Double-layer tablet containing ezetimibe and fenofibrate and preparation method thereof

Abstract

The invention provides a double-layer tablet containing ezetimibe and fenofibrate. The double-layer tablet comprises an ezetimibe quick release layer and a fenofibrate slow release layer, the ezetimibe quick-release layer comprises ezetimibe, a quick-release layer filler, a quick-release layer surfactant, a quick-release layer adhesive, a quick-release layer disintegrating agent and a quick-release layer lubricant; the fenofibrate sustained-release layer comprises fenofibrate, a sustained-release layer filler, a sustained-release layer disintegrating agent, a sustained-release layer adhesive, a sustained-release layer solubilizer, a sustained-release layer sustained-release framework material and a sustained-release layer lubricant. The invention also provides a preparation method of the double-layer tablet. The double-layer tablet provided by the invention can be used for clinical treatment of hypercholesterolemia, hypertriglyceridemia and mixed dyslipidemia, the levels of triglyceride, total cholesterol and LDL-C are comprehensively reduced, the level of HDL-C is increased, and the occurrence rate of adverse reactions is relatively low.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and in particular to a bilayer tablet containing ezetimibe and fenofibrate and a method for preparing the same. Background Technology

[0002] Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide. Dyslipidemia, as a core risk factor for atherosclerotic cardiovascular disease (ASCVD), is a pathological state characterized by elevated cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and decreased high-density lipoprotein cholesterol (HDL-C). When blood lipids are at abnormal levels for a long period of time, lipids in the blood will gradually deposit on the blood vessel walls, forming atherosclerotic plaques, leading to narrowing and hardening of blood vessels, obstructing blood flow, and greatly increasing the risk of serious cardiovascular diseases such as coronary heart disease, myocardial infarction, and stroke.

[0003] Lipid-lowering drugs can effectively regulate blood lipid levels and reduce the risk of ASCVD. Common lipid-lowering drugs, such as statins, fibrates, and cholesterol absorption inhibitors, regulate blood lipids through different mechanisms of action. However, monotherapy often has limitations and cannot fully meet the complex treatment needs of different patients with dyslipidemia. For example, statins mainly lower cholesterol and LDL-C, but have limited effect on lowering triglycerides (TG), and some patients are intolerant to statins. Fibrates, when used alone, are not very effective in lowering cholesterol.

[0004] Current combined treatments for regulating blood lipid levels often employ the separate administration of ezetimibe and fenofibrate as monotherapy. For example, Huang Haitao et al. studied the effects of fenofibrate combined with ezetimibe on metabolic indicators and vascular endothelial function in the treatment of type 2 diabetes mellitus complicated with hyperlipidemia. They demonstrated that fenofibrate combined with ezetimibe has good efficacy in treating type 2 diabetes mellitus complicated with hyperlipidemia and can effectively improve metabolic indicators such as blood lipids and blood glucose, as well as vascular endothelial function. However, their use of separate administration of ezetimibe and fenofibrate as monotherapy resulted in poor patient adherence. Summary of the Invention

[0005] In view of this, the purpose of this application is to provide a bilayer tablet containing ezetimibe and fenofibrate and a method for preparing the same. The bilayer tablet provided by this application has good dissolution and high bioavailability, and good patient compliance.

[0006] Formulating ezetimibe and fenofibrate into a combination formulation can improve patient medication adherence. However, the dissolution synchronicity problem caused by the difference in solubility between ezetimibe and fenofibrate is a major issue currently existing in the preparation of combination formulations. Ezetimibe belongs to Biopharmaceutics Class II compounds, with a water solubility of only about 0.008 mg / mL at 25°C. It has high lipophilicity (log P≈4.5) and an oral bioavailability of only 35-65%, mainly limited by slow dissolution rate and P-glycoprotein (P-gp) efflux. Fenofibrate also suffers from poor water solubility, resulting in incomplete dissolution profiles and unstable bioavailability.

[0007] Based on this, this application provides a bilayer tablet containing ezetimibe and fenofibrate, comprising an immediate-release ezetimibe layer and a sustained-release fenofibrate layer;

[0008] The ezetimibe immediate-release layer comprises:

[0009] 1wt%~10wt% ezetimibe;

[0010] 5wt%~20wt% immediate-release layer filler;

[0011] 1wt%~3wt% of immediate-release surfactant;

[0012] 1wt%~5wt% immediate-release layer adhesive;

[0013] 1wt%~5wt% of immediate-release layer disintegrant;

[0014] 0.1wt%~1.5wt% of quick-release layer lubricant;

[0015] The fenofibrate extended-release layer comprises:

[0016] 10wt%~60wt% fenofibrate;

[0017] 10wt%~30wt% of sustained-release layer filler;

[0018] 1wt%~6wt% of sustained-release layer disintegrant;

[0019] 2wt%~5wt% of slow-release layer adhesive;

[0020] 1wt%~8wt% of sustained-release layer solubilizer;

[0021] 10wt%~40wt% of sustained-release layer and sustained-release skeleton material;

[0022] 0.1~2% slow-release lubricant.

[0023] In some specific implementations, the ezetimibe quick-release layer filler includes one or more of corn starch, microcrystalline cellulose, and mannitol.

[0024] The immediate-release surfactant includes Gelucire. ® One or more of the following: mixture, sodium dodecyl sulfate, and poloxamer 188;

[0025] The immediate-release layer adhesive includes one or more of povidone, hydroxypropyl methylcellulose E5, and copovidone;

[0026] The immediate-release layer disintegrant includes one or more of F-MELT® Type M, croscarmellose sodium, and croscarmellose.

[0027] The quick-release layer lubricant includes one or more of magnesium stearate, colloidal silica, and talc.

[0028] In the fenofibrate sustained-release layer, the sustained-release layer filler includes one or more of anhydrous dicalcium phosphate, corn starch, microcrystalline cellulose, and lactose;

[0029] The sustained-release layer disintegrant includes one or more of croscarmellose sodium, croscarmellose and sodium carboxymethyl starch;

[0030] The sustained-release layer adhesive includes one or more of ethyl cellulose, hydroxypropyl cellulose, and povidone;

[0031] The sustained-release layer solubilizer includes one or more of sodium sulfobutyl betacyclodextrin, sodium dodecyl sulfate, and polysorbate 80;

[0032] The sustained-release layer's sustained-release matrix material includes one or more of Compritol® 888 ATO, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose;

[0033] The slow-release layer lubricant includes one or more of sodium fumarate stearate, talc, and magnesium stearate.

[0034] In some specific implementations, the filler in the ezetimibe immediate-release layer is mannitol;

[0035] The immediate-release layer surfactant is Gelucire. ® mixture;

[0036] The immediate-release layer adhesive is copolyvinylpyrrolidone;

[0037] The immediate-release layer disintegrant is F-MELT® Type M;

[0038] The quick-release layer lubricant is magnesium stearate;

[0039] In the fenofibrate sustained-release layer, the sustained-release layer filler is lactose;

[0040] The sustained-release layer disintegrant is cross-linked sodium carboxymethyl cellulose;

[0041] The slow-release layer adhesive is ethyl cellulose;

[0042] The solubilizer for the sustained-release layer is sodium sulfobutyl betacyclodextrin;

[0043] The sustained-release layer's sustained-release framework material is Compritol® 888 ATO;

[0044] The slow-release layer lubricant is sodium fumarate stearate.

[0045] In some specific implementations, the ezetimibe immediate-release layer includes:

[0046] 1.5wt%~8.5wt% of ezetimibe;

[0047] 5wt%~15wt% mannitol;

[0048] 1wt%~2.5wt% Gelucire ® mixture;

[0049] 1wt%~2wt% copolyvinylpyrrolidone;

[0050] 1wt%~4wt% F-MELT® Type M;

[0051] 0.2wt%~1.3wt% magnesium stearate;

[0052] The fenofibrate extended-release layer comprises:

[0053] 25wt%~60wt% fenofibrate;

[0054] 10wt%~15wt% lactose;

[0055] 1.5wt%~3wt% of croscarmellose sodium;

[0056] 2wt%~4wt% ethyl cellulose;

[0057] 2wt%~8wt% sodium sulfobutyl betacyclodextrin;

[0058] 10wt%~35wt% Compritol® 888 ATO;

[0059] Sodium stearate fumarate, 0.5wt%~1.5wt%.

