Ezetimibe compound preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an ezetimibe compound preparation and a preparation method thereof.The ezetimibe compound preparation comprises an ezetimibe composition and a statins pharmaceutical composition, the ezetimibe composition and the statins pharmaceutical composition are assembled together and do not make direct contact with each other, the dosage form of the ezetimibe composition is microtablets, and the dosage form of the ezetimibe composition is microtablets. The dosage form of the statins pharmaceutical composition is a film-coated tablet, and the assembly mode is bagging, bottling or capsule filling. The stability is improved, and the coefficient of variation is reduced.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a compound ezetimibe preparation and a preparation method. BACKGROUND

[0002] Ezetimibe effectively reduces the absorption of intestinal cholesterol by selectively inhibiting small intestinal cholesterol transporters, reduces plasma cholesterol levels and liver cholesterol reserves. Statins block the intracellular hydroxymethyl valerate metabolic pathway by competitively inhibiting the endogenous cholesterol synthesis rate-limiting enzyme HMG-CoA reductase, thereby reducing total cholesterol (TC) and low-density lipoprotein (LDL). The combination of ezetimibe and statins has a stronger effect on reducing low-density lipoprotein cholesterol and does not significantly increase side effects compared to single use.

[0003] Domestic ezetimibe-statin tablets have been comprehensively studied. For example, patent application CN117883398A discloses a double-layer tablet containing ezetimibe and rosuvastatin and a preparation method thereof, which comprises the following steps: S1, preparing ezetimibe granules; S2, preparing rosuvastatin calcium powder; S3, pressing the ezetimibe granules and the rosuvastatin calcium powder into double-layer tablets using a double-layer tablet press; and S4, coating.

[0004] Patent application CN107028906A discloses a compound tablet containing ezetimibe and rosuvastatin and a preparation method thereof. The compound tablet is prepared by coating the ezetimibe granules and the rosuvastatin granules obtained by granulation, then adding a disintegrant and a lubricant and pressing them into tablets; the ezetimibe granules are composed of ezetimibe, a filler, a solubilizer, a binder and a disintegrant; and the rosuvastatin granules are composed of rosuvastatin, a filler, a stabilizer, a disintegrant and a binder.

[0005] These products mainly have the following problems.

[0006] 1. Stability: The original research and commercially available dosage forms are oral solid double-layer tablets coated with a film. During long-term storage, the increase in related substances will reduce the safety of the product.

[0007] 2. Patient adaptability: Oral administration is the simplest method of drug delivery, and ordinary tablets are a common form of oral administration, which is a quantitative drug delivery method by compressing solid materials into tablets. The original research preparation has a large volume, which is difficult for some patients to swallow. The quantitative drug delivery method of ordinary tablets also cannot flexibly adjust the drug dosage.

[0008] 3. In vivo pharmacokinetics: Ezetimibe acts in the hepatic- intestinal circulation phase, and shows a "multi-peak phenomenon" on the blood concentration-time curve. Data shows that the AUC 0-96 , C max , T1 / 2 The coefficient of variation of the pharmacokinetic parameters of ezetimibe in healthy people is 64.2%, 67.2%, and 63.6%, respectively. The pharmacokinetic parameters of ezetimibe in healthy people show high individual variation. SUMMARY

[0009] The present application aims to provide an ezetimibe compound preparation and a preparation method, improve stability, and reduce the coefficient of variation.

[0010] The present application provides an ezetimibe compound preparation, which comprises an ezetimibe composition and a statin drug composition. The ezetimibe composition and the statin drug composition are assembled together and do not directly contact each other. The dosage form of the ezetimibe composition is a microtablet, the dosage form of the statin drug composition is a film-coated tablet, and the assembly is in the form of a bag, a bottle, or a capsule.

