Compound ezetimibe rosuvastatin calcium tablet and preparation method thereof

Abstract

The invention provides a compound ezetimibe and rosuvastatin calcium tablet and a preparation method thereof.The preparation method comprises the steps that ezetimibe particles are prepared through a wet granulation method, rosuvastatin calcium particles are obtained through direct mixing, then the ezetimibe particles serve as a first layer, the rosuvastatin calcium particles serve as a second layer, an upper-layer tablet and a lower-layer tablet are prepared through a double-layer tablet press, and the upper-layer tablet and the lower-layer tablet are coated to obtain the compound ezetimibe and rosuvastatin calcium tablet. The compound ezetimibe rosuvastatin calcium tablet has the advantages of being stable in content, good in quality, high in stability and the like. The whole preparation method is simple, efficient, cost-saving and more suitable for commercial batch production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a compound ezetimibe and rosuvastatin calcium tablet and a preparation method thereof. Background Art

[0002] Hyperlipidemia is one of the main causes of coronary heart disease and stroke. With the aging of my country's population and the improvement of living standards, the number of patients with hyperlipidemia is also increasing.

[0003] The combined use of ezetimibe and rosuvastatin calcium can more effectively treat hyperlipidemia. Ezetimibe has poor solubility and rosuvastatin calcium has poor stability. The combined preparation of the two can solve the solubility problem of ezetimibe and the stability problem of rosuvastatin calcium.

[0004] CN1002451161A discloses an embodiment of preparing dispersible tablets of ezetimibe and rosuvastatin, but ezetimibe and rosuvastatin are not granulated separately, resulting in an effect of ezetimibe on rosuvastatin, an increase in related substances, and failure to ensure the stability of rosuvastatin.

[0005] CN102357096A discloses a compound preparation of ezetimibe and rosuvastatin, which is characterized in that rosuvastatin granules are first prepared, ezetimibe is then added, and finally the granules are compressed into tablets. Although the former can effectively control the interference of ezetimibe on rosuvastatin, after being compressed into tablets together, a part of rosuvastatin enters the ezetimibe layer under the action of strong pressure. The internal environment of the ezetimibe layer, such as pH value and auxiliary material components, is different from that of the rosuvastatin layer, resulting in a significant increase in rosuvastatin-related substances in this part.

[0006] CN107028906A discloses a compound preparation with ezetimibe and rosuvastatin as active ingredients, which is characterized in that ezetimibe and rosuvastatin calcium are granulated and coated separately and then tableted, thereby ensuring the stability of the two drugs. However, this method requires granulation and coating of the two ingredients, and the process is relatively complicated.

[0007] CN201310567999 discloses a method for preparing a double-layer tablet with ezetimibe and rosuvastatin as active ingredients, which is characterized in that the raw material of the ezetimibe layer is micronized and then wet granulated, and the rosuvastatin layer is prepared by wet granulation and tableted using a double-layer tablet press. This method solves the mutual influence between ezetimibe and rosuvastatin, but rosuvastatin is wet-instable, and wet granulation causes a significant increase in related substances in the rosuvastatin layer.

[0008] CN201980020077 discloses a combination preparation with ezetimibe and rosuvastatin as active ingredients, wherein the ezetimibe layer is fluidized bed granulated, and the rosuvastatin layer is dry granulated, and then a double-layer tablet press is used to press the two drugs into double-layer tablets. This method ensures the stability of the two drugs and solves the problem of related substances of the wet instability of the rosuvastatin layer. However, this method requires two complex granulation methods, fluidized bed granulation and dry granulation. The process is relatively complex and time-consuming, and is not easy to mass produce.

[0009] Therefore, it is very necessary to invent a process that can solve the problems of ezetimibe solubility and rosuvastatin stability and is easy to produce. Summary of the invention

[0010] The purpose of the present invention is to prepare ezetimibe granules by a wet granulation method on the basis of the existing technology, directly mix them to obtain rosuvastatin calcium granules, then use the ezetimibe granules as the first layer and the rosuvastatin calcium granules as the second layer, use a double-layer tablet press to obtain upper and lower layer tablets, and coat them to prepare compound ezetimibe and rosuvastatin calcium tablets, which have the advantages of stable content, good quality, high stability, etc.

[0011] Another object of the present invention is to provide a method for preparing the above-mentioned compound ezetimibe and rosuvastatin calcium tablets. The entire preparation method is simple, efficient and cost-saving, and is more suitable for commercial batch production.

