A formulation comprising ezetimibe and atorvastatin calcium and a method for preparing the same

Abstract

The present application belongs to the technical field of pharmaceutical preparations, and relates to a combined preparation of ezetimibe and atorvastatin calcium, in particular to a preparation containing ezetimibe and atorvastatin calcium and a preparation method thereof. A double-layer tablet is formed by an ezetimibe layer and an atorvastatin calcium layer, the ezetimibe layer is composed of ezetimibe and a first excipient, and the atorvastatin calcium layer is composed of atorvastatin calcium and a second excipient; the second excipient does not contain an alkaline stabilizer, and kaolin is used as a filler in the second excipient. By adding kaolin as a filler, the present application can not only avoid the addition of an alkaline adjusting agent, but also improve the stability of ezetimibe and atorvastatin calcium.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and relates to a combination formulation of ezetimibe and atorvastatin calcium, specifically to a formulation containing ezetimibe and atorvastatin calcium and its preparation method. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Atorvastatin calcium is used to treat hypercholesterolemia, which often has an insidious onset and is usually asymptomatic. Studies have shown that hypercholesterolemia, characterized by elevated low-density lipoprotein cholesterol or total cholesterol, is an important risk factor for atherosclerotic cardiovascular disease. Atorvastatin calcium can significantly reduce the risk of morbidity and mortality from atherosclerotic cardiovascular disease by lowering low-density lipoprotein cholesterol in the blood.

[0004] Ezetimibe is the first and only cholesterol absorption inhibitor that selectively inhibits cholesterol transport proteins in the small intestine, effectively reducing cholesterol absorption in the intestine and lowering plasma cholesterol levels and liver cholesterol reserves. As an adjunct therapy in addition to dietary control, ezetimibe can be used alone or in combination with HMG-CoA reductase inhibitors (statins) to treat primary (heterozygous familial or non-familial) hypercholesterolemia, lowering total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B).

[0005] Numerous studies have found that the combination therapy of ezetimibe and atorvastatin calcium has excellent therapeutic effects. The combination tablets containing ezetimibe and atorvastatin calcium were developed by Merck to lower total cholesterol levels and increase high-density lipoprotein cholesterol levels. Since the two drugs have different mechanisms of action, the combination formulation offers greater efficacy and a broader market prospect.

[0006] However, during the development of the compound formulation, the inventors unexpectedly discovered that there is an interaction between ezetimibe and atorvastatin calcium. Ezetimibe accelerates the degradation of atorvastatin calcium, which requires an alkaline stabilizer (such as calcium hydrogen phosphate) to remain stable. The alkaline stabilizer accelerates the degradation of ezetimibe. Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide a formulation comprising ezetimibe and atorvastatin calcium, and a method for preparing the same. This invention not only avoids the need for adding alkalinity regulators but also improves its stability.

[0008] To achieve the above objectives, the technical solution of the present invention is as follows:

[0009] On one hand, a formulation comprising ezetimibe and atorvastatin calcium, comprising a bilayer tablet formed by an ezetimibe layer and an atorvastatin calcium layer, wherein the ezetimibe layer is composed of ezetimibe and a first excipient, and the atorvastatin calcium layer is composed of atorvastatin calcium and a second excipient; the second excipient is free of an alkaline stabilizer, and kaolin is used as a filler in the second excipient.

[0010] This invention first prepares ezetimibe and atorvastatin calcium into two layers using excipients to minimize contact between them, thereby reducing their interaction. Simultaneously, to address the issue that alkaline substances like calcium hydrogen phosphate cannot simultaneously guarantee the stability of both ezetimibe and atorvastatin calcium, kaolin is used as a filler in the atorvastatin calcium layer. Experiments have shown that adding kaolin as a filler to the atorvastatin calcium layer ensures the stability of atorvastatin calcium without adversely affecting the stability of ezetimibe, thus avoiding the need for alkalinity modifiers and improving overall stability.