[0060] This application provides a bilayer tablet containing ezetimibe and fenofibrate, comprising an ezetimibe immediate-release layer and a fenofibrate sustained-release layer. The ezetimibe immediate-release layer enables rapid release of ezetimibe, allowing for rapid onset of action; the fenofibrate sustained-release layer enables slow release of fenofibrate, maintaining the effective drug concentration in the body and prolonging the duration of action. This ensures that ezetimibe inhibits intestinal cholesterol absorption, while fenofibrate accelerates triglyceride metabolism, achieving a complementary mechanism of action and producing a synergistic effect greater than the sum of its parts (1+1>2). It can be used for the clinical treatment of hypercholesterolemia, hypertriglyceridemia, and mixed dyslipidemia, comprehensively reducing triglyceride, total cholesterol, and LDL-C levels while increasing HDL-C levels, with a low incidence of adverse reactions. Furthermore, this application optimizes the formulation of the ezetimibe immediate-release layer and the fenofibrate sustained-release layer, synergistically improving the water solubility and dissolution rate of ezetimibe and fenofibrate, increasing the oral bioavailability of both drugs, reducing individual variability, and ensuring synergistic lipid-lowering efficacy. Moreover, the bilayer tablets provided in this application only need to be taken once a day, which significantly reduces the frequency of medication and improves patient medication adherence, making them especially suitable for patients with dyslipidemia who need to take medication for a long time.

[0061] This application also provides a method for preparing the bilayer tablet described in the above technical solution, comprising the following steps:

[0062] 1) Ezetimibe, instant-release layer filler, instant-release layer surfactant, instant-release layer binder, instant-release layer disintegrant and instant-release layer lubricant are mixed to obtain ezetimibe granules;

[0063] 2) After mixing fenofibrate, sustained-release layer filler, sustained-release layer disintegrant, sustained-release layer binder, sustained-release layer solubilizer and sustained-release layer skeleton material, granulation is performed. The resulting granules are then mixed with the sustained-release layer lubricant to obtain fenofibrate granules.

[0064] 3) The ezetimibe granules and fenofibrate granules are compressed in a bilayer tableting machine to obtain a bilayer tablet comprising an ezetimibe immediate-release layer and a fenofibrate sustained-release layer.

[0065] In some specific implementations, step a) specifically includes the following steps:

[0066] a1) Premix ezetimibe, instant-release layer surfactant, instant-release layer binder and instant-release layer disintegrant to obtain a first mixture;

[0067] a2) Mix the first mixture with the immediate-release layer filler to obtain the second mixture;

[0068] a3) The second mixture is mixed with the quick-release layer lubricant to obtain ezetimibe particles;

[0069] Step b) specifically includes the following steps:

[0070] b1) Premix fenofibrate, sustained-release layer filler, sustained-release layer disintegrant, sustained-release layer binder and sustained-release layer skeleton material to obtain a premix;

[0071] b2) The premix is ​​granulated, and the slow-release layer solubilizer is added in the form of atomization during the granulation process to obtain wet granules;

[0072] b3) The wet particles are granulated and then dried to obtain dry particles;

[0073] b4) After the dry particles are granulated, they are mixed with the slow-release lubricant to obtain fenofibrate particles.

[0074] In some specific implementations, the ezetimibe and fenofibrate are independently pre-processed by pulverization to obtain ezetimibe powder and fenofibrate powder respectively.

[0075] The D of the ezetimibe powder 90 <5μm;

[0076] The D of the fenofibrate powder 90 <10μm.

[0077] In some specific implementations, the concentration of the aqueous solution of the sustained-release layer solubilizer is 5wt%~15wt% during atomization.

[0078] The atomization pressure is 1 bar to 3 bar.

[0079] In some specific implementations, the screen size for sizing the wet particles is 14 mesh to 20 mesh;

[0080] The sieve particle size for sizing the dry granules is 14-20 mesh.

[0081] In some specific implementations, the core hardness of the compressed tablet is 50N~150N.

[0082] This application employs a direct powder compression process to prepare ezetimibe immediate-release granules and a wet granulation process to prepare fenofibrate sustained-release granules. This synergistic approach improves the water solubility and dissolution rate of both ezetimibe and fenofibrate, enhances the oral bioavailability of the two drugs, reduces individual variability, and ensures synergistic lipid-lowering efficacy. Furthermore, it ensures the formability and stability of the formulation and simplifies the production process, making it suitable for industrial-scale production. This application also employs a "material layering and filling + one-time molding and pressing" method to prepare bilayer tablets. This method ensures the physicochemical stability and functionality of both the ezetimibe immediate-release layer and the fenofibrate sustained-release layer, while also ensuring a tight bond between the two layers, preventing separation or cross-contamination, and meeting the standard quality requirements for tablets. Experimental results show that the bilayer tablets prepared in this application have good dissolution curves, with ezetimibe dissolving rapidly and fenofibrate dissolving slowly, continuing until complete dissolution after 12 hours. Compared with the simultaneous use of ezetimibe immediate-release tablets and fenofibrate extended-release tablets, the bilayer tablets provided in this application can significantly improve the bioavailability of ezetimibe and fenofibrate, significantly reduce serum TC, TG, and LDL-C levels in patients, significantly increase serum HDL-C levels in patients, and have a significantly lower overall incidence of adverse reactions. Attached Figure Description

[0083] Figure 1 Due to weight differences in ezetimibe immediate-release tablets;

[0084] Figure 2 For the difference in weight of fenofibrate extended-release tablets;

[0085] Figure 3 For hardness fluctuations in bilayer tablets;

[0086] Figure 4 The dissolution curve of ezetimibe;

[0087] Figure 5 The dissolution curve for fenofibrate; Detailed Implementation

[0088] It should be understood that the expression “one or more of…” individually includes each of the objects described after the expression, as well as various different combinations of two or more of the described objects, unless otherwise understood from the context and usage. The expression “and / or” combined with three or more described objects should be understood to have the same meaning, unless otherwise understood from the context.

[0089] The terms “including,” “having,” or “containing,” including the use of their grammatical synonyms, should generally be understood as open-ended and non-restrictive, for example, not excluding other unstated elements or steps, unless otherwise specifically stated or understood from the context.

[0090] It should be understood that the order of steps or the sequence of actions is not important as long as this application remains operational. Furthermore, two or more steps or actions can be performed simultaneously.

[0091] The use of any and all instances or exemplary language such as “e.g.” or “include” in this document is intended merely to better illustrate the application and does not constitute a limitation on the scope of the application. No language in this specification should be construed as indicating that any unclaimed element is essential to the practice of this application.

[0092] Furthermore, the numerical ranges and parameters used to define this application are approximate values, and the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any numerical value inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise explicitly stated, it should be understood that all ranges, quantities, values, and percentages used in this disclosure are modified with the word "approximately." Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a specific value or range.

[0093] This application provides a bilayer tablet containing ezetimibe and fenofibrate, comprising an immediate-release ezetimibe layer and a sustained-release fenofibrate layer;

[0094] The ezetimibe immediate-release layer comprises:

[0095] 1wt%~10wt% ezetimibe;

[0096] 5wt%~20wt% immediate-release layer filler;

[0097] 1wt%~3wt% of immediate-release surfactant;

[0098] 1wt%~5wt% immediate-release layer adhesive;

[0099] 1wt%~5wt% of immediate-release layer disintegrant;

[0100] 0.1wt%~1.5wt% of quick-release layer lubricant;

[0101] The fenofibrate extended-release layer comprises:

[0102] 10wt%~60wt% fenofibrate;

[0103] 10wt%~30wt% of sustained-release layer filler;

[0104] 1wt%~6wt% of sustained-release layer disintegrant;

[0105] 2wt%~5wt% of slow-release layer adhesive;

[0106] 1wt%~8wt% of sustained-release layer solubilizer;

[0107] 10wt%~40wt% of sustained-release layer and sustained-release skeleton material;

[0108] 0.1~2% slow-release lubricant.