[0012] The technical solution of the present invention is as follows:

[0013] A compound ezetimibe and rosuvastatin calcium tablet comprises a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, wherein the ezetimibe granules are used as the first layer, and the tablet comprises the following components: ezetimibe, a filler, a disintegrant, a binder, a solubilizer and a lubricant, wherein the preparation method of the ezetimibe granules is: firstly, the ezetimibe, the filler and the disintegrant are uniformly mixed, and then, wet granulation is performed with an aqueous solution containing a binder and a solubilizer, and after drying the whole granules, a lubricant is added and mixed uniformly, thereby obtaining the tablet; and rosuvastatin calcium granules are used as the second layer, and the tablet comprises the following components: rosuvastatin calcium, a filler, a glidant and a lubricant, wherein the preparation method of the rosuvastatin calcium granules is: directly and uniformly mixing rosuvastatin calcium, a filler, a disintegrant, a glidant and a lubricant, thereby obtaining the tablet.

[0014] For the present invention, the filler is one or more of lactose, mannitol, microcrystalline cellulose or corn starch, preferably lactose and microcrystalline cellulose; the disintegrant is one or more of cross-linked carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, and cross-linked polyvinylpyrrolidone, preferably cross-linked carboxymethyl cellulose sodium; the binder is one or more of povidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose, preferably povidone; the solubilizer is one or more of sodium lauryl sulfate, Tween 80 or poloxamer, preferably sodium lauryl sulfate; the lubricant is one or more of magnesium stearate, sodium stearyl fumarate or calcium stearate, preferably magnesium stearate; and the glidant is colloidal silicon dioxide.

[0015] In one embodiment, for the present invention, the ezetimibe granules include the following components in parts by weight: 10 parts of ezetimibe, 145-155 parts of lactose, 10-30 parts of microcrystalline cellulose, 5-25 parts of cross-linked sodium carboxymethyl cellulose, 4-12 parts of povidone, 3-5 parts of sodium lauryl sulfate, and 1-3 parts of magnesium stearate.

[0016] In a preferred embodiment, for the present invention, the ezetimibe granules include the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 14-26 parts of microcrystalline cellulose, 10-22 parts of cross-linked sodium carboxymethyl cellulose, 6-10 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate.

[0017] In a more preferred embodiment, for the present invention, the ezetimibe granules include the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 22 parts of microcrystalline cellulose, 16 parts of cross-linked sodium carboxymethyl cellulose, 6 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate;

[0018] 10 parts of ezetimibe, 150 parts of lactose, 20 parts of microcrystalline cellulose, 16 parts of croscarmellose sodium, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate;

[0019] 10 parts of ezetimibe, 150 parts of lactose, 18 parts of microcrystalline cellulose, 16 parts of cross-linked carboxymethyl cellulose sodium, 10 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate;

[0020] 10 parts of ezetimibe, 150 parts of lactose, 26 parts of microcrystalline cellulose, 10 parts of cross-linked carboxymethyl cellulose sodium, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate;

[0021] 10 parts of ezetimibe, 150 parts of lactose, 14 parts of microcrystalline cellulose, 22 parts of cross-linked carboxymethyl cellulose sodium, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate.

[0022] In one embodiment, for the present invention, the rosuvastatin calcium granules include the following components in parts by weight: 10 parts of rosuvastatin calcium, 55-65 parts of lactose, 12-16 parts of microcrystalline cellulose, 3-5 parts of cross-linked sodium carboxymethyl cellulose, 0.5-1.5 parts of colloidal silicon dioxide, and 0.5-1.5 parts of magnesium stearate.

[0023] In a preferred embodiment, for the present invention, the rosuvastatin calcium granules include the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate.

[0024] For example, for the compound ezetimibe rosuvastatin calcium tablets provided by the present invention, it includes a double-layer tablet obtained by double-layer tableting of ezetimibe granules and rosuvastatin calcium granules, with ezetimibe granules as the first layer, including the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 22 parts of microcrystalline cellulose, 16 parts of cross-linked carboxymethyl cellulose sodium, 6 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; rosuvastatin calcium granules as the second layer, including the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked carboxymethyl cellulose sodium, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate. Wherein, the mass ratio of ezetimibe to rosuvastatin calcium is 1:1 during tableting.

[0025] For example, for the compound ezetimibe rosuvastatin calcium tablets provided by the present invention, it includes a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, with ezetimibe granules as the first layer, including the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 20 parts of microcrystalline cellulose, 16 parts of cross-linked carboxymethyl cellulose sodium, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; rosuvastatin calcium granules as the second layer, including the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked carboxymethyl cellulose sodium, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate. Wherein, the mass ratio of ezetimibe to rosuvastatin calcium is 1:1 during tableting.