[0011] This invention has found that by using a double-layer tablet structure and employing kaolin as a filler in the atorvastatin calcium layer, the addition of an alkalinity regulator can be avoided, thus improving the stability of ezetimibe and atorvastatin calcium. However, the uniformity is related to the mass ratio of the ezetimibe layer to the atorvastatin calcium layer. In some embodiments, the mass ratio of the ezetimibe layer to the atorvastatin calcium layer is 2:1 to 8. Studies have shown that under these conditions, better uniformity of the formulation can be ensured.

[0012] Studies have shown that, based on the above-mentioned methods, the particle size of ezetimibe affects its dissolution rate. In some embodiments, the particle size of ezetimibe is: 5μm≤D 90 ≤60μm. Under these conditions, the dissolution rate of ezetimibe is more suitable. D 90 This indicates the particle size at which the cumulative particle size distribution number (CPD) of a sample reaches 90%. Physically, it means that 90% of the particles are smaller (or larger) than this value.

[0013] Studies have shown that, based on the above-mentioned methods, the particle size of atorvastatin calcium affects its dissolution. In some embodiments, the particle size of atorvastatin calcium is: 5μm≤D 90 ≤60μm. Under these conditions, the dissolution rate of atorvastatin calcium is more suitable.

[0014] In some embodiments, the first excipient comprises one or more of lactose monohydrate, microcrystalline cellulose, povidone, crostomeric sodium carboxymethyl cellulose, sodium lauryl sulfate, and magnesium stearate. When lactose monohydrate, microcrystalline cellulose, povidone, crostomeric sodium carboxymethyl cellulose, sodium lauryl sulfate, and magnesium stearate are added simultaneously, their mass ratio is 60–100:60–100:8–12:6–12:8–10:2. Specifically, in the ezetimibe layer, the weight percentage of lactose monohydrate can be 30–50%; the weight percentage of microcrystalline cellulose can be 30–50%; the weight percentage of povidone can be 4–6%; the weight percentage of crostomeric sodium carboxymethyl cellulose can be 3–6%; the weight percentage of sodium lauryl sulfate can be 4–5%; and the weight percentage of magnesium stearate can be 0.9–1.1%.

[0015] In some embodiments, the second excipient further includes one or more of microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. When microcrystalline cellulose, croscarmellose sodium, and magnesium stearate are added simultaneously, their mass ratio is 13–39:3–9:1.5–3.5. In the atorvastatin calcium layer, the weight percentage of microcrystalline cellulose can be 13–39%; the weight percentage of croscarmellose sodium can be 3–9%; and the weight percentage of magnesium stearate can be 1.5–3.5%.

[0016] In some embodiments, the weight content of ezetimibe in the ezetimibe layer is 4-6%, more preferably 4.5-5.5%, and even more preferably 4.9-5.1%.

[0017] In some embodiments, the atorvastatin calcium layer contains 8-19% by weight, more preferably 10-11%, and even more preferably 10.80-10.95% by weight.

[0018] In some embodiments, the kaolin content in the atorvastatin calcium layer is 38–70% by weight, more specifically 43–61%.

[0019] On the other hand, a method for preparing the above-mentioned formulation comprising ezetimibe and atorvastatin calcium includes the following steps:

[0020] Ezetimibe is mixed evenly with the first excipient to obtain ezetimibe layer particles;

[0021] Atorvastatin calcium is mixed evenly with the second excipient to obtain atorvastatin calcium layer particles;

[0022] The tablets are prepared by double-compressing ezetimibe layer particles and atorvastatin calcium layer particles.

[0023] In this invention, the double-layer tablets can be obtained by directly pressing them using a double-layer tablet press.

[0024] In some embodiments, during the preparation of the ezetimibe layer particles, ezetimibe, lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and sodium lauryl sulfate are mixed together, a binder is added, and wet granulation is performed. The granules are then dried, sized, and finally mixed with magnesium stearate to obtain the final product. Ezetimibe layer particles prepared in this manner exhibit better uniformity.

