not micronized), and Comparative Example 5 (lack of disintegrant).

[0110] Refer to the method for checking the content uniformity in Chinese Pharmacopoeia 2020 edition Volume IV 0941. Grind, dissolve and dilute each tablet separately, and determine the absolute content of ezetimibe in each tablet by high performance liquid chromatography (HPLC).

[0111] Calculate the mean (X - ) and standard deviation (S), and the key indicator A+2.2S value for measuring uniformity. According to the Pharmacopoeia, if A+2.2S≤15.0, the content uniformity is determined to meet the requirements.

[0112] The results are shown in Table 2 and Figure 1 and Figure 2 .

[0113] Table 2: Test results of ezetimibe content uniformity (n=10).

[0114] Group Average content (mg) Standard deviation (S) A+2.2S value Determination result Example 1 10.2 0.32 10.9 Compliant Example 2 5.1 0.25 9.7 Compliant Example 3 20.1 0.48 12.7 Compliant Comparative Example 1 9.8 1.85 29.9 Non-compliant Comparative Example 3 10.5 2.21 35.4 Non-compliant Comparative Example 5 10.1 1.42 23.2 Non-compliant

[0115] Conclusion: The A+2.2S value of ezetimibe in each product of the embodiments of the present application is far below the limit value of 15.0, and the content uniformity is excellent. The uniformity of the comparative example 1 does not meet the requirements of the pharmacopoeia because the drug and excipients are separated due to excessive mixing. The uniformity of the comparative example 3 does not meet the requirements of the pharmacopoeia because the raw material particles are too large to be uniformly dispersed. The uniformity of the comparative example 5 does not meet the requirements of the pharmacopoeia because the mixture is poor in uniformity due to the lack of disintegrating agent. This proves that the raw material pretreatment (micronization) and the step-by-step mixing and lubrication process of the present application play a key role in ensuring the uniformity of low-dose components.

[0116] Test Example 2

[0117] Dissolution curve comparison test

[0118] Objective: To evaluate the release behavior of the tablets in the in vitro dissolution medium and verify whether they can meet the requirements of synchronous high-efficiency release of double APIs.

[0119] Method:

[0120] The second method (paddle method) of General Test 0931 in the Chinese Pharmacopoeia 2020 Edition was used. 900 mL of pH 6.8 phosphate buffer was used as the dissolution medium, the temperature was 37.0±0.5℃, and the rotation speed was 50 rpm.

[0121] The tablets of example 2, comparative example 2 (high-temperature compression), comparative example 4 (high-humidity mixing), and comparative example 5 (lack of disintegrating agent) were taken for operation, respectively.

[0122] Samples were taken at 5, 10, 15, 30, 45, and 60 minutes, and an equal volume of medium was added. The concentrations of ezetimibe and atorvastatin were determined by HPLC, and the cumulative dissolution rate (%) was calculated.

[0123] The results are shown in Table 3 and Figure 3 (schematic).

[0124] Table 3: Comparison of cumulative dissolution rate of double APIs at 30 minutes (% n=6)

[0125] Group Ezetimibe dissolution Atorvastatin dissolution Example 2 88.5±3.1 95.2±2.5 Comparative Example 2 65.3±4.8 71.8±3.9* Comparative Example 4 72.1±5.2 68.4±4.1* Comparative Example 5 55.6±6.7 90.5±3.0

[0126] Note: The low dissolution rate of atorvastatin in comparative examples 2 and 4 may be related to the degradation of APIs under high temperature and high humidity.

[0127] Conclusion: The ezetimibe and atorvastatin in the product of Example 2 of the present application both reached high dissolution of more than 85% within 30 minutes, and the release behaviors were synchronized. The dissolution of Comparative Example 2 decreased due to the degradation of some API or the change of the property of the excipient caused by the too high tabletting temperature. The dissolution of Comparative Example 4 decreased due to the degradation of API caused by the high humidity environment. The dissolution of Comparative Example 5 was hindered due to the slow tablet disintegration caused by the lack of cross-linked povidone. It is proved that the prescription and low-temperature and low-humidity process of the present application are the key to ensure the high dissolution of the double API.