[0026] For example, for the compound ezetimibe rosuvastatin calcium tablets provided by the present invention, it includes a double-layer tablet obtained by double-layer tableting of ezetimibe granules and rosuvastatin calcium granules, with ezetimibe granules as the first layer, including the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 18 parts of microcrystalline cellulose, 16 parts of cross-linked carboxymethyl cellulose sodium, 10 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; rosuvastatin calcium granules as the second layer, including the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked carboxymethyl cellulose sodium, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate. Wherein, the mass ratio of ezetimibe to rosuvastatin calcium is 1:1 during tableting.

[0027] For example, for the compound ezetimibe rosuvastatin calcium tablets provided by the present invention, it includes a double-layer tablet obtained by double-layer tableting of ezetimibe granules and rosuvastatin calcium granules, with ezetimibe granules as the first layer, including the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 26 parts of microcrystalline cellulose, 10 parts of cross-linked carboxymethyl cellulose sodium, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; rosuvastatin calcium granules as the second layer, including the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked carboxymethyl cellulose sodium, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate. Wherein, the mass ratio of ezetimibe to rosuvastatin calcium is 1:1 during tableting.

[0028] For example, for the compound ezetimibe and rosuvastatin calcium tablets provided by the present invention, it includes a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, with ezetimibe granules as the first layer, including the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 14 parts of microcrystalline cellulose, 22 parts of cross-linked carboxymethyl cellulose sodium, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; rosuvastatin calcium granules as the second layer, including the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked carboxymethyl cellulose sodium, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate. Wherein, the mass ratio of ezetimibe to rosuvastatin calcium is 1:1 during tableting.

[0029] The present invention also provides a method for preparing the above-mentioned compound ezetimibe and rosuvastatin calcium tablets, comprising the following steps:

[0030] (1) Preparation of ezetimibe granules: ezetimibe is mixed with a filler and a disintegrant, and then wet granulated with an aqueous solution containing a binder and a solubilizer. After drying the granules, a lubricant is added and mixed to obtain ezetimibe granules.

[0031] (2) After sieving rosuvastatin calcium, filler, disintegrant and glidant, directly mix them evenly, and then mix them evenly with lubricant to obtain rosuvastatin calcium granules.

[0032] (3) The ezetimibe granules obtained in step (1) are used as the first layer, and the rosuvastatin calcium granules obtained in step (2) are used as the second layer, and the two layers of tablets are prepared by a double-layer tablet press, and the tablets are coated to obtain compound ezetimibe and rosuvastatin calcium tablets.

[0033] For the present invention, the filler is one or more of lactose, mannitol, microcrystalline cellulose or corn starch, preferably lactose and microcrystalline cellulose; the disintegrant is one or more of cross-linked carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, and cross-linked polyvinylpyrrolidone, preferably cross-linked carboxymethyl cellulose sodium; the binder is one or more of povidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose, preferably povidone; the solubilizer is one or more of sodium lauryl sulfate, Tween 80 or poloxamer, preferably sodium lauryl sulfate; the lubricant is one or more of magnesium stearate, sodium stearyl fumarate or calcium stearate, preferably magnesium stearate; and the glidant is colloidal silicon dioxide.

[0034] In the present invention, in step (2), the product is sieved through a 20-60 mesh sieve, preferably a 40 mesh sieve.

[0035] In the present invention, in step (3), the mass ratio of ezetimibe to rosuvastatin calcium is 1:1-3, preferably 1:1, the ezetimibe granules obtained in step (1) are used as the first layer, and the rosuvastatin calcium granules obtained in step (2) are used as the second layer, and a double-layer tablet press is used to obtain an upper and lower layer tablet.