[0025] In some embodiments, during the preparation of the atorvastatin calcium layer particles, atorvastatin calcium, kaolin, microcrystalline cellulose, croscarmellose sodium, and a portion of magnesium stearate are mixed, and then dry granulation is performed. The granulated particles are then mixed with the remaining magnesium stearate to obtain the final product. Ezetimibe layer particles prepared in this manner exhibit better uniformity.

[0026] In some embodiments, the tablets are coated with a film coating premix after bilayer compression.

[0027] The beneficial effects of this invention are as follows:

[0028] 1. The formulation containing ezetimibe and atorvastatin calcium provided by the present invention is made into a double-layer tablet, which reduces the contact between ezetimibe and atorvastatin calcium; at the same time, kaolin is used as a filler in the atorvastatin calcium layer, which can ensure the stability of atorvastatin calcium without promoting the degradation of ezetimibe.

[0029] 2. In the formulation containing ezetimibe and atorvastatin calcium provided by the present invention, the weight ratio of the ezetimibe layer to the atorvastatin calcium layer is 2:1 to 8. Using this weight ratio to prepare bilayer tablets can ensure that the weight difference between each layer is minimal, the contact area between the two layers is minimal, and the mutual interference between the two layers is reduced.

[0030] 3. In the formulation containing ezetimibe and atorvastatin calcium provided by the present invention, the particle size D of ezetimibe and atorvastatin calcium is... 90 With a particle size of ≤60μm, this particle size ensures both the uniformity of material mixing and the rapid dissolution of tablets.

[0031] 4. The formulation containing ezetimibe and atorvastatin calcium provided by the present invention exhibits overall stable formulation quality, with no significant changes in dissolution and related substances during long-term storage. Detailed Implementation

[0032] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments and comparative examples.

[0033] Example 1:

[0034] Table 1. Formula for Izzy Wheat Bloal Layer

[0035] <![CDATA[Ezetimibe (D 90 = 58 μm)]]> 10 Lactose monohydrate 80 microcrystalline cellulose 80 Sodium croscarmellose 10 Povidone 10 Sodium dodecyl sulfate 8 magnesium stearate 2 total 200

[0036] Ezetimibe, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate were mixed evenly according to the formula ratio in Table 1. The mixture was then granulated, dried, and sized using a prepared 50% concentration of povidone solution. Magnesium stearate was added and mixed evenly to obtain ezetimibe layer granules.

[0037] Table 2 Atorvastatin Calcium Layer Prescription

[0038] <![CDATA[Atorvastatin Calcium (D 90 90 10.9 White clay 43.1 microcrystalline cellulose 39 Sodium croscarmellose 5 magnesium stearate 2 total 100

[0039] Atorvastatin calcium, kaolin, microcrystalline cellulose, croscarmellose sodium, and 1 / 2 of the prescribed amount of magnesium stearate were mixed according to the formulation ratio in Table 2, and then dry granulated. The remaining magnesium stearate was then added and mixed evenly to obtain atorvastatin calcium layer granules.

[0040] Ezetamib granules and atorvastatin calcium granules were added to different feeders of a double-layer tablet press and pressed into double-layer tablets. Then, the tablets were coated with a film coating premix to obtain the double-layer tablets of Example 1.

[0041] Example 2:

[0042] Table 3. Formula for Izzy Wheat Bloal Layer

[0043] <![CDATA[Ezetimibe (D 90 = 36 μm)]]> 10 Lactose monohydrate 100 microcrystalline cellulose 60 Sodium croscarmellose 8 Povidone 12 Sodium dodecyl sulfate 8 magnesium stearate 2 total 200

[0044] According to the formulation ratio in Table 3, ezetimibe, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and sodium dodecyl sulfate are mixed evenly, granulated, dried, and sized with a prepared 50% concentration of povidone solution, and magnesium stearate is added and mixed evenly to obtain ezetimibe layer granules.

