Fenofibrate capsule and preparation method thereof

Abstract

The invention discloses a fenofibrate-containing pharmaceutical composition, which is characterized in that the fenofibrate-containing pharmaceutical composition comprises fenofibrate, a filler, a disintegrating agent, a lubricant, an adhesive and a surfactant, the surfactant is teloxpol, the disintegrating agent adopts an internal and external addition method in the preparation process, and the lubricant adopts an internal and external addition method in the preparation process. By internally and externally adding the disintegrating agent and the lubricating agent, the defects of particle aggregation, dissolution speed reduction, poor stability and the like can be specifically solved, and under the condition of micronization of the fenofibrate raw material, rapid dissolution, high bioavailability and stability of the fenofibrate capsule can be ensured at the same time.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a fenofibrate capsule and its preparation method, which solves the problems of low bioavailability of fenofibrate capsules, easy aggregation after micronization of raw materials, and "food effect". Background Technology

[0002] Fenofibrate, chemically named isopropyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionic acid, is a phenoxyaromatic acid derivative lipid-lowering drug widely used clinically to treat hypertriglyceridemia, mixed hyperlipidemia, and low high-density lipoprotein cholesterol (HDL-C). As a peroxisome proliferator-activated receptor α (PPAR-α) agonist, fenofibrate regulates lipoprotein metabolism by activating PPAR-α, significantly reducing serum triglycerides (TG), moderately increasing HDL-C, and promoting the conversion of low-density lipoprotein (LDL) into smaller, denser particles, thus improving the risk of atherosclerosis. The molecular formula of fenofibrate is C2. 20 H 21 ClO4 has a molecular weight of 360.84. The structure of fenofibrate is as follows:

[0003]

[0004] Fenofibrate is a typical BCS Class II drug. Its poor solubility and low bioavailability result in low bioavailability, with an oral bioavailability of only 35%. Furthermore, fenofibrate exhibits a significant "food effect," meaning that absorption in the digestive tract increases when administered shortly after a meal (when the patient is full), compared to administration on an empty stomach. Food enhances the bioavailability of fenofibrate, so taking it without food can significantly reduce absorption. Compared to administration on an empty stomach, the commercially available fenofibrate-containing product Tricor... ® (Abbot) exhibits increased absorption rate when the animal is well-fed.

[0005]

[0006] Chinese patent CN202011054024.7 discloses a fenofibrate tablet composition, wherein each 1000 tablets contains: 1g of fenofibrate with a D90 of 6-8 micrometers, 8-18g of polyethylene glycol 6000, 5-14g of calcium dihydrogen phosphate, 30-50g of microcrystalline cellulose, 20-30g of hydroxypropyl cellulose E5, 8-16g of polysorbate-80, and 1-2g of magnesium stearate. The introduction of polyethylene glycol and calcium dihydrogen phosphate plays a positive role in the stability of the micronized fenofibrate tablet composition, solving the problem of decreased dissolution during storage. However, polyethylene glycol 6000 is highly hygroscopic and easily absorbs water in high humidity environments, which can easily lead to clumping of the micronized fenofibrate particles, affecting subsequent dissolution.

[0007] Chinese patent CN201180018407.1 discloses an oral pharmaceutical composition comprising fenofibrate acid or a pharmaceutically acceptable salt thereof and an alkalizing agent. The alkalizing agent may be calcium carbonate, calcium hydroxide, calcium hydrogen phosphate, calcium phosphate, magnesium carbonate, magnesium hydroxide, etc. The alkalizing agent is in direct contact with fenofibrate acid or a pharmaceutically acceptable salt thereof. After exposure to the in vivo environment, the alkalizing agent can increase the pH of the microenvironment surrounding fenofibrate acid, thereby increasing the water solubility of fenofibrate acid and thus its bioavailability. However, the alkalizing agent may neutralize gastric acid, causing gastric discomfort or rebound increase in gastric acid secretion. The local high pH environment may damage the intestinal mucosa. At the same time, the alkalizing agent accelerates drug degradation after absorbing moisture.