[0109] The bilayer tablet provided in this application includes an ezetimibe immediate-release layer, which enables rapid release of ezetimibe, allowing the drug to take effect quickly. In some specific implementations, the ezetimibe immediate-release layer includes:

[0110] 1wt%~10wt% ezetimibe;

[0111] 5wt%~20wt% immediate-release layer filler;

[0112] 1wt%~3wt% of immediate-release surfactant;

[0113] 1wt%~5wt% immediate-release layer adhesive;

[0114] 1wt%~5wt% of immediate-release layer disintegrant;

[0115] 0.1wt%~1.5wt% of quick-release layer lubricant.

[0116] Those skilled in the art will understand that the weight percentage of each component in this application refers to the percentage of each component to the total weight of the bilayer tablet.

[0117] The ezetimibe immediate-release layer includes ezetimibe, a cholesterol absorption inhibitor that specifically adheres to the brush border of the small intestinal villi and effectively reduces cholesterol absorption in the intestine by inhibiting the cholesterol transporter NPC1L1. In some specific implementations, the content of ezetimibe is 1wt% to 10wt%, preferably 1.5wt% to 8.5wt%.

[0118] The ezetimibe immediate-release layer includes an immediate-release layer filler. In some specific implementations, the immediate-release layer filler includes, but is not limited to, corn starch, microcrystalline cellulose, and mannitol, and may be one or more of these. When the immediate-release layer filler is a combination of multiple substances, this application does not have any special restrictions on its specific amount. In some specific implementations, the immediate-release layer filler is preferably mannitol. In some specific implementations, the content of the immediate-release layer filler is 5wt%~20wt%, preferably 6wt%~15wt%.

[0119] The ezetimibe immediate-release layer includes an immediate-release surfactant, and in some specific implementations, the immediate-release surfactant includes, but is not limited to, Gelucire. ®The mixture, sodium dodecyl sulfate, and poloxamer 188 can be one or more of these substances. When the immediate-release layer surfactant is a combination of multiple substances, this application does not have any particular limitation on its specific amount. In some specific implementations, the immediate-release layer surfactant is preferably Gelucire. ® Mixture. In some specific implementations, the content of the immediate-release layer filler is 1wt% to 3wt%, preferably 1.5wt% to 2.5wt%.

[0120] The ezetimibe immediate-release layer includes an immediate-release layer binder. In some specific implementations, the immediate-release layer binder includes, but is not limited to, povidone, hydroxypropyl cellulose E5, and copovidone, and may be one or more of these. When the immediate-release layer binder is a combination of multiple substances, this application does not have any special restrictions on its specific amount. In some specific implementations, the immediate-release layer binder is preferably copovidone. In some specific implementations, the content of the immediate-release layer binder is 1wt% to 5wt%, preferably 1wt% to 3wt%.

[0121] The ezetimibe immediate-release layer includes an immediate-release layer disintegrant. In some specific implementations, the immediate-release layer disintegrant includes, but is not limited to, F-MELT® Type M, croscarmellose sodium, and croscarmellose, and may be one or more of these. When the immediate-release layer disintegrant is a combination of multiple substances, this application does not have any special limitation on its specific amount. In some specific implementations, the immediate-release layer disintegrant is preferably F-MELT® Type M. In some specific implementations, the content of the immediate-release layer disintegrant is 1wt% to 5wt%, preferably 1.5wt% to 4wt%.

[0122] The ezetimibe quick-release layer includes a quick-release layer lubricant. In some specific implementations, the quick-release layer lubricant includes, but is not limited to, magnesium stearate, colloidal silica, and talc, and may be one or more of these. When the quick-release layer lubricant is a combination of multiple substances, this application does not have any special restrictions on its specific amount. In some specific implementations, the quick-release layer lubricant is preferably magnesium stearate. In some specific implementations, the content of the quick-release layer lubricant is 0.1wt% to 1.5wt%, preferably 0.2wt% to 1wt%.

[0123] The bilayer tablet provided in this application includes a fenofibrate sustained-release layer, which enables the slow release of fenofibrate, maintains the effective drug concentration in the body, and prolongs the duration of action. In some specific implementations, the fenofibrate sustained-release layer includes:

[0124] 10wt%~60wt% fenofibrate;

[0125] 10wt%~30wt% of sustained-release layer filler;

[0126] 1wt%~6wt% of sustained-release layer disintegrant;

[0127] 2wt%~5wt% of slow-release layer adhesive;

[0128] 1wt%~8wt% of sustained-release layer solubilizer;

[0129] 10wt%~40wt% of sustained-release layer and sustained-release skeleton material;

[0130] 0.1~2% slow-release lubricant.

[0131] The fenofibrate sustained-release layer includes fenofibrate, a fibrate-based lipid-regulating drug that primarily regulates the expression of lipoprotein metabolism-related genes by activating peroxisome proliferator-activated receptor α (PPARα). Upon PPARα activation, fenofibrate enhances lipoprotein lipase activity, accelerating the breakdown of very low-density lipoprotein (VLDL) and triglycerides, thereby significantly reducing plasma TG levels. Simultaneously, fenofibrate can reduce VLDL synthesis in the liver and promote its breakdown, further reducing TG levels. Fenofibrate also increases HDL-C levels by promoting reverse cholesterol transport, returning cholesterol from peripheral tissues to the liver for metabolism, thus reducing cholesterol deposition on blood vessel walls. Furthermore, fenofibrate improves lipoprotein particle quality, reducing small, dense LDL and increasing large, sparse LDL. In some specific implementations, the fenofibrate content is 10wt%~60wt%, preferably 20wt%~50wt%, and more preferably 25wt%~45wt%. In some specific implementations, the mass ratio of ezetimibe and fenofibrate in the bilayer tablet is 10:200, 15:180, 30:150, 10:120, 10:300, 10:100, etc., preferably 10:200.

[0132] The fenofibrate sustained-release layer includes a sustained-release layer filler. In some specific implementations, the sustained-release layer filler includes, but is not limited to, anhydrous dicalcium phosphate, corn starch, microcrystalline cellulose, and lactose, and may be one or more of these. When the sustained-release layer filler is a combination of multiple substances, this application does not have any special restrictions on its specific amount. In some specific implementations, the sustained-release layer filler is preferably lactose. In some specific implementations, the content of the sustained-release layer filler is 10wt%~30wt%, preferably 10wt%~25wt%.

[0133] The fenofibrate sustained-release layer includes a sustained-release layer disintegrant. In some specific implementations, the sustained-release layer disintegrant includes, but is not limited to, croscarmellose sodium, croscarmellose, and sodium carboxymethyl starch, and may be one or more of these. When the sustained-release layer disintegrant is a combination of multiple substances, this application does not have any special restrictions on its specific amount. In some specific implementations, the sustained-release layer is preferably croscarmellose sodium. In some specific implementations, the content of the sustained-release layer disintegrant is 1 wt% to 6 wt%, preferably 1 wt% to 5 wt%.

[0134] The fenofibrate sustained-release layer includes a sustained-release layer adhesive. In some specific implementations, the sustained-release layer adhesive includes, but is not limited to, ethyl cellulose, hydroxypropyl cellulose, and povidone, and may be one or more of these. When the sustained-release layer adhesive is a combination of multiple substances, this application does not have any particular limitation on its specific amount. In some specific implementations, the sustained-release layer adhesive is preferably ethyl cellulose. In some specific implementations, the amount of the sustained-release layer adhesive is 2wt% to 5wt%, preferably 2wt% to 4wt%.

