Pinefibrate tablet and preparation method thereof

Abstract

The invention relates to the technical field of oral non-biological medicine preparations, in particular to a Pingfibrate tablet and a preparation method thereof, and aims to solve the problem that the Pingfibrate tablet is relatively slow in dissolution speed, and the Pingfibrate tablet prepared by the preparation method of the Pingfibrate tablet can improve the content uniformity of Pingfibrate and improve the bioavailability of the Pingfibrate tablet. The impurities of the palmacate tablet are reduced; the palmitate tablet comprises the following components in percentage by weight: 0.05%-0.1% of palmitate, 70%-90% of a filling agent, 1%-8% of a disintegrating agent, 1%-5% of a flow aid, 1%-5% of a lubricating agent and 2%-4% of a coating material.

Description

Technical Field

[0001] This application belongs to the field of oral non-biological drug formulation technology, specifically relating to a pemafibrate tablet and its preparation method. Background Technology

[0002] Pemabright is a PPARα receptor agonist that inhibits triglyceride synthesis in the liver and increases LPL activity by modulating the expression of target genes, thereby reducing triglyceride concentration and increasing HDL cholesterol. Clinically, pemafibrate tablets are used as a novel lipid-lowering drug, exhibiting lipid-lowering effects, increasing high-density lipoprotein (HDL), and anti-atherosclerotic effects.

[0003] Pemabectin tablets (trade name: PARMODIA, strength 0.1mg) are developed and manufactured by Kowa Co., Ltd. They were approved for marketing in Japan in 2017 and officially approved for marketing in China on April 14, 2025. Currently, they are not marketed in the United States or Europe. Pemabectin is a selective peroxisome proliferator-activated receptor α (PPARα) modulator. By specifically activating the PPARα receptor, it regulates lipid metabolism in the liver, thereby reducing plasma triglyceride levels and increasing high-density lipoprotein cholesterol levels.

[0004] However, if the dissolution rate of pemafibrate tablets is slow when taken orally, it can have many adverse effects on drug absorption, efficacy, and safety. Summary of the Invention

[0005] In view of the technical problems existing in the prior art, this application provides a pemafid tablet and a method for preparing the same.

[0006] Firstly, this application provides a Pemabet tablet, which adopts the following technical solution: A Pembavertine tablet, by weight percentage, comprises 0.05%-0.1% Pembavertine, 70%-90% filler, 1%-8% disintegrant, 1%-5% glidant, 1%-5% lubricant, and 2%-4% coating material.

[0007] By adopting the above technical solutions, pemafid is the core component of pemafid tablets. The filler provides the basic weight and volume of the pemafid tablets, ensuring they achieve suitable weight and volume to meet production and administration requirements. Furthermore, the filler can be mixed with the pemafid tablets, improving the overall material flowability and compressibility, preventing tight binding during compression, and reducing looseness and brittleness. The disintegrant accelerates tablet disintegration while balancing the hardness of the pemafid tablets, preventing excessively rapid disintegration that could lead to brittleness and disintegration efficiency during production, ensuring timely disintegration after entering the gastrointestinal tract, and improving the dissolution effect of the pemafid tablets. The gliding agent improves the flowability of the material, aiding in mixing and tableting during the preparation process of pemafid tablets, ensuring the uniformity of pemafid tablet quality; the lubricant has a certain gliding effect and can synergistically improve the flow efficiency of the material with the gliding agent, further ensuring tablet quality. The coating material is a thin film or sugar coating component on the outer surface of pemafibrate tablets, which can protect the pemafibrate tablets, improve their usability, and regulate drug release.

[0008] Therefore, through the synergistic effect of the above-mentioned 0.05%-0.1% pemabet, 70%-90% filler, 1%-8% disintegrant, 1%-5% glidant, 1%-5% lubricant and 2%-4% coating material, the pemabet tablets can be dissolved relatively quickly.

[0009] Furthermore, the filler is selected from at least one of microcrystalline cellulose, mannitol, lactose, starch, dextrin, glucose, and dicalcium phosphate.

[0010] By adopting the above technical solution, the filler can dissolve or quickly disperse in gastrointestinal fluid, without physically hindering the dissolution of pemafibrate, and can also assist in the dispersion of pemafibrate, which is conducive to the rapid dissolution of pemafibrate.

[0011] Furthermore, the disintegrant is selected from at least one of starch, sodium carboxymethyl starch, hydroxypropyl cellulose, and crospovidone.

[0012] By adopting the above technical solution, the rapid disintegration and dispersion of pemafibrate tablets in the body (such as the gastrointestinal tract) can be promoted, creating conditions for the dissolution of pemafibrate and thus ensuring the efficacy of the drug.

[0013] Furthermore, the flow aid is selected from at least one of colloidal silica and talc.

[0014] By adopting the above technical solutions, the fluidity of the preparation process of pemafibrate tablets can be improved, the problem of poor material flow during the preparation process of pemafibrate tablets can be solved, and the content uniformity of pemafibrate tablets can be improved.

[0015] Furthermore, the lubricant is selected from at least one of magnesium stearate, calcium stearate, sodium stearate, and glyceryl monostearate and glyceryl distearate.

[0016] By adopting the above technical solutions, friction or adhesion between materials and equipment, and within the materials, can be reduced during the preparation of pemafibet tablets, ensuring smooth molding and demolding of pemafibet tablets during the tableting process, while reducing losses during production and stabilizing the quality of pemafibet tablets.

[0017] Furthermore, the disintegrant is a mixture of crospovidone and sodium carboxymethyl starch.