[0128] Test Example 3

[0129] Accelerated stability test

[0130] Objective: To investigate the change of related substances of the product under the condition of accelerated test, and to evaluate the influence of the process on the stability of the drug.

[0131] Method:

[0132] The tablet samples of Example 2, Comparative Example 2 (high-temperature tabletting) and Comparative Example 4 (high-humidity mixing) were placed in an accelerated stability test box with the condition of 40℃±2℃ / 75%RH±5%RH.

[0133] The samples were taken at the end of 0, 1, 2, 3 and 6 months. The content of ezetimibe and atorvastatin was determined by HPLC, and the content of single unknown impurity and total impurity was detected according to the method in the product quality standard.

[0134] The results are shown in Table 4.

[0135] Table 4: Change of related substances and content after 6 months of accelerated test (%,n=2).

[0136] Group Ezetimibe content variation Atorvastatin content variation Maximum single impurity Total impurities Example 2 -1.2％ -1.5％ 0.12 0.45 Comparative Example 2 -3.8％ -5.1％ 0.35 1.52 Comparative Example 4 -4.5％ -8.2％ 0.41 1.88

[0137] Conclusion: After 6 months of accelerated test, the content of the main drug of the product of Example 2 of the present application decreased very little, and the related substances increased slowly, which was far lower than that of the comparative examples. The main drug of the products of Comparative Example 2 (high-temperature tabletting) and Comparative Example 4 (high-humidity mixing) degraded significantly, and the impurities increased obviously. This fully proves that the chemical stability of atorvastatin which is sensitive to moisture and heat is effectively ensured by controlling the tabletting temperature and the humidity of the production environment, so as to ensure the long-term quality of the product.

[0138] Test Example 4

[0139] Test of key physical properties of tablet

[0140] Objective: To comprehensively evaluate the hardness, friability and disintegration time of the tablet, and to evaluate the mechanical strength and formability.

[0141] Method:

[0142] Hardness: The hardness of 10 tablets was determined randomly using a tablet hardness tester (Model: YD-20), and the average value was taken.

[0143] Friability: Referring to the method in Chinese Pharmacopoeia 2020, Vol. 4, 0923, a certain number of tablets (about 6.5 g) were placed in a friability tester and rotated at a speed of 25 r / min for 100 times, and the percentage of weight loss was calculated.

[0144] Disintegration time: Referring to the method in Chinese Pharmacopoeia 2020, Vol. 4, 0921, a disintegration tester (Model: BJS-2) was used to determine the time required for 6 tablets to completely disintegrate and pass through the sieve with pure water as the medium.

[0145] The results are shown in Table 5.

[0146] Table 5: Test results of tablet physical properties

[0147]

[0148]

[0149] Note: Example 5 has a serious disintegration time due to the lack of disintegrating agent.

[0150] Conclusion: The product of Example 2 has moderate hardness, and the friability is far below the industry's conventional requirement of 1%, indicating that the tablet has good mechanical strength, strong wear resistance, and is not prone to produce debris, which is beneficial for packaging and transportation. The disintegration is rapid, which lays a foundation for the rapid dissolution of the subsequent drug. Example 1 has a low hardness and high friability due to improper mixing process of the lubricant, which may affect the compressibility of the granules. Example 5 cannot disintegrate normally due to the defect in the prescription. It is proved that the complete prescription and process of the present application are the guarantee for obtaining ideal physical properties.

[0151] Test example summary:

[0152] The above series of test examples verify the excellent effect of the present application:

[0153] 1) Content uniformity: The content uniformity A+2.2S value of ezetimibe in the product of Example is all <13 (n=10), which is far below the limit value of 15.0 specified in the Pharmacopoeia, while the content uniformity of the comparative examples all exceeds the limit value, among which Example 3 (not micronized) is as high as 35.4.

[0154] 2) Dissolution behavior: In pH 6.8 phosphate buffer, the dissolution rates of ezetimibe and atorvastatin in the product of Example 2 are as high as 88.5% and 95.2% (n=6) at 30 minutes, respectively. In contrast, the dissolution rate of ezetimibe in Example 2 (high-temperature tabletting) and Example 5 (without disintegrating agent) is only 65.3% and 55.6%, respectively.