[0008] Because fenofibrate is a lipophilic compound, it is almost insoluble in water (high oil-water partition coefficient), resulting in poor oral absorption and low bioavailability. Absorption is also affected by the state of food intake (better absorption at full weight, worse at fasting), leading to large fluctuations in blood drug concentration. While micronization can improve dissolution, it easily leads to particle aggregation and a decrease in dissolution after storage. To address this issue, current technologies generally attempt to solve it at the formulation level, using methods such as adding excipients and employing more complex processes to overcome its low bioavailability. Although existing technologies have some effect on improving the dissolution of fenofibrate at the formulation level, there has been little research on its long-term stability, especially the long-term stability after micronization of the raw material. While more complex formulations have some effect, their impact is limited, restricting the clinical application scenarios of fenofibrate. Summary of the Invention

[0009] In view of the shortcomings of the prior art, the purpose of this invention is to provide a pharmaceutical composition containing fenofibrate, which has rapid dissolution, high bioavailability, significantly reduced food effect, and no raw material aggregation, making it suitable for large-scale production.

[0010] To achieve the above objectives, the present invention has obtained the following technical solution through extensive experimental research and improvement on existing formulations and processes: a pharmaceutical composition containing fenofibrate, comprising fenofibrate, a filler, a disintegrant, a lubricant, a binder, and a surfactant, wherein the surfactant is tylosap, the disintegrant is prepared by internal and external addition, and the lubricant is prepared by internal and external addition.

[0011] In this invention, the internal and external addition of disintegrants and lubricants during the preparation process is one of the key technical aspects for achieving the desired effect. Internal disintegrants maintain the porous structure of the micronized particles, preventing granulation densification, while external disintegrants rapidly overcome particle aggregation, achieving instantaneous dissolution. The synergistic effect of internal and external disintegrants forms an "inside-out" disintegration pattern, ensuring fenofibrate is fully exposed to the dissolution medium. Internal lubricants protect the micronized particles during granulation, reducing aggregation, while external lubricants precisely regulate flowability during the mixing stage, preventing excessive lubricant from encapsulating drug particles and ensuring production feasibility. Simultaneously employing the internal and external addition of disintegrants and lubricants in fenofibrate capsule production significantly optimizes formulation performance and production efficiency. The synergistic effect of internal and external disintegrants overcomes the aggregation barrier of micronized drugs, while the precise regulation of the release process by internal and external lubricants balances granulation protection and final flowability, reducing the total amount of excipients and improving process tolerance. This approach is particularly suitable for the industrial production of high-drug-loading, poorly soluble drug formulations such as fenofibrate capsules.

[0012] In this invention, the surfactant tyloxapol is one of the key technologies for achieving the desired technical effects. Using tyloxapol as the surfactant in fenofibrate formulations can solve the absorption and stability problems of fenofibrate. First, tyloxapol has highly efficient solubilizing ability; its critical micelle concentration (CMC) is significantly lower than that of common surfactants (such as sodium dodecyl sulfate SDS), and it can form stable micelles at very low dosages, effectively encapsulating fenofibrate molecules and improving their apparent solubility. Second, tyloxapol can reduce fenofibrate's dependence on lipids in food by promoting lymphatic transport (similar to the bile acid pathway), thereby reducing the absorption difference between feeding and fasting states. Finally, the polymer structure of tyloxapol (polyoxyethylene-polyoxypropylene copolymer) can adsorb onto the surface of micronized fenofibrate particles, forming a three-dimensional barrier that prevents particle aggregation during long-term storage, thus facilitating the long-term preservation of fenofibrate.