[0011] Preferably, the ezetimibe composition comprises the following components by weight: ezetimibe 1-20 parts filler 10-80 parts binder 0-10 parts disintegrant 0.5-10 parts lubricant 1-5 parts The statin drug composition comprises the following components by weight: statin drug 1-20 parts filler 10-80 parts disintegrant 0.5-10 parts

[0012] Preferably, in the ezetimibe composition, the filler is one or more of erythritol, mannitol, starch, lactose, and microcrystalline cellulose (preferably a mixture of lactose and microcrystalline cellulose), the binder is one or more of PEG6000, hydroxypropyl cellulose, and povidone, the disintegrant is one or more of croscarmellose sodium, sodium carboxymethyl starch, and cross-linked povidone, and the lubricant is one or more of magnesium stearate, talc, and silicon dioxide.

[0013] Preferably, in the statin drug composition, the statin drug is rosuvastatin, the filler is one or more of erythritol, mannitol, starch, anhydrous calcium hydrogen phosphate, lactose, and microcrystalline cellulose, and the disintegrant is one or more of croscarmellose sodium, sodium carboxymethyl starch, cross-linked povidone, and low-substituted hydroxypropyl cellulose.

[0014] Preferably, the ezetimibe composition is filled into capsule A, the statin drug composition is filled into capsule B, and the capsule A and the capsule B are filled into a capsule at the same time.

[0015] Preferably, the capsule is a hard capsule, which has better moisture-proof effect and can control lower moisture content.

[0016] The application provides a preparation method of the compound ezetimibe preparation, wherein an ezetimibe composition and a statin composition are prepared respectively, and then the ezetimibe composition and the statin composition are assembled together through bagging, bottling or capsule filling to obtain the compound ezetimibe preparation. The preparation method of the ezetimibe composition comprises the following steps: mixing and dispersing ezetimibe, a filler, a binder, a disintegrant and a lubricant to obtain a dispersion, and then tabletting to obtain the ezetimibe composition. The preparation method of the statin composition comprises the following steps: mixing and dispersing a statin, a filler and a disintegrant to obtain a dispersion, and then tabletting and coating the dispersion to obtain the statin composition.

[0017] Preferably, in the preparation method of the ezetimibe composition, the step of mixing and dispersing comprises the following steps: mixing and dispersing the ezetimibe and part of the filler; adding the disintegrant and the binder into the above compound and mixing and dispersing; adding the rest of the filler into the above compound and mixing and dispersing; wet granulating the mixed material and drying; dispersing the dried material; and adding the lubricant into the above compound and mixing and dispersing.

[0018] Preferably, in the preparation method of the statin composition, the step of mixing and dispersing comprises the following steps: mixing and dispersing the statin and part of the filler; adding the disintegrant into the above compound and mixing and dispersing; adding the rest of the filler into the above compound and mixing and dispersing; drying the mixed material; and dispersing the dried material.

[0019] Preferably, the coating is fluidized bed coating or coating machine coating.

[0020] The tabletting operation comprises the following steps: using a small punch die to tablet the dispersion and the auxiliary materials; the diameter of the small punch die is 1-3 mm, the number of punch pins on a single punch head is 4-7, and the shape of the punch die is one or more of the following: planar type, planar bevel, planar arc edge and double convex surface type.

[0021] The compound ezetimibe preparation has the advantages of simple prescription, good stability and dissolution rate, easy swallowing, flexible administration strategy and the like.

[0022] The compound preparation of evolocumab of the present application has a simple prescription, and the evolocumab and statins are prepared into small-dose micro-tablets, so that the administration scheme can be flexibly adjusted, the micro-tablets have good swallowability due to small volume, and have good compliance for special groups and people who have difficulty in swallowing ordinary tablets.

[0023] The present application improves the stability of the preparation. The evolocumab and statins are completely separated, and the evolocumab micro-tablets and statin micro-tablets do not contact each other, and impurities are not generated due to the contact of the two main components.

[0024] The present application reduces individual variation. The rosuvastatin layer uses non-alkaline materials, which can reduce gastrointestinal symptoms and other adverse reactions; the material with good fluidity is used to replace magnesium stearate, which ensures the fluidity of the material while reducing the amount of magnesium stearate in the total prescription, thereby reducing the competition of metal ions and evolocumab combined sterol transporter NPC1L1; the evolocumab main component is prepared into small-volume micro-tablets, which can be uniformly dispersed, and the variation caused by single-point concentrated absorption is avoided. Through research and comparison of pharmacokinetics, it is found that the individual variation of the preparation prepared by the present application is lower than that of the original preparation, and the blood drug concentration is more stable. DETAILED DESCRIPTION

[0025] Example 1 A preparation method of a compound preparation of evolocumab, comprising the following steps: 1. Obtain raw materials: evolocumab 450g, lactose 1000g, hydroxypropyl cellulose 150g, sodium carboxymethyl starch 120g, and microcrystalline cellulose 800g.