[0045] Table 4 Atorvastatin Calcium Layer Prescription

[0046] <![CDATA[Atorvastatin Calcium (D 90 = 35 μm)]]> 21.7 White clay 111.1 microcrystalline cellulose 55.2 Sodium croscarmellose 8 magnesium stearate 4 total 200

[0047] Atorvastatin calcium, kaolin, microcrystalline cellulose, croscarmellose sodium, and 1 / 2 of the prescribed amount of magnesium stearate were mixed according to the formulation ratio in Table 4, and then dry granulated. The remaining magnesium stearate was then added and mixed evenly to obtain atorvastatin calcium layer granules.

[0048] Ezetamib granules and atorvastatin calcium granules were added to different feeders of a double-layer tablet press and pressed into double-layer tablets. Then, the tablets were coated with a film coating premix to obtain the double-layer tablets of Example 2.

[0049] Example 3:

[0050] Table 5. Formula based on folded wheat layer

[0051] <![CDATA[Ezetimibe (D 90 = 18 μm)]]> 10 Lactose monohydrate 70 microcrystalline cellulose 90 Sodium croscarmellose 12 Povidone 8 Sodium dodecyl sulfate 8 magnesium stearate 2 total 200

[0052] According to the formulation ratio in Table 5, ezetimibe, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate are mixed evenly, granulated, dried, and sized with a prepared 50% concentration of povidone solution, and magnesium stearate is added and mixed evenly to obtain ezetimibe layer granules.

[0053] Table 6 Atorvastatin Calcium Layer Prescription

[0054] <![CDATA[Atorvastatin Calcium (D 90 = 19 μm)]]> 43.4 White clay 240.6 microcrystalline cellulose 90 Sodium croscarmellose 18 magnesium stearate 8 total 400

[0055] Atorvastatin calcium, kaolin, microcrystalline cellulose, croscarmellose sodium, and 1 / 2 of the prescribed amount of magnesium stearate were mixed according to the formulation ratio in Table 6, and then dry granulated. The remaining magnesium stearate was then added and mixed evenly to obtain atorvastatin calcium layer granules.

[0056] Ezetamib granules and atorvastatin calcium granules were added to different feeders of a double-layer tablet press and pressed into double-layer tablets. Then, the tablets were coated with a film coating premix to obtain the double-layer tablets of Example 3.

[0057] Example 4:

[0058] Table 7 Prescriptions based on folded wheat layer

[0059] <![CDATA[Ezetimibe (D 90 = 7 μm)]]> 10 Lactose monohydrate 60 microcrystalline cellulose 100 Sodium croscarmellose 12 Povidone 6 Sodium dodecyl sulfate 10 magnesium stearate 2 total 200

[0060] According to the formula ratio in Table 7, ezetimibe, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and sodium dodecyl sulfate are mixed evenly, granulated, dried, and sized with a prepared 50% concentration of povidone solution, and magnesium stearate is added and mixed evenly to obtain ezetimibe layer granules.

[0061] Table 8 Atorvastatin Calcium Layer Prescription

[0062] <![CDATA[Atorvastatin Calcium (D 90 = 6 μm)]]> 86.8 White clay 560 microcrystalline cellulose 105.2 Sodium croscarmellose 32 magnesium stearate 16 total 800

[0063] Atorvastatin calcium, kaolin, microcrystalline cellulose, croscarmellose sodium, and 1 / 2 of the prescribed amount of magnesium stearate were mixed according to the formulation ratio in Table 8, and then dry granulated. The remaining magnesium stearate was then added and mixed evenly to obtain atorvastatin calcium layer granules.

[0064] Ezetamib granules and atorvastatin calcium granules were added to different feeders of a double-layer tablet press and pressed into double-layer tablets. Then, the tablets were coated with a film coating premix to obtain the double-layer tablets of Example 4.