[0013] In this invention, the types of internal and external disintegrants, as well as internal and external lubricants, are key technical factors in achieving the desired effects. The internal disintegrant is croscarmellose sodium, which is embedded within the granules during the granulation stage. After drying, it forms an "internal skeleton," rapidly absorbing water through capillary action upon contact with water. The swelling force disintegrates the granules from the inside, releasing micronized fenofibrate. The external disintegrant is sodium carboxymethyl starch, distributed between the granules in the final product. Upon contact with water, it expands instantly, rapidly disrupting the overall capsule structure and preventing the aggregation layer on the granule surface from hindering dissolution. The internal lubricant is stearic acid, and the external lubricant is sodium stearate fumarate. Through a staged mechanism of action, they synergistically optimize formulation performance, achieving both process feasibility and dissolution efficiency. The internal lubricant is stearic acid, which partially melts during the granulation stage to form a uniform lubricating film. This prevents micronized fenofibrate from agglomerating under high pressure, reduces the risk of granulation wall adhesion, and increases particle porosity, facilitating the function of the disintegrant cross-linked sodium carboxymethyl cellulose. The external lubricant is sodium stearate fumarate, added during the final mixing stage. Its needle-like crystalline structure rapidly improves particle flowability, ensuring a capsule filling weight difference of ≤±3%, while avoiding dissolution delays caused by excessive drug encapsulation in traditional lubricants such as magnesium stearate. Both stearic acid and sodium stearate fumarate are free of metallic impurities (such as magnesium ions in magnesium stearate), preventing catalytic oxidative degradation of fenofibrate.

[0014] In this invention, the ratio of internally added disintegrant to externally added disintegrant, and the ratio of internally added lubricant to externally added lubricant, are among the key technical aspects for achieving the desired effect. The disintegrant is added internally and externally during preparation. Excessive internal disintegrant absorption leads to decreased particle hardness, while insufficient internal disintegrant can cause over-densification during granulation. When the mass ratio of fenofibrate to internally added disintegrant is 1:0.1-0.4, it embeds itself within the particles during granulation, forming a porous network structure that ensures rapid drug release from within. Excessive external disintegrant can easily cause capsule shell rupture, while insufficient external disintegrant results in insufficient disintegration force. A mass ratio of fenofibrate to externally added disintegrant of 1:0.02-0.06 allows for rapid water absorption and swelling in the final product, breaking through the external aggregation layer for release. Preferably, the mass ratio of fenofibrate to internally added disintegrant is 1:0.2, and the mass ratio of fenofibrate to externally added disintegrant is 1:0.04. The lubricant is added internally and externally during preparation. If too much internal lubricant is added, excess lubricant migrates to the particle surface, hindering disintegration; if too little internal lubricant is added, the desired lubrication effect cannot be achieved. When the mass ratio of fenofibrate to internal lubricant is 1:0.01-0.04, a lubricating film is formed during the granulation stage, preventing the micronized fenofibrate from agglomerating under high pressure. If too much external lubricant is added, excess external lubricant coats the drug particles; if too little external lubricant is added, particle flowability will decrease. When the mass ratio of fenofibrate to external lubricant is 1:0.005-0.012, flowability is improved during the mixing stage, ensuring uniform filling of the fenofibrate capsules. Preferably, the mass ratio of fenofibrate to internal lubricant is 1:0.02, and the mass ratio of fenofibrate to external lubricant is 1:0.01.

[0015] In this invention, the choice of formulation is one of the factors in achieving the technical effect. In fenofibrate capsule formulations, the filler is one or more of lactose, corn starch, or microcrystalline cellulose, which can significantly improve formulation performance and production feasibility. Lactose, with its excellent flowability and water solubility, ensures capsule filling accuracy (weight difference ≤ ±3%) and promotes rapid drug dissolution. Corn starch, as an economical choice, also possesses natural disintegration properties, which can shorten disintegration time and reduce costs. Microcrystalline cellulose, with its antihygroscopicity and multifunctionality, can both enhance particle strength and support high drug loading. Preferably, the filler is lactose. The binder is one or more of povidone, hydroxypropyl methylcellulose, starch, and dextrin, which can significantly optimize formulation process and performance. Povidone (such as povidone K30) can form strong particles at low dosages (2%-5%) due to its strong binding force and solvent compatibility (both water and ethanol), which is especially suitable for formulations with high drug loading. Hydroxypropyl methylcellulose not only provides binding but also improves wettability and promotes drug dissolution. Starch and dextrin are economical and safe natural binders that are inexpensive and suitable for sensitive populations. When used in conjunction with disintegrants, they can reduce the need for additional disintegrants. Preferably, the binder is povidone.