[0135] The fenofibrate sustained-release layer includes a sustained-release layer solubilizer. In some specific implementations, the sustained-release layer solubilizer includes, but is not limited to, sodium sulfobutyl beta-cyclodextrin, sodium dodecyl sulfate, and polysorbate 80, and may be one or more of these. When the sustained-release layer solubilizer is a combination of multiple substances, this application does not have any special limitation on its specific amount. In some specific implementations, the sustained-release layer solubilizer is preferably sodium sulfobutyl beta-cyclodextrin. In some specific implementations, the amount of the sustained-release layer solubilizer is 1wt% to 8wt%, preferably 2wt% to 7wt%.

[0136] The fenofibrate sustained-release layer includes a sustained-release matrix material. In some specific implementations, the sustained-release matrix material includes, but is not limited to, Compritol® 888 ATO, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose, and may be one or more of these. When the sustained-release matrix material is a combination of multiple substances, this application does not have any special restrictions on its specific amount. In some specific implementations, the sustained-release matrix material is preferably Compritol® 888 ATO. In some specific implementations, the amount of the sustained-release matrix material is 10wt% to 40wt%, preferably 10wt% to 35wt%.

[0137] The fenofibrate sustained-release layer includes a sustained-release lubricant. In some specific implementations, the sustained-release lubricant includes, but is not limited to, sodium fumarate stearate, talc, and magnesium stearate, and may be one or more of these. When the sustained-release lubricant is a combination of multiple substances, this application does not have any special limitation on its specific amount. In some specific implementations, the sustained-release lubricant is preferably sodium fumarate stearate. In some specific implementations, the amount of the sustained-release lubricant is 0.1wt% to 2wt%, preferably 0.1wt% to 1.5wt%.

[0138] In a typical implementation, the ezetimibe immediate-release layer in the bilayer tablet comprises:

[0139] 1.5wt%~8.5wt% of ezetimibe;

[0140] 5wt%~15wt% mannitol;

[0141] 1wt%~2.5wt% Gelucire ® mixture;

[0142] 1wt%~2wt% copolyvinylpyrrolidone;

[0143] 1wt%~4wt% F-MELT® Type M;

[0144] 0.2wt%~1.3wt% magnesium stearate;

[0145] The fenofibrate extended-release layer comprises:

[0146] 25wt%~60wt% fenofibrate;

[0147] 10wt%~15wt% lactose;

[0148] 1.5wt%~3wt% of croscarmellose sodium;

[0149] 2wt%~4wt% ethyl cellulose;

[0150] 2wt%~8wt% sodium sulfobutyl betacyclodextrin;

[0151] 10wt%~35wt% Compritol® 888 ATO;

[0152] Sodium stearate fumarate, 0.5wt%~1.5wt%.

[0153] This application optimizes the formulation of the ezetimibe immediate-release layer and the fenofibrate sustained-release layer to synergistically improve the water solubility and dissolution rate of ezetimibe and fenofibrate, thereby increasing the oral bioavailability of the two drugs, reducing individual differences, and ensuring synergistic lipid-lowering efficacy.

[0154] This application also provides a method for preparing the bilayer tablet described in the above technical solution, comprising the following steps:

[0155] 1) Ezetimibe, instant-release layer filler, instant-release layer surfactant, instant-release layer binder, instant-release layer disintegrant and instant-release layer lubricant are mixed to obtain ezetimibe granules;

[0156] 2) After mixing fenofibrate, sustained-release layer filler, sustained-release layer disintegrant, sustained-release layer binder, sustained-release layer solubilizer and sustained-release layer skeleton material, granulation is performed. The resulting granules are then mixed with the sustained-release layer lubricant to obtain fenofibrate granules.

[0157] 3) The ezetimibe granules and fenofibrate granules are compressed in a bilayer tableting machine to obtain a bilayer tablet comprising an ezetimibe immediate-release layer and a fenofibrate sustained-release layer.

[0158] This application uses a powder direct compression process to prepare ezetimibe immediate-release granules and a wet granulation process to prepare fenofibrate sustained-release granules. This can synergistically improve the water solubility and dissolution rate of ezetimibe and fenofibrate, increase the oral bioavailability of the two drugs, reduce individual differences, ensure synergistic lipid-lowering efficacy, and also ensure the formability and stability of the formulation, while simplifying the production process and making it suitable for industrial-scale production.

[0159] This application uses a powder direct compression process to prepare ezetimibe immediate-release granules, specifically including the following steps:

[0160] a1) Premix ezetimibe, instant-release layer surfactant, instant-release layer binder and instant-release layer disintegrant to obtain a first mixture;

[0161] a2) Mix the first mixture with the immediate-release layer filler to obtain the second mixture;

[0162] a3) The second mixture is mixed with the quick-release layer lubricant to obtain ezetimibe particles.

[0163] This application first premixes ezetimibe, an immediate-release layer surfactant, an immediate-release layer binder, and an immediate-release layer disintegrant to obtain a first mixture. In some specific implementations, the premixing speed is 10 rpm to 20 rpm, for example, 10 rpm, 15 rpm, 20 rpm, etc.; the time is 10 min to 20 min, for example, 10 min, 15 min, 20 min, etc. Before mixing, it is preferable to pre-treat the ezetimibe by pulverizing, preferably using an air jet mill. In some specific implementations, the particle size D of the pulverized ezetimibe powder is... 90 <5μm.

[0164] After obtaining the first mixture, it is mixed with an immediate-release layer filler to obtain the second mixture. In some specific implementations, the mixing speed is 10 rpm to 20 rpm, such as 10 rpm, 15 rpm, 20 rpm, etc.; the mixing time is 20 min to 30 min, such as 20 min, 25 min, 30 min, etc.

[0165] After obtaining the second mixture, it is mixed with an instant-release lubricant to obtain ezetimibe particles. In some specific implementations, the mixing speed is 10 rpm to 20 rpm, such as 10 rpm, 15 rpm, 20 rpm, etc.; the mixing time is 3 min to 8 min, such as 3 min, 5 min, 8 min, etc., preferably 5 min.

[0166] This application uses wet granulation to prepare fenofibrate sustained-release granules, specifically including the following steps:

[0167] b1) Premix fenofibrate, sustained-release layer filler, sustained-release layer disintegrant, sustained-release layer binder and sustained-release layer skeleton material to obtain a premix;

[0168] b2) The premix is ​​granulated, and the slow-release layer solubilizer is added in the form of atomization during the granulation process to obtain wet granules;

[0169] b3) The wet particles are sieved and granulated, then dried to obtain dry particles;

[0170] b4) After the dry particles are sieved and granulated, they are mixed with the slow-release lubricant to obtain fenofibrate particles.

[0171] This application premixes fenofibrate, a sustained-release layer filler, a sustained-release layer disintegrant, a sustained-release layer binder, and a sustained-release layer skeleton material to obtain a premix. In some specific implementations, the premixing is carried out in a wet granulator, with a stirring speed of 100 rpm to 150 rpm, such as 100 rpm, 110 rpm, 120 rpm, 130 rpm, 140 rpm, and 150 rpm; a chopping speed of 500 rpm to 1000 rpm, such as 500 rpm, 600 rpm, 700 rpm, 800 rpm, 900 rpm, and 1000 rpm; and a time of 10 min to 20 min, such as 10 min, 15 min, and 20 min. Prior to mixing, the fenofibrate is preferably pre-treated by pulverization, preferably using an air jet mill. In some specific implementations, the particle size D of the pulverized fenofibrate powder is... 90 <10μm.

[0172] After obtaining the premix, it is granulated. During the granulation process, the slow-release layer solubilizer is added in an atomized form to obtain wet granules. In this application, the slow-release layer solubilizer is first dissolved in water to obtain an aqueous solution of the slow-release layer solubilizer. Then, while the premix is ​​being wet-granulated, the aqueous solution of the slow-release layer solubilizer is sprayed into a wet granulator in an atomized form for granulation. In some specific implementations, the concentration of the aqueous solution of the slow-release layer solubilizer is 5wt%~15wt%, preferably 5wt%~10wt%, for example, 5%, 10%, 12%, 15%, etc. In some specific implementations, the atomization pressure is 1 bar~3 bar. After the aqueous solution of the slow-release layer solubilizer is added, stirring continues for 3~5 minutes to obtain wet granules.