[0065] Comparative Example 1:

[0066] Table 9. Formula based on folded wheat layer

[0067] <![CDATA[Ezetimibe (D 90 = 28 μm)]]> 10 Lactose monohydrate 70 microcrystalline cellulose 90 Sodium croscarmellose 10 Povidone 10 Sodium dodecyl sulfate 8 magnesium stearate 2 total 200

[0068] According to the formula ratio in Table 9, ezetimibe, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate are mixed evenly, granulated, dried, and sized with a prepared 50% concentration of povidone solution, and magnesium stearate is added and mixed evenly to obtain ezetimibe layer granules.

[0069] Table 10 Atorvastatin Calcium Layer Prescription

[0070] <![CDATA[Atorvastatin Calcium (D 90 = 25 μm)]]> 10.9 White clay 23 microcrystalline cellulose 19.1 Sodium croscarmellose 5 magnesium stearate 2 total 60

[0071] Atorvastatin calcium, kaolin, microcrystalline cellulose, croscarmellose sodium, and 1 / 2 of the prescribed amount of magnesium stearate were mixed according to the formulation ratio in Table 10, and then dry granulated. The remaining magnesium stearate was then added and mixed evenly to obtain atorvastatin calcium layer granules.

[0072] Ezetamib granules and atorvastatin calcium granules were added to different feeders of a double-layer tablet press and pressed into double-layer tablets. Then, the tablets were coated with a film coating premix to obtain the double-layer tablets of Comparative Example 1.

[0073] Comparative Example 2:

[0074] Table 11 Prescriptions based on zebu layer

[0075] <![CDATA[Ezetimibe (D 90 = 18 μm)]]> 10 Lactose monohydrate 90 microcrystalline cellulose 70 Sodium croscarmellose 12 Povidone 6 Sodium dodecyl sulfate 10 magnesium stearate 2 total 200

[0076] According to the formula ratio in Table 11, ezetimibe, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and sodium dodecyl sulfate are mixed evenly, granulated, dried, and sized with a prepared 50% concentration of povidone solution, and magnesium stearate is added and mixed evenly to obtain ezetimibe layer granules.

[0077] Table 12 Atorvastatin Calcium Layer Prescription

[0078] <![CDATA[Atorvastatin Calcium (D 90 = 16 μm)]]> 86.8 White clay 660 microcrystalline cellulose 205.2 Sodium croscarmellose 32 magnesium stearate 16 total 1000

[0079] Atorvastatin calcium, kaolin, microcrystalline cellulose, croscarmellose sodium, and 1 / 2 of the prescribed amount of magnesium stearate were mixed according to the formulation ratio in Table 12, and then dry granulated. The remaining magnesium stearate was then added and mixed evenly to obtain atorvastatin calcium layer granules.

[0080] Ezetamib granules and atorvastatin calcium granules were added to different feeders of a double-layer tablet press and pressed into double-layer tablets. Then, the tablets were coated with a film coating premix to obtain the double-layer tablets of Comparative Example 2.

[0081] Comparative Example 3:

[0082] Table 13 Prescriptions based on folded wheat layer

[0083] <![CDATA[Ezetimibe (D 90 = 86 μm)]]> 10 Lactose monohydrate 80 microcrystalline cellulose 80 Sodium croscarmellose 10 Povidone 10 Sodium dodecyl sulfate 8 magnesium stearate 2 total 200

[0084] According to the formula ratio in Table 13, ezetimibe, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and sodium dodecyl sulfate are mixed evenly, granulated, dried, and sized with a prepared 50% concentration of povidone solution, and magnesium stearate is added and mixed evenly to obtain ezetimibe layer granules.

[0085] Table 14 Atorvastatin Calcium Layer Prescription

[0086] <![CDATA[Atorvastatin Calcium (D 90 = 88 μm)]]> 43.4 White clay 210.6 microcrystalline cellulose 120 Sodium croscarmellose 18 magnesium stearate 8 total 400

[0087] Atorvastatin calcium, kaolin, microcrystalline cellulose, croscarmellose sodium, and 1 / 2 of the prescribed amount of magnesium stearate were mixed according to the formulation ratio in Table 14, and then dry-granulated. The remaining magnesium stearate was then added and mixed evenly to obtain atorvastatin calcium layer granules.