[0026] The evolocumab is mixed and dispersed with lactose, hydroxypropyl cellulose, sodium carboxymethyl starch, and microcrystalline cellulose to obtain a dispersion. The dispersion mixing and dispersing step is: the evolocumab is mixed and dispersed with part of the filler (50% of the total weight); the disintegrant and the binder are added to the above-mentioned compound, and mixed and dispersed; the remaining filler is added to the above-mentioned compound, and mixed and dispersed; the mixed material is wet granulated and dried; the dried material is dispersed; and the lubricant is added to the above-mentioned compound, and mixed and dispersed.

[0027] The dispersion is tableted to obtain the evolocumab composition. The tableting operation is: the dispersion and the auxiliary materials are tableted using a small punch mold; the diameter of the small punch mold is 1-3 mm, the number of punch pins on a single punch head is 4-7, and the shape of the punch mold is one or more of a planar type, a planar bevel, a planar arc edge, and a double-convex type.

[0028] 2. Obtain raw materials: statin rosuvastatin 450g, mannitol 1800g, and low-substitution hydroxypropyl cellulose 120g.

[0029] To the rosuvastatin, mannitol, low-substituted hydroxypropyl cellulose are added, and the mixture is dispersed and mixed to obtain a mixed dispersion. The step of dispersing and mixing is as follows: the statin and part of the filler (50% of the total weight) are mixed and dispersed; the above compound is added with a disintegrant, and mixed and dispersed; the above compound is added with the remaining filler, and mixed and dispersed; the mixed material is dried; and the dried material is dispersed.

[0030] The mixed dispersion is tabletted, and the tabletted operation is as follows: the dispersion and the excipient are tabletted using a small punch; the diameter of the small punch is 1-3 mm, the number of punches on a single punch is 4-7, and the punch shape is one or more of a flat type, a flat bevel, a flat arc, and a double convex type.

[0031] The obtained tablet is coated to obtain a statin composition.

[0032] 3. The ezetimibe microtablet and the rosuvastatin calcium microtablet obtained in each of the above examples are respectively filled into the same hard capsule to obtain an ezetimibe compound preparation.

[0033] Example 2 Compared with Example 1, the difference between Example 2 and Example 1 is that the raw material ratio is different.

[0034] The raw material of the ezetimibe composition is: ezetimibe 450 g, erythritol 2340 g, povidone 150 g, and croscarmellose sodium 30 g.

[0035] The raw material of the statin composition is: statin 450 g, anhydrous calcium hydrogen phosphate 2310 g, and croscarmellose sodium 30 g. The other aspects are the same as in Example 1.

[0036] Example 3 Compared with Example 1, the difference between Example 3 and Example 1 is that the raw material ratio is different.

[0037] The raw material of the ezetimibe composition is: ezetimibe 450 g, mannitol 2070 g, and cross-linked povidone 90 g.

[0038] The raw material of the statin composition is: statin 450 g, lactose 1860 g, and carboxymethyl starch sodium 120 g. The other aspects are the same as in Example 1.

[0039] Example 4 The ezetimibe compound preparation of Examples 1-3 is subjected to dissolution test: Dissolution test (paddle method): 900 ml of phosphate buffer solution is used as the dissolution medium, the temperature is 37±0.5℃, the rotation speed is 75 rpm, the capsule is put into the dissolution cup to start the experiment, and the sample is taken out for determination at 15 minutes.

[0040] The dissolution results of the ezetimibe compound preparations of Examples 1-3 are shown in the following table.

[0041]

[0042] The dissolution results show that the preparations prepared in Examples 1-3 all have a dissolution of more than 85% at 15 min, and can rapidly take effect in vivo.