[0173] After obtaining wet granules, they are granulated. In some specific implementations, the sieve particle size for granulation is 14-20 mesh, such as 14 mesh, 15 mesh, or 20 mesh. After granulation, they are dried. In some specific implementations, the drying is specifically fluidized bed drying, with the material temperature not exceeding 60°C and the particle moisture content not exceeding 1%.

[0174] After drying, dry granules are obtained, and these granules are then granulated again. In some specific implementations, the sieve particle size for granulation is 14-20 mesh. After granulation, the dry granules are mixed with a slow-release lubricant to obtain fenofibrate granules. In some specific implementations, the mixing time is 3-8 minutes, preferably 5 minutes.

[0175] After obtaining ezetimibe granules and fenofibrate granules, they are compressed into tablets using a double-layer tableting machine to obtain a double-layer tablet comprising an ezetimibe immediate-release layer and a fenofibrate sustained-release layer. In some specific implementations, the tablet core hardness is 50N~150N, for example, 50N, 60N, 70N, 80N, 90N, 100N, 110N, 120N, 130N, 140N, 150N, etc. Excessive core hardness will affect the dissolution of ezetimibe and fenofibrate, while insufficient core hardness is detrimental to tablet formation. In some specific implementations, the weight difference between each layer is controlled within 5% during tableting.

[0176] The bilayer tablets provided in this application are suitable for the clinical treatment of hypercholesterolemia, hypertriglyceridemia, and mixed dyslipidemia. Ezetimibe and fenofibrate work synergistically to lower triglycerides, total cholesterol, and LDL-C levels, while increasing HDL-C levels, with a low incidence of adverse reactions. In the bilayer tablets provided in this application, the immediate-release layer of ezetimibe and the sustained-release layer of fenofibrate have distinct structures and independent functions, avoiding potential drug interactions and ensuring the safety and efficacy of the formulation.

[0177] The present application is further illustrated below with reference to embodiments. The scope of protection of the present application is not limited to the following embodiments.

[0178] In the following embodiments, all raw materials are commercially available.

[0179] Example 1

[0180] Prepare ezetimibebufenofibrate bilayer tablets according to the formulation shown in Table 1.

[0181] Table 1. Formulation of the bilayer tablet in Example 1

[0182]

[0183] The preparation method is as follows:

[0184] 1) Preparation process of ezetimibe immediate-release granules:

[0185] A. Ezetamide powder is obtained by pulverizing the raw material using an air jet mill, with the particle size controlled within D. 90 <5μm;

[0186] B. Weigh out the prescribed amounts of ezetimibe powder, mannitol, Gelucire® mixture, copovidone VA64, F-MELT® Type M, and magnesium stearate, respectively.

[0187] C. Place ezetimibe powder, Gelucire® mixture, copovidone VA64, and F-MELT® Type M in a mixer for premixing at a speed of 10 rpm to 20 rpm for 10 to 20 min.

[0188] D. Add mannitol to the mixer for a second mixing at a speed of 10-20 rpm for 20-30 minutes.

[0189] E. Add magnesium stearate to the mixer and mix at 10-20 rpm for 5 minutes to obtain ezetimibe immediate-release granules.

[0190] 2) Preparation process of fenofibrate sustained-release granules:

[0191] A. Fenofibrate, the active pharmaceutical ingredient, is pulverized using an air jet mill to obtain fenofibrate powder, with particle size controlled by D. 90 <10μm;

[0192] B. Weigh out the prescribed amounts of fenofibrate powder, lactose, croscarmellose sodium ND-2HS, ethyl cellulose, sodium sulfobutyl betacyclodextrin, Compritol® 888 ATO, and sodium stearate fumarate, respectively.

[0193] C. Add sodium sulfobutyl betacyclodextrin to purified water, stir well, and prepare a 10% solution;

[0194] D. Granulation: Place fenofibrate powder, lactose, croscarmellose sodium ND-2HS, ethyl cellulose, and Compritol® 888 ATO into a wet granulator and premix for 10 to 20 minutes. Then turn on the wet granulator and control the atomization pressure to 1 to 3 bar. Spray the solution obtained in step C) into the wet granulator in the form of an atomizer for granulation. After the purified water is sprayed out, continue stirring for 3 to 5 minutes.

[0195] E. Wet granulation: Soft materials are granulated using a 14-20 mesh sieve;

[0196] F. Drying: Transfer the material to a fluidized bed dryer for further drying. The material temperature should not exceed 60℃, and the particle moisture content should not exceed 1%.

[0197] G. Dry granulation: After drying, the granules are granulated using a 14-20 mesh sieve.

[0198] H. Blending: Transfer the granulated particles into a blender, add sodium stearate fumarate, and blend for 5 minutes to obtain fenofibrate sustained-release particles.

[0199] 3) Double-layer structure sustained-release tablet compression:

[0200] Ezetimibe immediate-release granules and fenofibrate sustained-release granules were placed in different hoppers of a rotary double-layer tablet press. The tablet press was turned on to produce ezetimibe-fenofibrate double-layer sustained-release tablets. The tablet core hardness was controlled between 50N and 150N, and the weight difference between each layer was controlled between 0 and 5%.

[0201] Following the preparation method of Example 1, three batches of ezetimibe immediate-release granules and fenofibrate sustained-release granules were prepared in parallel. The powder properties of the two types of granules were tested, and the specific test results are shown in Table 2.

[0202] Table 2. Powder properties of three batches of ezetimibe immediate-release granules and fenofibrate sustained-release granules

[0203]

[0204] As shown in Table 1, the powder science data of the three batches of particles prepared using this application are similar, indicating that the preparation method of this application has good reproducibility; the particles all have good flowability, indicating that the particle quality prepared by the formulation and preparation method of this application is stable and controllable.

[0205] The three batches of granules were compressed into bilayer tablets. The differences in tablet weight between the ezetimibe immediate-release layer and the fenofibrate extended-release layer, as well as the hardness of the bilayer extended-release tablets, were measured in the three batches. The results are shown below. Figure 1 , Figure 2 and Figure 3 ,in, Figure 1 Due to weight differences in ezetimibe immediate-release tablets, Figure 2 Due to the weight difference of fenofibrate extended-release tablets, Figure 3 This refers to the hardness fluctuation of bilayer tablets. Figure 1 and Figure 2 It can be seen that the weight differences of the ezetimibe and fenofibrate layers are stable and can be controlled within ±5%. Figure 3 It can be seen that the hardness of the three batches of bilayer tablets can be controlled within the range of 50~150N, and the hardness fluctuations are relatively similar, indicating that the bilayer tableting process is stable and controllable.

[0206] Example 2

[0207] Prepare ezetimibebufenofibrate bilayer tablets according to the formulation shown in Table 3.

[0208] Table 3. Example 2: Bilayer Tablet Formulation

[0209]

[0210] The preparation method is the same as in Example 1 of the application.

[0211] Example 3

[0212] Prepare ezetimibebufenofibrate bilayer tablets according to the formulation shown in Table 4.

[0213] Table 4. Formulation of the double-layer tablet in Example 3

[0214]

[0215] The preparation method is the same as in Example 1 of the application.

[0216] Example 4

[0217] Prepare ezetimibebufenofibrate bilayer tablets according to the formulation shown in Table 5.

[0218] Table 5. Example 4: Bilayer Tablet Formulation

[0219]

[0220] The preparation method is the same as in Example 1 of the application.

[0221] Example 5

[0222] Prepare ezetimibebufenofibrate bilayer tablets according to the formulation shown in Table 6.