[0036] Adopt the technical scheme of the present invention, the advantages are as follows:

[0037] The present invention adopts a wet granulation method to prepare ezetimibe granules, directly mix to obtain rosuvastatin calcium granules, then use the ezetimibe granules as the first layer and the rosuvastatin calcium granules as the second layer, use a double-layer tablet press to obtain upper and lower two-layer tablets, and coat to prepare compound ezetimibe and rosuvastatin calcium tablets, which have the advantages of stable content, good quality, high stability, etc.; the entire preparation method is simple, efficient and cost-saving, and is more suitable for commercial batch production. DETAILED DESCRIPTION

[0038] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0039] Example 1

[0040] A compound ezetimibe and rosuvastatin calcium tablet comprises a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, wherein the ezetimibe granules as the first layer are made of the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 20 parts of microcrystalline cellulose, 16 parts of cross-linked sodium carboxymethyl cellulose, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; and the rosuvastatin calcium granules as the second layer are made of the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate; the details are as follows:

[0041]

[0042] The preparation method thereof comprises the following steps:

[0043] (1) Ezetimibe is uniformly mixed with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and povidone and sodium lauryl sulfate are added to 33 parts of water to prepare an aqueous solution as a binder for wet granulation, drying, granulation, and then mixing with magnesium stearate to obtain ezetimibe granules;

[0044] (2) Rosuvastatin calcium, lactose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and colloidal silicon dioxide are passed through a 40-mesh sieve and mixed evenly, and then mixed with magnesium stearate to obtain rosuvastatin calcium granules.

[0045] (3) The two kinds of granules obtained in step (1) and step (2) are placed in different feed containers at a mass ratio of ezetimibe to rosuvastatin calcium of 1:1, with ezetimibe granules as the first layer and rosuvastatin calcium granules as the second layer, and are subjected to a double-layer tablet press to obtain upper and lower layer tablets, which are then coated to obtain compound ezetimibe and rosuvastatin calcium tablets.

[0046] Example 2

[0047] A compound ezetimibe and rosuvastatin calcium tablet comprises a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, wherein the ezetimibe granules as the first layer are made of the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 22 parts of microcrystalline cellulose, 16 parts of cross-linked sodium carboxymethyl cellulose, 6 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; and the rosuvastatin calcium granules as the second layer are made of the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate; the details are as follows:

[0048]

[0049] The preparation method thereof comprises the following steps:

[0050] (1) Ezetimibe is uniformly mixed with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and povidone and sodium lauryl sulfate are added to 33 parts of water to prepare an aqueous solution as a binder for wet granulation, drying, granulation, and then mixing with magnesium stearate to obtain ezetimibe granules;

[0051] (2) Rosuvastatin calcium, lactose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and colloidal silicon dioxide are passed through a 40-mesh sieve and mixed evenly, and then mixed with magnesium stearate to obtain rosuvastatin calcium granules.

[0052] (3) The two kinds of granules obtained in step (1) and step (2) are placed in different feed containers at a mass ratio of ezetimibe to rosuvastatin calcium of 1:1, with ezetimibe granules as the first layer and rosuvastatin calcium granules as the second layer, and are subjected to a double-layer tablet press to obtain upper and lower layer tablets, which are then coated to obtain compound ezetimibe and rosuvastatin calcium tablets.

[0053] Example 3

[0054] A compound ezetimibe and rosuvastatin calcium tablet comprises a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, wherein the ezetimibe granules as the first layer are made of the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 18 parts of microcrystalline cellulose, 16 parts of cross-linked sodium carboxymethyl cellulose, 10 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; and the rosuvastatin calcium granules as the second layer are made of the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate; the details are as follows:

[0055]

[0056] The preparation method thereof comprises the following steps:

[0057] (1) Ezetimibe is uniformly mixed with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and povidone and sodium lauryl sulfate are added to 33 parts of water to prepare an aqueous solution as a binder for wet granulation, drying, granulation, and then mixing with magnesium stearate to obtain ezetimibe granules;

[0058] (2) Rosuvastatin calcium, lactose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and colloidal silicon dioxide are passed through a 40-mesh sieve and mixed evenly, and then mixed with magnesium stearate to obtain rosuvastatin calcium granules.

[0059] (3) The two kinds of granules obtained in step (1) and step (2) are placed in different feed containers at a mass ratio of ezetimibe to rosuvastatin calcium of 1:1, with ezetimibe granules as the first layer and rosuvastatin calcium granules as the second layer, and are subjected to a double-layer tablet press to obtain upper and lower layer tablets, which are then coated to obtain compound ezetimibe and rosuvastatin calcium tablets.

[0060] Example 4

[0061] A compound ezetimibe and rosuvastatin calcium tablet comprises a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, wherein the ezetimibe granules as the first layer are made of the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 26 parts of microcrystalline cellulose, 10 parts of cross-linked sodium carboxymethyl cellulose, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; and the rosuvastatin calcium granules as the second layer are made of the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate; the details are as follows:

[0062]

[0063] The preparation method thereof comprises the following steps:

[0064] (1) Ezetimibe is uniformly mixed with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and povidone and sodium lauryl sulfate are added to 33 parts of water to prepare an aqueous solution as a binder for wet granulation, drying, granulation, and then mixing with magnesium stearate to obtain ezetimibe granules;

[0065] (2) Rosuvastatin calcium, lactose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and colloidal silicon dioxide are passed through a 40-mesh sieve and mixed evenly, and then mixed with magnesium stearate to obtain rosuvastatin calcium granules.