[0088] Ezetamib granules and atorvastatin calcium granules were added to different feeders of a double-layer tablet press and pressed into double-layer tablets. Then, the tablets were coated with a film coating premix to obtain the double-layer tablets of Comparative Example 3.

[0089] Comparative Example 4:

[0090] Table 15 Prescriptions based on folded malt layer

[0091] <![CDATA[Ezetimibe (D 90 = 26 μm)]]> 10 Lactose monohydrate 90 microcrystalline cellulose 70 Sodium croscarmellose 10 Povidone 10 Sodium dodecyl sulfate 8 magnesium stearate 2 total 200

[0092] Ezetimibe, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate were mixed evenly according to the formulation ratio in Table 15. The mixture was then granulated, dried, and sized using a prepared 50% concentration of povidone solution. Magnesium stearate was added and mixed evenly to obtain ezetimibe layer granules.

[0093] Table 16 Atorvastatin Calcium Layer Prescription

[0094] <![CDATA[Atorvastatin Calcium (D 90 = 28 μm)]]> 21.7 Lactose monohydrate 106 microcrystalline cellulose 60.3 Sodium croscarmellose 8 magnesium stearate 4 total 200

[0095] Atorvastatin calcium, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and 1 / 2 of the prescribed amount of magnesium stearate were mixed according to the formulation ratio in Table 16, and then dry-granulated. The remaining magnesium stearate was then added and mixed evenly to obtain atorvastatin calcium layer granules.

[0096] Ezetamib granules and atorvastatin calcium granules were added to different feeders of a double-layer tablet press and pressed into double-layer tablets. Then, the tablets were coated with a film coating premix to obtain the double-layer tablets of Comparative Example 4.

[0097] Comparative Example 5:

[0098] Table 17 Prescriptions based on folded wheat layer

[0099] <![CDATA[Ezetimibe (D 90 = 26 μm)]]> 10 Lactose monohydrate 85 microcrystalline cellulose 75 Sodium croscarmellose 8 Povidone 10 Sodium dodecyl sulfate 10 magnesium stearate 2 total 200

[0100] According to the formula ratio in Table 17, ezetimibe, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate are mixed evenly, granulated, dried, and sized with a prepared 50% concentration of povidone solution, and magnesium stearate is added and mixed evenly to obtain ezetimibe layer granules.

[0101] Table 18 Atorvastatin Calcium Layer Prescription

[0102] <![CDATA[Atorvastatin Calcium (D 90 = 28 μm)]]> 21.7 Pregelatinized starch 106.3 microcrystalline cellulose 60 Sodium croscarmellose 8 magnesium stearate 4 total 200

[0103] Atorvastatin calcium, pregelatinized starch, microcrystalline cellulose, croscarmellose sodium, and 1 / 2 of the prescribed amount of magnesium stearate were mixed according to the formulation ratio in Table 18, and then dry-granulated. The remaining magnesium stearate was then added and mixed evenly to obtain atorvastatin calcium layer granules.

[0104] Ezetamib granules and atorvastatin calcium granules were added to different feeders of a double-layer tablet press and pressed into double-layer tablets. Then, the tablets were coated with a film coating premix to obtain the double-layer tablets of Comparative Example 5.

[0105] Comparative Example 6:

[0106] Table 19 Prescriptions based on folded wheat layer

[0107] <![CDATA[Ezetimibe (D 90 = 26 μm)]]> 10 Lactose monohydrate 95 microcrystalline cellulose 65 Sodium croscarmellose 9 Povidone 10 Sodium dodecyl sulfate 9 magnesium stearate 2 total 200

[0108] According to the formula ratio in Table 19, ezetimibe, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate are mixed evenly, granulated, dried, and sized with a prepared 50% concentration of povidone solution, and magnesium stearate is added and mixed evenly to obtain ezetimibe layer granules.