[0043] Comparative Example 1 The original preparation was used as a comparative example for the study.

[0044] The process is described as follows: ezetimibe (10 mg / tablet) and lactose (141 mg / tablet), croscarmellose sodium (12 mg / tablet), sodium lauryl sulfate (4 mg / tablet), povidone (5 mg / tablet) are granulated by wet granulation using water as a wetting agent, and the obtained ezetimibe granules are mixed with microcrystalline cellulose (24 mg / tablet) and magnesium stearate (1 mg / tablet) to obtain ezetimibe layer granules. Rosuvastatin calcium (20 mg / tablet) is directly mixed with lactose (122 mg / tablet), microcrystalline cellulose (47 mg / tablet), croscarmellose sodium (3 mg / tablet), magnesium stearate (1.2 mg / tablet), and silicon dioxide (1.2 mg / tablet) to obtain a rosuvastatin calcium layer powder. The obtained ezetimibe and rosuvastatin layer mixture is tabletted to obtain a double-layer tablet, and the obtained double-layer tablet is coated to obtain the product.

[0045] Example 5 The ezetimibe compound preparations of Example 3 and Comparative Example 1 were detected by high performance liquid chromatography at 0 months and after accelerated storage for 6 months, respectively, and the detection method is as follows. The detection method is derived from the Rosuvastatin Ezetimibe Tablet I Drug Registration Standard (JX20230140).

[0046] Solvent: acetonitrile: water (40:60).

[0047] Chromatographic conditions: hexylphenylsilane-bonded silica gel is used as the filler (Phenomenex Gemini C6-phenyl, 4.6 mm X 150 mm, 3 μm or a chromatographic column with equivalent performance); a phosphoric acid solution (take 1 ml of 85% phosphoric acid and add 1000 ml of water to dissolve) is used as mobile phase A, and methanol is used as mobile phase B for gradient elution; the column temperature is 25°C; the detection wavelength is 245 nm, and the flow rate is 1.0 ml per minute. The injection volume is 20 ul. The automatic injector temperature is 7°C. The gradient elution program is as follows:

[0048] The detection results are shown in Table 1.

[0049] Table 1 Stability results of the compound preparation of ezetimibe in Example 3 and Comparative Example 1

[0050] The impurities listed in the above table are prepared according to the import registration standard, and are all degradation impurities of the preparation, which need to be controlled.

[0051] The impurity size and impurity growth rate of the preparation prepared in Example 3 at 0 days and after 6 months of acceleration are better than those of Comparative Example 1. Through optimization of the process and the prescription, the stability of the product prepared by the application is further improved, and the product quality and safety are improved.

[0052] Example 6 Test scheme: 30 subjects are selected for the test in a fasting and postprandial manner, respectively, and a single-center, randomized, open, two-preparations, single-dose, four-cycle, complete repeated cross test design is adopted for drug administration. Reasonable blood sampling points and washout periods are designed, and a verified LC-MS / MS method is used to determine the drug concentrations of free ezetimibe, total ezetimibe and rosuvastatin in plasma.

[0053] The pharmacokinetic data of ezetimibe in Example 3 / Comparative Example 1 are shown in the following table:

[0054] The C max and AUC 0-96 The coefficient of variation is significantly smaller than that of Comparative Example 1, indicating that the compound preparation of ezetimibe prepared by the application has more stable blood drug concentration, reduced individual variation, and improved effectiveness and stability of product efficacy compared with the commercially available double-layer tablets.

[0055] It should be understood by those skilled in the art that the above discussion of any embodiment is only exemplary and is not intended to imply that the scope of protection of the present application is limited to these examples; the above embodiments or technical features in different embodiments can also be combined, and the steps can be implemented in any order, and there are many other changes of different aspects of one or more embodiments of the present application as described above. In order to be brief, they are not provided in detail.

[0056] One or more embodiments of the present application are intended to cover all such alternatives, modifications and variations falling within the broad scope of the present application. Therefore, any omissions, modifications, equivalent replacements, improvements, etc. made within the spirit and principles of one or more embodiments of the present application should be included in the scope of protection of the present application.