[0066] (3) The two kinds of granules obtained in step (1) and step (2) are placed in different feed containers at a mass ratio of ezetimibe to rosuvastatin calcium of 1:1, with ezetimibe granules as the first layer and rosuvastatin calcium granules as the second layer, and are subjected to a double-layer tablet press to obtain upper and lower layer tablets, which are then coated to obtain compound ezetimibe and rosuvastatin calcium tablets.

[0067] Example 5

[0068] A compound ezetimibe and rosuvastatin calcium tablet comprises a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, wherein the ezetimibe granules as the first layer are made of the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 14 parts of microcrystalline cellulose, 22 parts of cross-linked sodium carboxymethyl cellulose, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; and the rosuvastatin calcium granules as the second layer are made of the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate; the details are as follows:

[0069]

[0070] The preparation method thereof comprises the following steps:

[0071] (1) Ezetimibe is uniformly mixed with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and povidone and sodium lauryl sulfate are added to 33 parts of water to prepare an aqueous solution as a binder for wet granulation, drying, granulation, and then mixing with magnesium stearate to obtain ezetimibe granules;

[0072] (2) Rosuvastatin calcium, lactose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and colloidal silicon dioxide are passed through a 40-mesh sieve and mixed evenly, and then mixed with magnesium stearate to obtain rosuvastatin calcium granules.

[0073] (3) The two kinds of granules obtained in step (1) and step (2) are placed in different feed containers at a mass ratio of ezetimibe to rosuvastatin calcium of 1:1, with ezetimibe granules as the first layer and rosuvastatin calcium granules as the second layer, and are subjected to a double-layer tablet press to obtain upper and lower layer tablets, which are then coated to obtain compound ezetimibe and rosuvastatin calcium tablets.

[0074] Comparative Example 1

[0075] A compound ezetimibe and rosuvastatin calcium tablet comprises a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, wherein the ezetimibe granules as the first layer are made of the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 20 parts of microcrystalline cellulose, 16 parts of cross-linked sodium carboxymethyl cellulose, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; and the rosuvastatin calcium granules as the second layer are made of the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate; the details are as follows:

[0076]

[0077] The preparation method thereof comprises the following steps:

[0078] (1) Ezetimibe is uniformly mixed with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and povidone and sodium lauryl sulfate are added to 33 parts of water to prepare an aqueous solution as a binder for wet granulation, drying, granulation, and then mixing with magnesium stearate to obtain ezetimibe granules;

[0079] (2) Rosuvastatin calcium, lactose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and colloidal silicon dioxide are passed through a 40-mesh sieve and mixed evenly, and then mixed with magnesium stearate to obtain rosuvastatin calcium granules.

[0080] (3) The two kinds of granules obtained in step (1) and step (2) are placed in different feed containers at a mass ratio of ezetimibe to rosuvastatin calcium of 1:1, with rosuvastatin calcium as the first layer and ezetimibe granules as the second layer, and are subjected to a double-layer tablet press to obtain upper and lower layer tablets, which are then coated to obtain compound ezetimibe and rosuvastatin calcium tablets.

[0081] Comparative Example 2

[0082] A compound ezetimibe and rosuvastatin calcium tablet comprises a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, wherein the ezetimibe granules as the first layer are made of the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 20 parts of microcrystalline cellulose, 16 parts of cross-linked sodium carboxymethyl cellulose, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; and the rosuvastatin calcium granules as the second layer are made of the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate; the details are as follows:

[0083]

[0084]

[0085] The preparation method thereof comprises the following steps:

[0086] (1) Ezetimibe is uniformly mixed with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and povidone and sodium lauryl sulfate are added to 33 parts of water to prepare an aqueous solution as a binder for wet granulation, drying, granulation, and then mixing with magnesium stearate to obtain ezetimibe granules;

[0087] (2) Rosuvastatin calcium is mixed with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, 18 parts of water is added as a wetting agent for wet granulation, drying, and granulation, and then mixed with colloidal silicon dioxide and magnesium stearate to obtain rosuvastatin calcium granules.