[0155] 3) Stability: The active content of the product of Example 2 decreased less than 1.5% and the total impurities increased to only 0.45% after 6 months of accelerated testing at 40°C ± 2°C / 75% RH ± 5% RH. The atorvastatin content of Comparative Example 2 (high temperature compression) and Comparative Example 4 (high humidity mixing) both decreased more than 5% and the total impurities increased to 1.52% and 1.88%, respectively.

[0156] 4) Physical properties: The hardness of the product of Example was moderate (85-90 N), the friability was low (<0.5%), and the disintegration was rapid (<4 minutes), all of which met the requirements of high quality tablets.

Claims

1. A process for the preparation of ezetimibe atorvastatin calcium tablet characterized in that, The tablet is made from the following components by weight: Atorvastatin calcium 5-20 parts; Ezetimibe 5-20 parts; Microcrystalline cellulose 30-60 parts; Lactose 10-30 parts; Crospovidone 3-8 parts; Hydroxypropyl cellulose 2-5 parts; Magnesium stearate 0.5-1.5 parts; Colloidal silicon dioxide 0.1-0.5 parts; The method comprises the following steps: (1) Pre-treatment of raw materials: atorvastatin calcium, ezetimibe, microcrystalline cellulose, lactose are respectively sieved through 80-100 mesh for use; (2) Mixing: the sieved atorvastatin calcium, ezetimibe, microcrystalline cellulose, lactose and crospovidone, hydroxypropyl cellulose are put into a mixer and mixed at a speed of 15-25 r / min for 20-30 minutes to obtain total mixed powder; (3) Lubrication: magnesium stearate and colloidal silicon dioxide are added to the total mixed powder and mixed at a speed of 10-15 r / min for 3-5 minutes to obtain final mixed granules; (4) Tabletting: the final mixed granules are tabletted by a high-speed tabletting machine, the tablet weight difference is controlled within ±3%, and the hardness is 70-100 N to obtain the tablet core.

2. The method of claim 1, wherein: The particle size D90 of atorvastatin calcium is ≤25 μm, and the particle size D90 of ezetimibe is ≤30 μm.

3. The method of claim 1, wherein: The mixer in step (2) is a three-dimensional motion mixer or a hopper mixer, and the mixing environment is controlled to have a relative humidity of ≤40% RH and a temperature of 25°C or lower.

4. The method of claim 1, wherein: The tabletting speed of the tabletting machine in step (4) is controlled at 10-30 million tablets / hour, and the temperature of the punch and die ring of the tabletting machine is controlled at 25-30°C during the tabletting process.

5. The method of claim 1, wherein: It further comprises step (5) film coating: using Opadry coating premix to form a film coating layer on the surface of the tablet core, the film coating layer accounting for 2%-4% of the weight of the tablet core.

6. The method of claim 5, wherein: The step (5) uses a high-efficiency coating pot, the air inlet temperature is controlled at 50-65°C, the pot body rotates at a speed of 5-10 r / min, and the coating liquid spraying speed is 10-20 mL / min.

7. A tablet of ezetimibe atorvastatin calcium prepared by the method of any one of claims 1-6, characterized in that: In a phosphate buffer at pH 6.8, the dissolution of ezetimibe is not less than 85% in 15 minutes, and the dissolution of atorvastatin is not less than 80% in 30 minutes, and the dissolution determination method conforms to the method in the Chinese Pharmacopoeia, and the rotation speed is 50 r / min.

8. The ezetimibe atorvastatin calcium tablet according to claim 7, characterized by: The tablet is placed under accelerated conditions of 40°C±2°C / 75%RH±5%RH for 6 months, and the related substance single impurity content of ezetimibe and atorvastatin is not more than 0.5%, and the total impurity content is not more than 1.5%.

9. The ezetimibe atorvastatin calcium tablet according to claim 7, wherein: The tablet is packaged by double-aluminum blister packaging or high-density polyethylene bottle packaging.

10. Use of the ezetimibe atorvastatin calcium tablet of claim 7 in the preparation of a medicament for treating hypercholesterolemia or familial hypercholesterolemia.

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