[0223] Table 6. Formulation of the bilayer tablet in Example 5

[0224]

[0225] The preparation method is the same as in Example 1 of the application.

[0226] Example 6

[0227] Prepare ezetimibebufenofibrate bilayer tablets according to the formulation shown in Table 7.

[0228] Table 7. Formulation of the double-layer tablet in Example 6

[0229]

[0230] The preparation method is the same as in Example 1 of the application.

[0231] Comparative Example 1

[0232] Compared with Example 1, the difference is that the raw materials ezetimibe and fenofibrate were not processed by an air jet mill, that is, raw ezetimibe and raw fenofibrate were used. The other formulations and preparation steps are the same as in Example 1.

[0233] Comparative Example 2

[0234] Prepare ezetimibebufenofibrate bilayer tablets according to the formulation shown in Table 8.

[0235] Table 8 Comparative Example 2: Bilayer Tablet Formulation

[0236]

[0237] The preparation method is the same as in Example 1 of the application.

[0238] Comparative Example 3

[0239] Prepare ezetimibebufenofibrate bilayer tablets according to the formulation shown in Table 9.

[0240] Table 9 Comparative Example 3 Bilayer Tablet Formulation

[0241]

[0242] The preparation method is the same as in Example 1 of the application.

[0243] Comparative Example 4

[0244] Prepare ezetimibebufenofibrate bilayer tablets according to the formulation shown in Table 10.

[0245] Table 10 Comparative Example 4: Bilayer Tablet Formulation

[0246]

[0247] The preparation method is the same as in Example 1 of the application.

[0248] Comparative Example 5

[0249] The difference compared to Example 1 lies in the preparation process of the fenofibrate sustained-release granules:

[0250] A. Fenofibrate, the active pharmaceutical ingredient, is pulverized using an air jet mill to obtain fenofibrate powder, with particle size controlled by D. 90 <10μm;

[0251] B. Weigh out the prescribed amounts of fenofibrate powder, lactose, croscarmellose sodium ND-2HS, ethyl cellulose, sodium sulfobutyl betacyclodextrin, Compritol® 888 ATO, and sodium stearate fumarate, respectively.

[0252] C. Mixing: Place fenofibrate powder, lactose, croscarmellose sodium ND-2HS, ethyl cellulose, sodium sulfobutyl betacyclodextrin, and Compritol® 888 ATO into a mixer, set the mixing speed to 10-20 rpm, and mix for 20-30 minutes.

[0253] D. Total mixing: Add sodium stearate fumarate and mix for 5 minutes to obtain fenofibrate sustained-release granules.

[0254] The other formulations and preparation steps are the same as in Example 1.

[0255] Comparative Example 6

[0256] Compared with Example 1, the difference is that a double-layer tablet with a pressing hardness higher than 150N is used, while the formulation and other preparation steps are the same as in Example 1.

[0257] Comparative Example 7

[0258] Compared with Example 1, the difference lies in the following process parameters in the preparation process of fenofibrate sustained-release particles:

[0259] E. Wet granulation: Soft materials are granulated using a 10-mesh sieve;

[0260] F. Drying: Transfer to a fluidized bed dryer for further drying, ensuring the material temperature does not exceed 60℃ and the particle moisture content is 1.5%.

[0261] G. Dry granulation: After drying, the granules are granulated using a 10-mesh sieve.

[0262] The other formulations and preparation steps are the same as in Example 1.

[0263] Ezetimibe immediate-release granules and fenofibrate sustained-release granules from Comparative Example 7 were tested for content uniformity according to the content uniformity test method 0941 of the 2025 edition of the Chinese Pharmacopoeia. The results showed that the content uniformity A+2.2S of both ezetimibe and fenofibrate was greater than 15, failing to meet the requirements. This indicates that the process parameters provided in this application are beneficial for tablet quality control and protect patient medication safety.

[0264] Comparative Example 8

[0265] Compared with Example 1, the difference is that a double-layer tablet with a hardness of less than 50N is pressed, while the formulation and other preparation steps are the same as in Example 1.

[0266] When performing double-layer tablet compression, a hardness below 50N is not conducive to tablet formation.

[0267] Application Example 1: In vitro dissolution test

[0268] The bilayer tablets prepared according to Examples 1 to 6 and Comparative Examples 1 to 6 of this application were subjected to dissolution curve determination according to the following detection method:

[0269] Take this product and place it in a settling basket. Perform the dissolution test according to the Chinese Pharmacopoeia 2025, using 900 ml of pH 6.8 phosphate buffer as the dissolution medium and a rotation speed of 75 rpm. Take 5 mL of solution at 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 12 h respectively, filter, and immediately replenish with the same volume and temperature of dissolution medium. Accurately measure 5 μL of the filtrate according to the chromatographic conditions under the Assay section and inject it into the liquid chromatograph. Record the color. Spectrum; Separately, accurately weigh an appropriate amount of ezetimibe reference standard, and quantitatively dilute it with a diluent to prepare a solution containing 1.1 mg of ezetimibe per 1 mL, as the ezetimibe stock solution; Separately, accurately weigh an appropriate amount of fenofibrate reference standard, and accurately add an appropriate amount of ezetimibe stock solution, dissolve and quantitatively dilute with a dissolution medium to prepare solutions containing 0.11 mg of ezetimibe and 1.1 mg of fenofibrate per 1 mL, as the reference solutions, and determine them using the same method. Specific dissolution data are shown in Tables 11 and 12; dissolution curves are shown in [reference missing]. Figure 4 and Figure 5 , Figure 4 The dissolution curve of ezetimibe. Figure 5 The dissolution curve for fenofibrate is shown.

[0270] Table 11 Ezetimibe dissolution data for Examples 1-6 and Comparative Examples 1-6

[0271]

[0272] Table 12 Fenofibrate dissolution data for Examples 1-6 and Comparative Examples 1-6

[0273]

[0274] From Table 11 and Table 12, Figure 4 and Figure 5 It can be known that:

[0275] 1. Based on the dissolution curve data of ezetimibe and fenofibrate in Examples 1 to 5, ezetimibe dissolves rapidly, while fenofibrate dissolves slowly, taking up to 12 hours to completely dissolve. Furthermore, the dissolution of the formulation exhibits good reproducibility. This indicates that in the bilayer tablets provided in this application, one layer achieves rapid release of ezetimibe by using Gelucire® mixture + copovidone VA64 to form a solid dispersion, improving the wetting properties of the lipophilic drug and enabling rapid onset of action. The other layer achieves slow release of fenofibrate by using sodium sulfobutyl betacyclodextrin + Compritol® 888ATO. This improves solubility through cyclodextrin inclusion and controls the release rate through the matrix material, maintaining the effective concentration of the drug in vivo and prolonging the duration of action.

[0276] 2. Based on the in vitro dissolution data of Example 1 and Comparative Example 1, the in vitro dissolution of the Comparative Example 1 sample, whose active pharmaceutical ingredient (API) particle size was not strictly controlled, was more than 60% slower than that of Example 1. This indicates that controlling the particle size of the API in this application is beneficial to improving the in vitro dissolution of the bilayer tablet. Ezetimibe belongs to Class II compounds in the Biopharmaceutics Classification System (BCS), and fenofibrate also has the problem of poor water solubility. Controlling the particle size of the API is beneficial to dissolution. Micronization increases the specific surface area of ​​the drug. Combined with the immediate-release / sustained-release formulation, ezetimibe dissolves rapidly and fenofibrate dissolves slowly and uniformly. The dissolution RSD values ​​are all less than 2%, which is greater than 5% compared to the dissolution RSD values ​​of commercially available single-component formulations, significantly reducing individual differences.