[0088] (3) The two kinds of granules obtained in step (1) and step (2) are placed in different feed containers at a mass ratio of ezetimibe to rosuvastatin calcium of 1:1, with rosuvastatin calcium as the first layer and ezetimibe granules as the second layer, and are subjected to a double-layer tablet press to obtain upper and lower layer tablets, which are then coated to obtain compound ezetimibe and rosuvastatin calcium tablets.

[0089] Comparative Example 3

[0090] A compound ezetimibe and rosuvastatin calcium tablet comprises a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, wherein the ezetimibe granules as the first layer are made of the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 20 parts of microcrystalline cellulose, 16 parts of cross-linked sodium carboxymethyl cellulose, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; and the rosuvastatin calcium granules as the second layer are made of the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate; the details are as follows:

[0091]

[0092]

[0093] The preparation method thereof comprises the following steps:

[0094] (1) mixing ezetimibe with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, adding povidone and sodium lauryl sulfate to 33 parts of water to prepare an aqueous solution as a binder, wet granulating, drying, granulating, and then mixing with magnesium stearate to obtain ezetimibe granules;

[0095] (2) Rosuvastatin calcium is uniformly mixed with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, 18 parts of water is added as a wetting agent for fluidized bed granulation, drying, and granulation, and then mixed with colloidal silicon dioxide and magnesium stearate to obtain rosuvastatin calcium granules.

[0096] (3) The two kinds of granules obtained in step (1) and step (2) are placed in different feed containers at a mass ratio of ezetimibe to rosuvastatin calcium of 1:1, with rosuvastatin calcium as the first layer and ezetimibe granules as the second layer, and are subjected to a double-layer tablet press to obtain upper and lower layer tablets, which are then coated to obtain compound ezetimibe and rosuvastatin calcium tablets.

[0097] Comparative Example 4

[0098] A compound ezetimibe and rosuvastatin calcium tablet comprises a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, wherein the ezetimibe granules as the first layer are made of the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 20 parts of microcrystalline cellulose, 16 parts of cross-linked sodium carboxymethyl cellulose, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; and the rosuvastatin calcium granules as the second layer are made of the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, 1 part of magnesium stearate, and 1 part of propyl gallate; the details are as follows:

[0099]

[0100]

[0101] The preparation method thereof comprises the following steps:

[0102] (1) Ezetimibe is micronized and passed through a 200-mesh sieve. The remaining raw materials and auxiliary materials are passed through an 80-mesh sieve for later use.

[0103] (2) mixing ezetimibe with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose uniformly, adding povidone and sodium lauryl sulfate to 33 parts of water to prepare an aqueous solution as a binder, wet granulating, drying, granulating, and then mixing with magnesium stearate to obtain ezetimibe granules;

[0104] (3) Rosuvastatin calcium is mixed with lactose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and propyl gallate, 18 parts of water is added as a wetting agent for wet granulation, drying, granulation, and then mixed with colloidal silicon dioxide and magnesium stearate to obtain rosuvastatin calcium granules.

[0105] (3) The two kinds of granules obtained in step (1) and step (2) are placed in different feed containers at a mass ratio of ezetimibe to rosuvastatin calcium of 1:1, with rosuvastatin calcium as the first layer and ezetimibe granules as the second layer, and are subjected to a double-layer tablet press to obtain upper and lower layer tablets, which are then coated to obtain compound ezetimibe and rosuvastatin calcium tablets.

[0106] Comparative Example 5

[0107] A compound ezetimibe and rosuvastatin calcium tablet comprises a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, wherein the ezetimibe granules as the first layer are made of the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 20 parts of microcrystalline cellulose, 16 parts of cross-linked sodium carboxymethyl cellulose, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; and the rosuvastatin calcium granules as the second layer are made of the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate; the details are as follows:

[0108]

[0109] The preparation method thereof comprises the following steps:

[0110] (1) Ezetimibe and rosuvastatin calcium are uniformly mixed with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose in a mass ratio of 1:1, and polyvidone and an aqueous solution of sodium lauryl sulfate are added as a binder solution to perform wet granulation, dry, and granulate, and then mix with colloidal silicon dioxide and magnesium stearate to obtain ezetimibe and rosuvastatin calcium total mixed granules.

[0111] (2) The total mixed granules obtained in step (1) are tableted and coated.