[0109] Table 20 Atorvastatin Calcium Layer Prescription

[0110] <![CDATA[Atorvastatin Calcium (D 90 = 28 μm)]]> 21.7 Calcium hydrogen phosphate 101.3 microcrystalline cellulose 65 Sodium croscarmellose 8 magnesium stearate 4 total 200

[0111] Atorvastatin calcium, calcium hydrogen phosphate, microcrystalline cellulose, croscarmellose sodium, and 1 / 2 of the prescribed amount of magnesium stearate were mixed according to the formulation ratio in Table 20, and then dry granulated. The remaining magnesium stearate was then added and mixed evenly to obtain atorvastatin calcium layer granules.

[0112] Ezetamib granules and atorvastatin calcium granules were added to different feeders of a double-layer tablet press and pressed into double-layer tablets. Then, the tablets were coated with a film coating premix to obtain the double-layer tablets of Comparative Example 6.

[0113] Experimental Example

[0114] Take 600 tablets each of Ezetimibe and Atorvastatin Calcium Tablets from Examples 1-4 and Comparative Examples 1-6, place them in petri dishes, and put them in an accelerated testing chamber (40℃ / RH75%). Take samples at 15 days and 30 days to examine dissolution, content uniformity, and related substances. The results are shown in Tables 1 and 2.

[0115] Dissolution method: paddle method, rotation speed: 75 rpm, volume: 900 mL, dissolution medium: pH 6.8 phosphate buffer + 0.2% Tween 80, sampling time: 30 min.

[0116] Table 21 Dissolution rate, content uniformity, and related material data of ezetimibe / atorvastatin calcium tablets in Examples 1-4

[0117]

[0118]

[0119] Table 22 Comparative Examples 1–6: Dissolution and related substances data of ezetimibe / atorvastatin calcium tablets

[0120]

[0121]

[0122] Table 21 shows that, under accelerated conditions, the content uniformity of the products in Examples 1-4 all met the requirements (A+2.2S≤15), the dissolution rate at 30 min was greater than 80%, related substances showed no significant change, the maximum single impurity was less than 0.2%, and the total impurity was less than 1.5%. Table 22 shows that, in Comparative Examples 1 and 2, when the weight ratio of the ezetimibe layer and the atorvastatin calcium layer was 1:0.3 and 1:5 respectively, the content uniformity (A+2.2S) was greater than 15, exceeding the specified range. In Comparative Example 3, when the particle size of the ezetimibe and atorvastatin calcium exceeded 60 micrometers, the dissolution rate of both ezetimibe and atorvastatin calcium decreased significantly, both being less than 80%. In Comparative Examples 4 and 5, the atorvastatin calcium layer used commonly used lactose monohydrate and pregelatinized starch as fillers, resulting in a significant increase in related substances during preparation. After 30 days under accelerated conditions, the increase in related substances was significant, far exceeding the specified limits. In Comparative Example 6, the atorvastatin calcium layer used the commonly used alkaline filler, calcium hydrogen phosphate. Related substances were significantly reduced compared to when lactose and pregelatinized starch were used; however, ezetimibe impurities increased significantly during accelerated storage. In summary, the ezetimibe-atorvastatin calcium tablets prepared by this invention are highly stable. During the preparation process and stable storage, dissolution rate, content uniformity, and related substances did not change significantly, demonstrating excellent quality stability and suitability for industrial production.