[0016] In this invention, the mass ratio of fenofibrate to filler, binder, and surfactant is also a factor in achieving the desired technical effect. A mass ratio of fenofibrate to filler of 1:0.4-1 provides sufficient carrier space to ensure flowability while avoiding excessive filler leading to overfilling. A mass ratio of fenofibrate to binder of 1:0.02-0.06 ensures particle strength while preventing excessive adhesion and delaying disintegration. A mass ratio of fenofibrate to surfactant of 1:0.0020-0.0030 enhances drug dissolution through trace solubilization without causing gastrointestinal irritation. This formulation system achieves an optimal balance between drug loading efficiency, dissolution rate, and production cost, making it particularly suitable for the industrial production needs of fenofibrate capsules. Preferably, the mass ratio of fenofibrate to filler is 1:0.6, the mass ratio of fenofibrate to binder is 1:0.04, and the mass ratio of fenofibrate to surfactant is 1:0.0025.

[0017] In this invention, the particle size of fenofibrate is also one of the factors contributing to the technical effect. Controlling the particle size of fenofibrate to D90 ≤ 50 μm can significantly improve the dissolution performance and bioavailability of the formulation. Micronized fenofibrate has a larger specific surface area, increasing the contact area between the drug and gastrointestinal fluid, thereby accelerating the dissolution rate. This particle size range ensures good flowability and filling uniformity. Preferably, the particle size of fenofibrate is D90 ≤ 30 μm. More preferably, the particle size of fenofibrate is D90 ≤ 20 μm.

[0018] Specifically, the present invention also provides a pharmaceutical composition containing fenofibrate, comprising the following components:

[0019]

[0020] The particle size of the fenofibrate is D90≤20μm.

[0021] The present invention also provides a method for preparing the above-mentioned fenofibrate pharmaceutical composition, comprising the following steps:

[0022] 1) Ingredients: Fenofibrate, lactose, sodium croscarmellose and stearic acid, tylosap, povidone, sodium carboxymethyl starch and sodium stearate;

[0023] 2) Preparation of granulation solution: Add purified water to a stainless steel container and stir. Slowly add povidone and continue stirring after adding. Slowly add tylosap and continue stirring after adding.

[0024] 3) Wet granulation: Mix fenofibrate, lactose, croscarmellose sodium, and stearic acid, add to the granulation solution and granulate, dry at 50℃ until the moisture content is ≤3%, and then granulate.

[0025] 4) Premixing: Add sodium carboxymethyl starch as an auxiliary material to the mixing tank for premixing. Set the mixing speed to 10-20 rpm and mix for 10-30 min. The relative humidity should be ≤40% and the temperature should be below 25℃.

[0026] 5) Total mixing: Sodium stearate fumarate and pre-mixed particles are mixed together. The mixing speed is set to 15-20 rpm and the mixture is mixed for 10 minutes to obtain the total mixed powder.

[0027] 6) Capsule filling: Fill capsules with the total powder mixture using a capsule filling machine, with relative humidity ≤40% and temperature below 25℃, to obtain fenofibrate capsules.

[0028] Compared with the prior art, the present invention has the following outstanding advantages and beneficial effects:

[0029] (1) By adding disintegrants and lubricants inside and outside, defects such as particle aggregation, decreased dissolution rate and poor stability can be specifically solved. Under the condition of micronization of fenofibrate raw materials, the rapid dissolution, high bioavailability and stability of fenofibrate capsules can be guaranteed at the same time.

[0030] (2) Adding tyloxacin as a surfactant can solve the absorption and stability problems of fenofibrate, reduce the dependence of fenofibrate on lipids in food, thereby reducing the absorption difference between eating and fasting states and reducing the "food effect".

[0031] (3) The fenofibrate capsules prepared by the present invention have high stability, good dissolution, etc., and the preparation process is simple and suitable for large-scale industrial production. Detailed Implementation

[0032] The present invention will be further described in detail below with reference to embodiments, but the implementation of the invention is not limited thereto.