[0112] Comparative Example 6

[0113] A compound ezetimibe and rosuvastatin calcium tablet comprises a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, wherein the ezetimibe granules as the first layer are made of the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 20 parts of microcrystalline cellulose, 16 parts of cross-linked sodium carboxymethyl cellulose, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; and the rosuvastatin calcium granules as the second layer are made of the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate; the details are as follows:

[0114]

[0115] The preparation method thereof comprises the following steps:

[0116] (1) adding ezetimibe, lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose to a fluidized bed granulator and mixing them uniformly, adding povidone and sodium lauryl sulfate to 33 parts of water to prepare an aqueous solution as a binder for fluidized bed granulation, drying the obtained granules in a fluidized bed dryer at 45° C., granulating, and then mixing with magnesium stearate to obtain ezetimibe granules;

[0117] (2) Rosuvastatin calcium is uniformly mixed with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and the resulting flakes are passed through a 0.8 mm sieve, and then mixed with colloidal silicon dioxide and magnesium stearate to obtain rosuvastatin calcium granules.

[0118] (3) The two kinds of granules obtained in step (1) and step (2) are placed in different feed containers at a mass ratio of ezetimibe to rosuvastatin calcium of 1:1, with ezetimibe granules as the first layer and rosuvastatin calcium granules as the second layer, and are subjected to a double-layer tablet press to obtain upper and lower layer tablets, which are then coated to obtain compound ezetimibe and rosuvastatin calcium tablets.

[0119] The products in Examples 1-5 and Comparative Examples 1-6 were tested for ezetimibe content and rosuvastatin calcium content, and the results were finally obtained as shown in Table 1.

[0120] Table 1 Ezetimibe content and rosuvastatin calcium content

[0121]

[0122] As shown in Table 1, the compound ezetimibe and rosuvastatin calcium tablets prepared in Examples 1-5 and Comparative Examples 2-6 have qualified contents of ezetimibe and rosuvastatin calcium. Changing the tableting order in Comparative Example 1 will increase the ezetimibe content and reduce the rosuvastatin calcium content. It can be concluded that the tableting order should be ezetimibe as the first layer and rosuvastatin calcium as the second layer. Based on the above research, the relevant substances and dissolution of Examples 1-5 and Comparative Examples 2-6 were investigated in the accelerated test, and the results are finally shown in Table 2.

[0123] Table 2 Related substances and dissolution rates in accelerated tests

[0124]

[0125]

[0126] As shown in Table 2, the compound ezetimibe rosuvastatin calcium tablets prepared in Examples 1-5 and Comparative Examples 2-3, the related substances and dissolution of Examples 1-5 and Comparative Example 6 are all qualified; the related substances in Comparative Examples 2 and 5 increase significantly under accelerated conditions. The detected amount of related substances in Comparative Example 3 is small but has a significant growth trend; the content of related substances in Comparative Example 4 is low after adding antioxidants, but due to the preparation method, the related substances also have an increasing trend; the preparation method of Comparative Example 6 is more complicated and time-consuming, and the effect is similar to that in Examples 1-5. The preparation method in Examples 1-5 is simpler and suitable for large-scale commercial batch production.

[0127] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A compound ezetimibe and rosuvastatin calcium tablet, comprising a double-layer tablet obtained by double-layer tabletting of ezetimibe granules and rosuvastatin calcium granules, with ezetimibe granules as the first layer, comprising the following components: ezetimibe, a filler, a disintegrant, a binder, a solubilizer and a lubricant, wherein the preparation method of the ezetimibe granules is: firstly, ezetimibe, a filler and a disintegrant are uniformly mixed, and then wet granulation is performed with an aqueous solution containing a binder and a solubilizer, and after drying the whole granules, a lubricant is added and mixed uniformly, so as to obtain the compound ezetimibe and rosuvastatin calcium tablet; the rosuvastatin calcium granules are as the second layer, comprising the following components: rosuvastatin calcium, a filler, a glidant and a lubricant, wherein, The preparation method of the rosuvastatin calcium granules is as follows: rosuvastatin calcium, a filler, a disintegrant, a glidant and a lubricant are directly mixed evenly to obtain the granules.

2. The compound ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that: The filler is one or more of lactose, mannitol, microcrystalline cellulose or corn starch, preferably lactose and microcrystalline cellulose; the disintegrant is one or more of cross-linked carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, and cross-linked povidone, preferably cross-linked carboxymethyl cellulose sodium; the binder is one or more of povidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose, preferably povidone; the solubilizer is one or more of sodium lauryl sulfate, Tween 80 or poloxamer, preferably sodium lauryl sulfate; the lubricant is one or more of magnesium stearate, sodium stearyl fumarate or calcium stearate, preferably magnesium stearate; and the glidant is colloidal silicon dioxide.