[0123] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A formulation comprising ezetimibe and atorvastatin calcium, characterized in that, A bilayer tablet is formed by an ezetimibe layer and an atorvastatin calcium layer, wherein the ezetimibe layer is composed of ezetimibe and a first excipient, and the atorvastatin calcium layer is composed of atorvastatin calcium and a second excipient; the second excipient does not contain an alkaline stabilizer, and kaolin is used as a filler in the second excipient; The particle size of ezetimibe is: 5μm≤D 90 ≤60μm; Atorvastatin calcium has a particle size of 5μm ≤ D. 90 ≤60μm; In the ezetimibe layer, the weight content of ezetimibe is 4-6%; The atorvastatin calcium content in the atorvastatin calcium layer is 8-19% by weight; The second excipient also includes microcrystalline cellulose, croscarmellose sodium, and magnesium stearate in a mass ratio of 13–39:3–9:1.5–3.5; in the atorvastatin calcium layer, the weight percentage of microcrystalline cellulose is 13–39%, the weight percentage of croscarmellose sodium is 3–9%, the weight percentage of magnesium stearate is 1.5–3.5%, and the weight percentage of kaolin is 38–70%. The weight ratio of ezetimibe layer to atorvastatin calcium layer is 2:1 to 8.

2. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 1, characterized in that, The first excipient includes one or more of lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, sodium dodecyl sulfate, and magnesium stearate.

3. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 2, characterized in that, The mass ratio of added lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, sodium dodecyl sulfate, and magnesium stearate is 60~100:60~100:8~12:6~12:8~10:

2.

4. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 2, characterized in that, The weight percentage of lactose monohydrate in the ezetimibe layer is 30-50%.

5. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 2, characterized in that, In the ezetimibe layer, the weight percentage of microcrystalline cellulose is 30-50%.

6. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 2, characterized in that, In the ezetimibe layer, the weight percentage of povidone is 4-6%.

7. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 2, characterized in that, In the ezetimibe layer, the weight percentage of cross-linked sodium carboxymethyl cellulose is 3-6%.

8. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 2, characterized in that, The weight percentage of sodium dodecyl sulfate in the ezetimibe layer is 4-5%.

9. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 2, characterized in that, The weight percentage of magnesium stearate in the ezetimibe layer is 0.9-1.1%.

10. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 1, characterized in that, The weight content of ezetimibe in the ezetimibe layer is 4.5-5.5%.

11. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 10, characterized in that, The weight content of ezetimibe in the ezetimibe layer is 4.9-5.1%.

12. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 1, characterized in that, The atorvastatin calcium content in the atorvastatin calcium layer is 10-11% by weight.

13. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 12, characterized in that, The atorvastatin calcium content in the atorvastatin calcium layer is 10.80~10.95% by weight.

14. The formulation comprising ezetimibe and atorvastatin calcium as described in claim 1, characterized in that, In the atorvastatin calcium layer, the weight content of kaolin is 43-61%.

15. A method for preparing a formulation comprising ezetimibe and atorvastatin calcium as described in any one of claims 1 to 14, characterized in that, Includes the following steps: Ezetimibe is mixed evenly with the first excipient to obtain ezetimibe layer particles; Atorvastatin calcium is mixed evenly with the second excipient to obtain atorvastatin calcium layer particles; The tablets are prepared by double-compressing ezetimibe layer particles and atorvastatin calcium layer particles.

16. The method for preparing the formulation comprising ezetimibe and atorvastatin calcium as described in claim 15, characterized in that, In the preparation process of the ezetimibe layer particles, ezetimibe, lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and sodium lauryl sulfate are mixed together, a binder is added for wet granulation, drying, granulation, and then magnesium stearate is added and mixed to obtain the final product.

17. The method for preparing the formulation comprising ezetimibe and atorvastatin calcium as described in claim 15, characterized in that, In the preparation process of the atorvastatin calcium layer particles, atorvastatin calcium, kaolin, microcrystalline cellulose, croscarmellose sodium and part of magnesium stearate are mixed and then dry granulated. The granulated particles are then mixed with the remaining magnesium stearate to obtain the final product.

18. The method for preparing the formulation comprising ezetimibe and atorvastatin calcium as described in claim 15, characterized in that, After double-layer compression, a film coating premix is ​​used for coating.

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