[0033] Example 1: Preparation of Fenofibrate Capsules

[0034] The formulation used to prepare a drug containing 200 mg of the active ingredient fenofibrate per capsule is as follows:

[0035]

[0036]

[0037] The preparation method is as follows:

[0038] 1) Ingredients: Fenofibrate, lactose, sodium croscarmellose and stearic acid, tylosap, povidone, sodium carboxymethyl starch and sodium stearate;

[0039] 2) Preparation of granulation solution: Add purified water to a stainless steel container and stir. Slowly add povidone over 2-3 minutes. After the addition is complete, continue stirring for 8-10 minutes. Slowly add tyloxapine over 2-3 minutes. After the addition is complete, continue stirring for 10-15 minutes.

[0040] 3) Wet granulation: Mix fenofibrate, lactose, croscarmellose sodium, and stearic acid, add to the granulation solution and granulate, dry at 50℃ until the moisture content is ≤3%, and then granulate.

[0041] 4) Premixing: Add sodium carboxymethyl starch as an auxiliary material to the mixing tank for premixing. Set the mixing speed to 10-20 rpm and mix for 10-30 min. The relative humidity should be ≤40% and the temperature should be below 25℃.

[0042] 5) Total mixing: Sodium stearate fumarate and pre-mixed particles are mixed together. The mixing speed is set to 15-20 rpm and the mixture is mixed for 10 minutes to obtain the total mixed powder.

[0043] 6) Capsule filling: Fill capsules with the total powder mixture using a capsule filling machine, with relative humidity ≤40% and temperature below 25℃, to obtain fenofibrate capsules.

[0044] Example 2: Preparation of Fenofibrate Capsules

[0045] The formulation used to prepare a drug containing 200 mg of the active ingredient fenofibrate per capsule is as follows:

[0046]

[0047] The preparation method is as described in Example 1.

[0048] Example 3: Preparation of Fenofibrate Capsules

[0049] The formulation used to prepare a drug containing 200 mg of the active ingredient fenofibrate per capsule is as follows:

[0050]

[0051] The preparation method is as described in Example 1.

[0052] Example 4: Preparation of Fenofibrate Capsules

[0053] The formulation used to prepare a drug containing 200 mg of the active ingredient fenofibrate per capsule is as follows:

[0054]

[0055] The preparation method is as described in Example 1.

[0056] Example 5: Preparation of Fenofibrate Capsules

[0057] The formulation used to prepare a drug containing 200 mg of the active ingredient fenofibrate per capsule is as follows:

[0058]

[0059] The preparation method is as described in Example 1.

[0060] Comparative Example 1: Preparation of Fenofibrate Capsules

[0061] The formulation used to prepare a drug containing 200 mg of the active ingredient fenofibrate per capsule is as follows:

[0062]

[0063] The preparation method is as described in Example 1. Compared with Example 1, Comparative Example 1 uses more disintegrants (crosslinked sodium carboxymethyl cellulose, sodium carboxymethyl starch), lubricants (stearic acid, sodium stearate fumarate), surfactants (tyloxapine), fillers (lactose), and binders (povidone).

[0064] Comparative Example 2: Preparation of Fenofibrate Capsules

[0065] The formulation used to prepare a drug containing 200 mg of the active ingredient fenofibrate per capsule is as follows:

[0066]

[0067] The preparation method is as described in Example 1. Compared with Example 1, Comparative Example 2 uses less disintegrant (crosslinked sodium carboxymethyl cellulose, sodium carboxymethyl starch), lubricant (stearic acid, sodium stearate fumarate), surfactant (tyloxapine), filler (lactose) and binder (povidone).

[0068] Comparative Example 3: Preparation of Fenofibrate Capsules

[0069] The formulation used to prepare a drug containing 200 mg of the active ingredient fenofibrate per capsule is as follows:

[0070]

[0071] The preparation method is the same as in Example 1. Compared with Example 1, Comparative Example 3 did not add the external disintegrant sodium carboxymethyl starch or the external lubricant sodium stearate.

[0072] Comparative Example 4: Preparation of Fenofibrate Capsules

[0073] The formulation used to prepare a drug containing 200 mg of the active ingredient fenofibrate per capsule is as follows:

[0074]

[0075] The preparation method is the same as in Example 1. Compared with Example 1, the external disintegrant in Comparative Example 4 is changed from sodium carboxymethyl starch to sodium croscarmellose, and the internal and external lubricants are changed to magnesium stearate.