[0277] 3. Comparative Example 2 uses a new disintegrant. Based on the dissolution data from Example 1 and Comparative Example 2, it can be seen that the in vitro dissolution was 20% slower after replacing the disintegrant, indicating that the disintegrant selected in this application is beneficial for the dissolution of bilayer tablets. The disintegrant F-MELT® Type M used in the preparation of the ezetimibe tablets in this application achieves a disintegration time of less than 2 minutes compared to commercially available formulations, while also facilitating optimal hardness of the bilayer sustained-release tablets and providing patients with a pleasant taste, thus improving patient compliance. This application selects specific cross-linked sodium carboxymethyl cellulose, which has capillary action, effectively guiding liquid delivery into the tablet's interior; simultaneously, the cross-linked chemical structure forms a substance that, although insoluble in water, is hydrophilic and highly absorbent, exhibiting excellent swelling properties.

[0278] 4. Comparative Example 3: Replacing the plasticizer. Based on the dissolution data from Example 1 and Comparative Example 3, it can be seen that after changing the plasticizer, fenofibrate dissolves 30% slower, and the dissolution uniformity is greater than 20%, which does not meet the requirements. However, it does not affect the dissolution of ezetimibe. This indicates that the plasticizer selected in this application is beneficial to the dissolution of the bilayer structure sustained-release tablets, effectively stabilizing blood drug concentration and improving patient safety. The dissolution of ezetimibe and fenofibrate does not affect each other, indicating that the bilayer structure designed in this application can avoid potential drug interactions, ensuring the safety and efficacy of the formulation.

[0279] 5. Comparative Example 4: Replacing the sustained-release material. Based on the dissolution data from Example 1 and Comparative Example 4, it can be seen that after replacing the sustained-release material, fenofibrate dissolves more than 10% slower, and the dissolution endpoint is not fully achieved, but it does not affect the dissolution of ezetimibe. This indicates that the sustained-release material selected in this application is beneficial to the dissolution of the bilayer structure sustained-release tablet, maximizing its lipid-lowering effect. It has good chemical inertness, an HLB value of 1, and does not swell or erode during release, effectively controlling drug release. In the formulation design of this application, there is a robust matrix sustained-release system, and the dissolution of ezetimibe and fenofibrate does not affect each other. This further demonstrates that the bilayer structure designed in this application can avoid potential interactions between drugs, ensuring the safety and efficacy of the formulation.

[0280] 6. Comparative Example 5 changed its preparation process. Based on the dissolution data from Example 1 and Comparative Example 5, it can be seen that after changing the preparation process, the weight difference of fenofibrate tablets exceeded 7.5%, which is non-compliant and exceeds the internal control limit of 5% set in this application. While the dissolution of fenofibrate was not significantly different from the example, the dissolution uniformity exceeded 20%, which is non-compliant. This indicates that the differentiated granulation process used in this application is adapted to the drug characteristics, which is beneficial to the dissolution of fenofibrate and to dissolution uniformity, greatly reducing individual variability in patient medication.

[0281] Furthermore, commercially available formulations suffer from complex processes, high costs, and poor stability. The processes used for single-drug sustained-release formulations cannot be directly applied to combination formulations, requiring consideration of the preparation needs of both drugs. Ezetimibe utilizes a direct powder compression process, avoiding drug stability degradation. This process involves fewer steps and is pollution-free. A three-step mixing method—premixing + secondary mixing + total mixing—ensures uniform content. The fenofibrate sustained-release layer employs a modified wet granulation process, atomizing a 5%–20% solution of sodium sulfobutylbetacyclodextrin, controlling particle moisture content to ≤1%, thus avoiding stability issues caused by fenofibrate's hygroscopic properties. Granulation ensures particle flowability, adapting to the requirements of bilayer tableting. Compared to commercially available sustained-release formulations prepared using microgranule coating, this process is simpler and involves fewer steps, resulting in lower costs and greater suitability for commercial production.

[0282] 7. Comparative Example 6 adjusted the hardness range. Based on the dissolution data from Example 1 and Comparative Example 6, it can be seen that when the hardness is greater than 150N, the in vitro dissolution of ezetimibe and fenofibrate is slowed by more than 20%. This indicates that the hardness range of this application is beneficial to the dissolution of the two active ingredients, maximizing their synergistic lipid-lowering effect.

[0283] 8. After adjusting the preparation process parameters of Comparative Example 7, the uniformity of ezetimibe content (A+2.2S) was greater than 15, and the uniformity of fenofibrate content (A+2.2S) was also greater than 15, both of which did not meet the requirements. This indicates that the process parameters of this application are beneficial to the quality control of this novel bilayer structure sustained-release tablet, protecting patient medication safety. Furthermore, the moisture content of the fenofibrate sustained-release granules was higher than 1.0%, and in its stability test, compared with the related substances in the examples, the related substances showed a significant increase. This indicates that the moisture control of the fenofibrate sustained-release granules in this application is beneficial to the stability of the formulation quality, ensuring medication safety and efficacy.

[0284] Application Example 2: Bioavailability Experiment

[0285] Twelve healthy male beagle dogs, weighing 10±1 kg, were used as experimental animals and divided into two groups of six each. A randomized crossover experimental design was adopted, and the bilayer tablets of Example 1 and the control group (which were simultaneously administered commercially available ezetimibe tablets and commercially available fenofibrate extended-release formulations) were randomly selected for in vivo pharmacokinetic studies. Blank blood samples were collected before administration (0 h), and blood samples were collected at 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, and 24.0 h after administration. After extraction, the concentrations of ezetimibe and fenofibrate in the blood samples were determined by gas chromatography-mass spectrometry. An in vivo analytical method for ezetimibe and fenofibrate was established, and pharmacokinetic parameters were calculated using a non-compartmental model method. The bioavailability of ezetimibe and fenofibrate in the two groups was calculated separately. The results are shown in Table 13.

[0286] Table 13 Bioavailability of ezetimibe and fenofibrate

[0287]

[0288] In vivo pharmacokinetic studies showed that, compared with the control group which used commercially available ezetimibe tablets and fenofibrate extended-release formulations, the present application formulated ezetimibe and fenofibrate into bilayer tablets, which significantly improved the bioavailability of both ezetimibe and fenofibrate.

[0289] The immediate-release layer of ezetimibe uses a mixture of Gelucire® and copovidone VA64 to form a solid dispersion, which improves the wettability of lipophilic drugs and overcomes the dissolution limitations of BCSII compounds, significantly improving bioavailability compared to commercially available formulations. The sustained-release layer of fenofibrate uses sodium sulfobutyl betacyclodextrin and Compritol® 888ATO, which improves solubility through cyclodextrin inclusion and controls the release rate through the matrix material. Compared to the micronization and simple surfactant combination commonly used in commercially available monotherapy sustained-release formulations, the solubilization and sustained-release effects are more synergistic, thus greatly improving bioavailability.

[0290] Application Example 3: Trial for the Treatment of Dyslipidemia

[0291] Two hundred patients diagnosed with hyperlipidemia were selected and divided into a control group (concurrently taking one tablet each of commercially available fenofibrate extended-release capsules 250mg and ezetimibe tablets 10mg orally once daily) and an example group (taking one tablet of Example 1 of this application once daily), with 100 patients in each group. All patients were treated continuously for 12 weeks, and clinical efficacy was observed before treatment, at week 4, and at week 12 of treatment, and changes in blood lipid levels were compared. The results are shown in Tables 14 and 15.

[0292] Table 14 Comparison of changes in various blood lipid indicators before and after the two groups (x±s, n=100)

[0293]

[0294] As shown in Table 14, there were no statistically significant differences in serum TC, TG, LDL-C and HDL-C levels between the example group and the control group before treatment (P>0.05); after treatment, serum TC, TG and LDL-C levels in both groups were significantly lower than before treatment, while HDL-C levels were significantly higher than before treatment (P<0.01).