Claims

1. A compound preparation of ezetimibe, characterized in that, The application relates to a compound preparation of ezetimibe and statin, which is assembled together without direct contact, wherein the ezetimibe composition is in the form of micro-tablets, the statin composition is in the form of film-coated tablets, and the assembling mode is bagging, bottling or capsule filling.

2. The ezetimibe complex preparation according to claim 1, wherein the ezetimibe is ezetimibe in a form of a hydrate or a solvate. The ezetimibe composition comprises the following components in weight parts: Ezetimibe 1-20 parts Filling agent 10-80 parts Binder 0-10 parts Disintegrant 0.5-10 parts Lubricant 1-5 parts. The statin composition comprises the following components in weight parts: Statin 1-20 parts Filling agent 10-80 parts Disintegrant 0.5-10 parts.

3. The ezetimibe complex preparation according to claim 2, wherein the complex is prepared by mixing ezetimibe and the pharmaceutically acceptable carrier in a weight ratio of 1 : 1 to 1 :

10. In the ezetimibe composition, the filling agent is one or more of erythritol, mannitol, starch, lactose and microcrystalline cellulose, the binder is one or more of PEG6000, hydroxypropyl cellulose and povidone, the disintegrant is one or more of croscarmellose sodium, sodium carboxymethyl starch and cross-linked povidone, and the lubricant is one or more of magnesium stearate, talc and silicon dioxide.

4. The ezetimibe complex preparation according to claim 2, wherein the complex is prepared by mixing ezetimibe and the pharmaceutically acceptable carrier in a weight ratio of 1 : 1 to 1 :

10. In the statin composition, the statin is rosuvastatin, the filling agent is one or more of erythritol, mannitol, starch, anhydrous calcium hydrogen phosphate, lactose and microcrystalline cellulose, and the disintegrant is one or more of croscarmellose sodium, sodium carboxymethyl starch, cross-linked povidone and low-substitution hydroxypropyl cellulose.

5. The ezetimibe complex preparation according to claim 1, wherein the complex is prepared by mixing ezetimibe and the pharmaceutically acceptable carrier in a weight ratio of 1 : 1 to 1 :

10. The ezetimibe composition is filled into capsule A, the statin composition is filled into capsule B, and the capsule A and the capsule B are filled into a capsule at the same time.

6. The ezetimibe complex preparation according to claim 5, wherein the complex is prepared by mixing ezetimibe and the pharmaceutically acceptable carrier in a weight ratio of 1 : 1 to 1 :

10. The capsule is a hard capsule.

7. A process for the preparation of a combined preparation of ezetimibe according to any one of claims 1 to 6, characterized in that, The ezetimibe composition and the statin composition are prepared respectively, and then assembled together through bagging, bottling or capsule filling to obtain the ezetimibe compound preparation. The preparation method of the ezetimibe composition comprises the following steps: mixing and dispersing ezetimibe, a filling agent, a binder, a disintegrant and a lubricant to obtain a dispersion, and then tabletting to obtain the ezetimibe composition. The preparation method of the statin composition comprises the following steps: mixing and dispersing a statin, a filling agent and a disintegrant to obtain a dispersion, and then tabletting and coating to obtain the ezetimibe composition.

8. The production method according to claim 7, wherein In the preparation method of the ezetimibe composition, the step of mixing and dispersing comprises the following steps: mixing and dispersing the ezetimibe and part of the filling agent, adding the disintegrant and the binder into the above compound and mixing and dispersing, adding the remaining filling agent into the above compound and mixing and dispersing, wet granulating the mixed material and drying the wet granulated material, dispersing the dried material, and adding the lubricant into the above compound and mixing and dispersing. In the preparation method of the statin composition, the step of mixing and dispersing comprises the following steps: mixing and dispersing the statin and part of the filling agent, adding the disintegrant into the above compound and mixing and dispersing, and adding the remaining filling agent into the above compound and mixing and dispersing.

9. The production method according to claim 7, wherein ​ The dried material is subjected to a dispersion treatment.

10. The production method according to claim 7, wherein The coating is carried out by fluidized bed coating or by a coating machine.

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