3. The compound ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that: The ezetimibe granules include the following components in parts by weight: 10 parts of ezetimibe, 145-155 parts of lactose, 10-30 parts of microcrystalline cellulose, 5-25 parts of cross-linked sodium carboxymethyl cellulose, 4-12 parts of povidone, 3-5 parts of sodium lauryl sulfate, and 1-3 parts of magnesium stearate.

4. The compound ezetimibe and rosuvastatin calcium tablets according to claim 3, characterized in that: The ezetimibe granules include the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 14-26 parts of microcrystalline cellulose, 10-22 parts of cross-linked sodium carboxymethyl cellulose, 6-10 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate.

5. The compound ezetimibe and rosuvastatin calcium tablets according to claim 3, characterized in that: The ezetimibe granules include the following components in parts by weight: 10 parts of ezetimibe, 150 parts of lactose, 22 parts of microcrystalline cellulose, 16 parts of croscarmellose sodium, 6 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; 10 parts of ezetimibe, 150 parts of lactose, 20 parts of microcrystalline cellulose, 16 parts of croscarmellose sodium, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; 10 parts of ezetimibe, 150 parts of lactose, 18 parts of microcrystalline cellulose, 16 parts of cross-linked carboxymethyl cellulose sodium, 10 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; 10 parts of ezetimibe, 150 parts of lactose, 26 parts of microcrystalline cellulose, 10 parts of cross-linked carboxymethyl cellulose sodium, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate; 10 parts of ezetimibe, 150 parts of lactose, 14 parts of microcrystalline cellulose, 22 parts of cross-linked carboxymethyl cellulose sodium, 8 parts of povidone, 4 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate.

6. The compound ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that: The rosuvastatin calcium granules include the following components in parts by weight: 10 parts of rosuvastatin calcium, 55-65 parts of lactose, 12-16 parts of microcrystalline cellulose, 3-5 parts of cross-linked sodium carboxymethyl cellulose, 0.5-1.5 parts of colloidal silicon dioxide, and 0.5-1.5 parts of magnesium stearate.

7. The compound ezetimibe and rosuvastatin calcium tablets according to claim 6, characterized in that: The rosuvastatin calcium granules include the following components in parts by weight: 10 parts of rosuvastatin calcium, 60 parts of lactose, 14 parts of microcrystalline cellulose, 4 parts of cross-linked sodium carboxymethyl cellulose, 1 part of colloidal silicon dioxide, and 1 part of magnesium stearate.

8. The method for preparing the compound ezetimibe and rosuvastatin calcium tablets according to claim 1, characterized in that: The steps include: (1) Preparation of ezetimibe granules: ezetimibe is mixed with a filler and a disintegrant, and then wet granulated with an aqueous solution containing a binder and a solubilizer. After drying the granules, a lubricant is added and mixed to obtain ezetimibe granules. (2) After sieving rosuvastatin calcium, filler, disintegrant and glidant, directly mix them evenly, and then mix them evenly with lubricant to obtain rosuvastatin calcium granules. (3) The ezetimibe granules obtained in step (1) are used as the first layer, and the rosuvastatin calcium granules obtained in step (2) are used as the second layer, and the two layers of tablets are prepared by a double-layer tablet press, and the tablets are coated to obtain compound ezetimibe and rosuvastatin calcium tablets.

9. The method for preparing the compound ezetimibe and rosuvastatin calcium tablets according to claim 8, characterized in that: The filler is one or more of lactose, mannitol, microcrystalline cellulose or corn starch, preferably lactose and microcrystalline cellulose; the disintegrant is one or more of cross-linked carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, and cross-linked povidone, preferably cross-linked carboxymethyl cellulose sodium; the binder is one or more of povidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose, preferably povidone; the solubilizer is one or more of sodium lauryl sulfate, Tween 80 or poloxamer, preferably sodium lauryl sulfate; the lubricant is one or more of magnesium stearate, sodium stearyl fumarate or calcium stearate, preferably magnesium stearate; the glidant is colloidal silicon dioxide.

10. The method for preparing the compound ezetimibe and rosuvastatin calcium tablets according to claim 8, characterized in that: In step (2), the particles are sieved through a 20-60 mesh sieve, preferably a 40 mesh sieve. In step (3), the mass ratio of ezetimibe to rosuvastatin calcium is 1:1-3, preferably 1:1, and the ezetimibe particles obtained in step (1) are used as the first layer, and the rosuvastatin calcium particles obtained in step (2) are used as the second layer, and a double-layer tablet press is used to obtain an upper and lower layer tablet.

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