[0295] After treatment, the reductions in TC, TG, and LDL-C in the example group were 43.2%, 37.7%, and 52.5%, respectively, while the increase in HDL-C was 63.9%, all significantly better than the control group (combination of two monotherapy drugs) (TC reduction of 31.9%, TG reduction of 14.6%, LDL-C reduction of 33.6%, and HDL-C increase of 26.0%). This indicates that the bilayer structure sustained-release tablets of this application can effectively improve multiple lipid indicators in patients with mixed lipolipidemia, achieving a synergistic effect of "1+1>2," and meeting unmet clinical needs. The drug meets the treatment needs of patients, and the rapid release of ezetimibe allows for quick onset of action. Meanwhile, the slow release of fenofibrate maintains the effective drug concentration in the body, prolonging the duration of action. Only one dose is required daily, significantly reducing the frequency of administration compared to combination of two single-drug regimens, thus improving patient compliance. This is particularly suitable for patients with dyslipidemia requiring long-term medication. Furthermore, the dose of fenofibrate in the bilayer structure sustained-release tablets of this application is smaller than that of commercially available sustained-release fenofibrate formulations, resulting in more significant effects in terms of bioavailability and treatment of dyslipidemia.

[0296] Table 15 Comparison of adverse reactions between the two groups

[0297]

[0298] As shown in Table 15, the total incidence of adverse reactions in the example group was 2.46%, while that in the control group was 16.32%. The incidence in the example group was significantly lower than that in the control group, and the difference was statistically significant (P < 0.5). This indicates that the bilayer tablets provided in this application ensure lipid-lowering efficacy while exhibiting good safety and tolerability, which helps improve patient treatment compliance.

[0299] The above description is merely a preferred embodiment of this application, but the scope of protection of this application is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in this application, based on the technical solution and application concept of this application, should be included within the scope of protection of this application.

Claims

1. A bilayer tablet comprising ezetimibe and fenofibrate, comprising an ezetimibe immediate release layer and a fenofibrate sustained release layer; the ezetimibe immediate release layer comprises: 1 wt% to 10 wt% of ezetimibe; 5 wt% to 20 wt% of immediate release layer filler; 1 wt% to 3 wt% of immediate release layer surfactant; 1 wt% to 5 wt% of immediate release layer binder; 1 wt% to 5 wt% of immediate release layer disintegrant; 0.1 wt% to 1.5 wt% of immediate release layer lubricant; the fenofibrate sustained release layer comprises: 10 wt% to 60 wt% of fenofibrate; 10 wt% to 30 wt% of sustained release layer filler; 1 wt% to 6 wt% of sustained release layer disintegrant; 2 wt% to 5 wt% of sustained release layer binder; 1 wt% to 8 wt% of sustained release layer solubilizer; 10 wt% to 40 wt% of sustained release layer sustained release matrix material; 0.1 to 2% of sustained release layer lubricant.

2. The bilayer tablet according to claim 1, characterized in that, in the ezetimibe immediate release layer, the immediate release layer filler comprises one or more of corn starch, microcrystalline cellulose and mannitol; The immediate release layer surfactant includes Gelucire ® one or more of a mixture, sodium lauryl sulfate, and poloxamer 188; the immediate release layer binder comprises one or more of povidone, hypromellose E5 and copovidone; the immediate release layer disintegrant comprises one or more of F-MELT® Type M, croscarmellose sodium and crospovidone; the immediate release layer lubricant comprises one or more of magnesium stearate, colloidal silicon dioxide and talc; in the fenofibrate sustained release layer, the sustained release layer filler comprises one or more of anhydrous dibasic calcium phosphate, corn starch, microcrystalline cellulose and lactose; the sustained release layer disintegrant comprises one or more of croscarmellose sodium, crospovidone and sodium starch glycolate; the sustained release layer binder comprises one or more of ethyl cellulose, hypromellose and povidone; the sustained release layer solubilizer comprises one or more of sulfobutyl ether beta cyclodextrin sodium, sodium lauryl sulfate and polysorbate 80; the sustained release layer sustained release matrix material comprises one or more of Compritol® 888 ATO, hypromellose and sodium carboxymethyl cellulose; the sustained release layer lubricant comprises one or more of sodium stearyl fumarate, talc and magnesium stearate.

3. The bilayer tablet according to claim 2, characterized in that, in the ezetimibe immediate release layer, the immediate release layer filler is mannitol; The immediate release layer surfactant is Gelucire ® mixture; the immediate release layer binder is copovidone; the immediate release layer disintegrant is F-MELT® Type M; the immediate release layer lubricant is magnesium stearate; in the fenofibrate sustained release layer, the sustained release layer filler is lactose; the sustained release layer disintegrant is croscarmellose sodium; the sustained release layer binder is ethyl cellulose; the sustained release layer solubilizer is sulfobutyl ether beta cyclodextrin sodium; the sustained release layer sustained release matrix material is Compritol® 888 ATO; the sustained release layer lubricant is sodium stearyl fumarate.

4. The bilayer tablet according to any one of claims 1 to 3, wherein the ezetimibe immediate release layer comprises: 1.5 wt% to 8.5 wt% of ezetimibe; 5 wt% to 15 wt% of mannitol; 1 wt% to 2.5 wt% of Gelucire ® mixture; 1 wt% to 2 wt% of copovidone; 1 wt% to 4 wt% of F-MELT® Type M; 0.2wt%~1.3wt% of magnesium stearate; The fenofibrate sustained release layer comprises: 25wt%~60wt% of fenofibrate; 10wt%~15wt% of lactose; 1.5wt%~3wt% of croscarmellose sodium; 2wt%~4wt% of ethyl cellulose; 2wt%~8wt% of sulfobutyl beta cyclodextrin sodium; 10wt%~35wt% of Compritol® 888 ATO; 0.5wt%~1.5wt% of sodium stearyl fumarate.

5. The preparation method of the bilayer tablet according to any one of claims 1~4, comprising the following steps: 1) mixing ezetimibe, immediate release layer filler, immediate release layer surfactant, immediate release layer binder, immediate release layer disintegrant and immediate release layer lubricant to obtain ezetimibe granules; 2) mixing fenofibrate, sustained release layer filler, sustained release layer disintegrant, sustained release layer binder, sustained release layer solubilizer and sustained release layer matrix material, granulating the mixture to obtain granules, and mixing the granules with sustained release layer lubricant to obtain fenofibrate granules; 3) tabletting the ezetimibe granules and the fenofibrate granules in a bilayer tablet press to obtain a bilayer tablet comprising an ezetimibe immediate release layer and a fenofibrate sustained release layer.

6. The preparation method according to claim 5, characterized in that, The step a) specifically comprises the following steps: a1) pre-mixing ezetimibe, immediate release layer surfactant, immediate release layer binder and immediate release layer disintegrant to obtain a first mixture; a2) mixing the first mixture with immediate release layer filler to obtain a second mixture; a3) mixing the second mixture with immediate release layer lubricant to obtain ezetimibe granules; The step b) specifically comprises the following steps: b1) pre-mixing fenofibrate, sustained release layer filler, sustained release layer disintegrant, sustained release layer binder and sustained release layer matrix material to obtain a pre-mixture; b2) granulating the pre-mixture, and adding sustained release layer solubilizer in the form of atomization during the granulation process to obtain wet granules; b3) drying the wet granules after sizing to obtain dry granules; b4) mixing the dry granules after sizing with sustained release layer lubricant to obtain fenofibrate granules.

7. The preparation method according to claim 6, characterized in that, The ezetimibe and the fenofibrate are independently subjected to crushing pretreatment to obtain ezetimibe powder and fenofibrate powder, respectively; The Dv90 of the ezetimibe powder is less than 10 μm. 90 <5 μm; The D90 of the Fenofibrate powder is less than 50 μm. 90 <10 μm.

8. The preparation method according to claim 6, characterized in that, The concentration of the aqueous solution of the sustained release layer solubilizer during atomization is 5wt%~15wt%; The pressure of the atomization is 1bar~3bar.

9. The preparation method according to claim 6, characterized in that, The screen mesh size for sizing the wet granules is 14mesh~20mesh; The screen mesh size for sizing the dry granules is 14mesh~20mesh.

10. The method of claim 5, wherein, The hardness of the tablet core is 50N~150N.

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