[0076] Comparative Example 5: Preparation of Fenofibrate Capsules

[0077] The formulation used to prepare a drug containing 200 mg of the active ingredient fenofibrate per capsule is as follows:

[0078]

[0079] The preparation method is the same as in Example 1. In Comparative Example 5, the surfactant was changed to sodium dodecyl sulfate compared to Example 1.

[0080] Example 6

[0081] Fenofibrate capsules prepared in Examples 1-5 and Comparative Examples 1-5 were examined for their properties, identification, content uniformity, dissolution, related substances content, microbial limits, and content. The results are shown in Tables 1 and 2.

[0082] Table 1. Formulation performance evaluation of fenofibrate capsules in Examples 1-5

[0083]

[0084]

[0085] Table 2. Formulation performance evaluation of fenofibrate capsules in Comparative Examples 1-5

[0086]

[0087] The test results in Tables 1 and 2 show that the fenofibrate capsules prepared in Examples 1-5 all meet the requirements in terms of appearance, identification, content uniformity, dissolution, related substances content, microbial limits, and content. In Comparative Example 1, due to the large amount of disintegrants and lubricants, the excessive coating of particles by these excipients limited dissolution. In Comparative Example 2, the small amount of disintegrants and lubricants resulted in insufficient disintegration power. Furthermore, uneven mixing caused the fenofibrate raw material to aggregate, leading to poor content uniformity and negatively impacting dissolution. In Comparative Example 3, the disintegrants and lubricants were not added internally or externally, causing the fenofibrate raw material to aggregate and thus reducing dissolution. In Comparative Example 4, although the disintegrants and lubricants were added internally and externally, the single type resulted in delayed dissolution and incomplete drug release. Additionally, magnesium stearate excessively coated the drug, further delaying dissolution. The magnesium ions in magnesium stearate catalyzed the oxidative degradation of fenofibrate, forming impurities. Examples 1-5 are preferred solutions in this scheme, and the various parameters in Example 1, including the types and proportions of excipients, are optimal. For example, fenofibrate, disintegrants and lubricants are in appropriate proportions, and other excipients are used in appropriate amounts. The overall combination of the above conditions results in fenofibrate capsules with high dissolution rate, high content and no aggregation of raw materials.

[0088] Example 7: In vivo pharmacokinetic experiment in beagle dogs

[0089] Healthy adult beagle dogs were randomly divided into two groups (Example 1 group and Comparative Example 5 group, administered one capsule at a time) and subjected to crossover experiments. In vivo pharmacokinetic studies were conducted on both fasting and post-feeding dogs. Dogs were fasted for 12 hours prior to the experiment. During the experiment, the feeding group was given 150g of lipid (half-lean minced pork) per dog, followed by drug administration; the fasting group was given 100ml of water, followed by drug administration. Feeding was scheduled 8 hours after drug administration. Blood samples (3ml each) were collected from the great saphenous vein of each group at predetermined times, anticoagulated with heparin, and centrifuged at low temperature to obtain plasma samples for analysis.

[0090] Table 3. In vivo pharmacokinetic data of the two formulations.

[0091]

[0092] According to the results in Table 3, the fenofibrate capsules prepared in Example 1 showed no significant difference in Cmax and AUC between fasting and eating states. The Cmax and AUC of the eating state were 1.11 and 1.08 times that of the fasting state, respectively. In Comparative Example 5, the Cmax and AUC of the eating state were 1.48 and 1.60 times that of the fasting state, respectively. This indicates that the use of tyloxapine as a surfactant in Example 1 helps to reduce the influence of the "food effect", improves the oral bioavailability of fenofibrate capsules, and its absorption is not affected by diet.

[0093] Example 8

[0094] The fenofibrate capsules prepared in Example 1 and the reference preparation were tested for related substances under accelerated conditions, and the results are shown in Table 4.

[0095] Table 4. Results of related substance determination for fenofibrate capsules in Example 1

[0096]

[0097]

[0098] Note: Acceleration conditions are 40℃±2℃ / 75%RH±5%RH.

[0099] According to the results in Table 4, the fenofibrate capsules prepared in the embodiments of the present invention have lower impurity content and better stability compared with the reference preparation. This indicates that the fenofibrate prepared in the present invention has good compatibility with each excipient, does not react with each other, has better stability, and can meet the requirements of quality standards.

[0100] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A pharmaceutical composition containing fenofibrate, characterized in that, It includes fenofibrate, filler, disintegrant, lubricant, binder and surfactant, wherein the surfactant is tylosap, the disintegrant is prepared by internal and external addition, and the lubricant is prepared by internal and external addition.

2. The pharmaceutical composition according to claim 1, characterized in that, When the disintegrant is prepared using an internal and external addition method, the internal disintegrant is croscarmellose sodium and the external disintegrant is carboxymethyl starch sodium.

3. The pharmaceutical composition according to claim 1, characterized in that, When the lubricant is prepared using an internal and external addition method, the internal lubricant is stearic acid and the external lubricant is sodium stearate fumarate.

4. The pharmaceutical composition according to claim 1, characterized in that, When the disintegrant is prepared using an internal and external addition method, the mass ratio of fenofibrate to the internally added disintegrant is 1:0.1-0.4, and the mass ratio of fenofibrate to the externally added disintegrant is 1:0.02-0.

06. Preferably, the mass ratio of fenofibrate to the internally added disintegrant is 1:0.2, and the mass ratio of fenofibrate to the externally added disintegrant is 1:0.

04.

5. The pharmaceutical composition according to claim 1, characterized in that, When the lubricant is prepared using an internal and external addition method, the mass ratio of fenofibrate to the internal lubricant is 1:0.01-0.04, and the mass ratio of fenofibrate to the external lubricant is 1:0.005-0.

012. Preferably, the mass ratio of fenofibrate to the internal lubricant is 1:0.02, and the mass ratio of fenofibrate to the external lubricant is 1:0.

01.

6. The pharmaceutical composition according to claim 1, characterized in that, The filler is one or more of lactose, corn starch, or microcrystalline cellulose, and the binder is one or more of povidone, hydroxypropyl methylcellulose, starch, and dextrin. Preferably, the filler is lactose and the binder is povidone.

7. The pharmaceutical composition according to claim 1, characterized in that, The mass ratio of fenofibrate to filler is 1:0.4-1, the mass ratio of fenofibrate to adhesive is 1:0.02-0.06, and the mass ratio of fenofibrate to surfactant is 1:0.0020-0.0030. Preferably, the mass ratio of fenofibrate to filler is 1:0.6, the mass ratio of fenofibrate to adhesive is 1:0.04, and the mass ratio of fenofibrate to surfactant is 1:0.0025.

8. The pharmaceutical composition according to claim 1, characterized in that, The particle size of the fenofibrate is D90≤50μm, preferably D90≤30μm, and more preferably D90≤20μm.

9. A pharmaceutical composition containing fenofibrate, characterized in that, It contains the following components: The particle size of the fenofibrate is D90≤20μm.

10. A method for preparing a fenofibrate pharmaceutical composition according to any one of claims 1-9, characterized in that, Includes the following steps: 1) Ingredients: Fenofibrate, lactose, sodium croscarmellose and stearic acid, tylosap, povidone, sodium carboxymethyl starch and sodium stearate; 2) Preparation of granulation solution: Add purified water to a stainless steel container and stir. Slowly add povidone and continue stirring after adding. Slowly add tylosap and continue stirring after adding. 3) Wet granulation: Mix fenofibrate, lactose, croscarmellose sodium, and stearic acid, add to the granulation solution and granulate, dry at 50℃ until the moisture content is ≤3%, and then granulate. 4) Premixing: Add sodium carboxymethyl starch as an auxiliary material to the mixing tank for premixing. Set the mixing speed to 10-20 rpm and mix for 10-30 min. The relative humidity should be ≤40% and the temperature should be below 25℃. 5) Total mixing: Sodium stearate fumarate and pre-mixed particles are mixed together. The mixing speed is set to 15-20 rpm and the mixture is mixed for 10 minutes to obtain the total mixed powder. 6) Capsule filling: Fill capsules with the total powder mixture using a capsule filling machine, with relative humidity ≤40% and temperature below 25℃, to obtain fenofibrate capsules.

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