[0018] By adopting the above technical solution, when cross-linked povidone and sodium carboxymethyl starch are mixed, the cross-linked povidone disintegrates into fine particles, and the slight expansion of sodium carboxymethyl starch can further disperse the particles, reduce drug particle agglomeration, increase the contact area between the drug and the dissolution medium, and accelerate the dissolution of pemafibrate. Through synergistic effect, the shortcomings of a single disintegrant can be made up for, and the disintegration efficiency can be significantly improved.

[0019] Furthermore, the mass ratio between crospovidone and sodium carboxymethyl starch is 1:1.

[0020] By adopting the above technical solution, the synergistic advantages of bipovidone and sodium carboxymethyl starch can be maximized, while balancing disintegration efficiency, process adaptability and cost, thereby improving the dissolution efficiency of pemafid tablets.

[0021] Secondly, this application provides a method for preparing pemafibrate tablets, comprising: mixing a disintegrant, a gliding agent, pemafibrate, a lubricant, and a filler to form a mixture; compressing the mixture into tablets to obtain initial pemafibrate tablets; and coating the initial pemafibrate tablets with a coating material to obtain pemafibrate tablets.

[0022] Understandably, the beneficial effects of the preparation method of pemafibrate tablets provided in this application are the same as those of pemafibrate tablets prepared by any of the above methods, and will not be repeated here.

[0023] Further, the disintegrant, gliding agent, pemabet, lubricant, and filler are mixed to form a mixture, comprising: mixing the disintegrant and gliding agent to form a first mixture; combining the first mixture, pemabet, and lubricant to form a second mixture; and mixing the second mixture with the filler to form a mixture.

[0024] By adopting the above technical solution, a mixture is formed by first forming a mixture, then forming a second mixture, and finally mixing with a filler. This stepwise mixing method utilizes the differences in physical properties of the components of pemafibrate tablets to solve the problems of uneven dispersion and content fluctuation during the preparation of pemafibrate tablets, thereby improving the content uniformity and disintegration and dissolution stability of pemafibrate tablets.

[0025] Furthermore, before mixing the disintegrant, gliding agent, pemabet, lubricant, and filler to form a mixture, the following steps are taken: the disintegrant, gliding agent, pemabet, lubricant, filler, and coating material are all sieved at 40-60 mesh.

[0026] By adopting the above technical solution, the disintegrant, glidant, pemafibrate, lubricant and filler particles after sieving are of uniform size, and can be evenly stressed during tableting, avoiding uneven density of pemafibrate tablets due to particle size differences. This can improve the uniformity of the content of active pharmaceutical ingredients and promote the disintegration and dissolution of pemafibrate tablets.

[0027] In summary, this application includes at least one of the following beneficial technical effects: 1. The synergistic effect of 0.05%-0.1% pemafibrate, 70%-90% filler, 1%-8% disintegrant, 1%-5% glidant, 1%-5% lubricant and 2%-4% coating material in the pemafibrate tablets of this application can ensure rapid dissolution of the pemafibrate tablets; 2. The disintegrant in this application comprises a mixture of crospovidone and sodium carboxymethyl starch. Further, the mass ratio of crospovidone to sodium carboxymethyl starch is 1:1, resulting in fine particles after crospovidone disintegration, and the slight expansion of sodium carboxymethyl starch further dispersing the particles, reducing drug particle agglomeration, increasing the contact area between the drug and the dissolution medium, and accelerating the dissolution of pemafibrate. This synergistic effect compensates for the shortcomings of a single disintegrant, significantly improving disintegration efficiency. It also maximizes the synergistic advantages of crospovidone and sodium carboxymethyl starch, balancing disintegration efficiency, process adaptability, and cost, thereby improving the dissolution efficiency of pemafibrate tablets. 3. In the preparation method of the pemafibrate tablets of this application, a mixture is formed by forming a first mixture, forming a second mixture, and then mixing with a filler. This stepwise mixing method utilizes the differences in physical properties of the components of the pemafibrate tablets to solve the problems of uneven dispersion and content fluctuation in the preparation process of pemafibrate tablets, thereby improving the content uniformity and disintegration and dissolution stability of the pemafibrate tablets. 4. In the preparation method of pemafibrate tablets of this application, the particle size of the raw materials for pemafibrate tablets is pulverized and screened, which can improve the uniformity of the content of active pharmaceutical ingredients and reduce the impurities of pemafibrate tablets. Most importantly, the screened raw materials are combined with specific excipients for process preparation, so that the dissolution and release can be advanced, effectively reducing the drug absorption time for patients. 5. The preparation method of the pemafibrate tablets of this application involves first preparing granules with a high proportion of pemafibrate, then pulverizing the granules, mixing them with direct-compression excipients, and compressing them into tablets. This improves the uniformity of the active ingredient content, reduces the level of tablet impurities, and results in pemafibrate tablets with faster dissolution and release. The process preparation can optimize production and effectively avoid the impact of process variables on product quality. Attached Figure Description

[0028] To more clearly illustrate the technical solutions in this disclosure, the accompanying drawings used in some embodiments of this application will be briefly introduced below. Obviously, the drawings described below are only drawings of some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings.

[0029] Figure 1 A liquid chromatogram of a pemafibrate tablet provided according to Example 1; Figure 2 This provides a dissolution curve of pemafibrate tablets in different dissolution media according to Example 1; Figure 3 A graph showing the release rate of pemafibrate tablets in 0.1 mol / L hydrochloric acid solution according to the examples; Figure 4 A graph showing the release rate of pemafibrate tablets according to the embodiment in a pH 4.5 acetate buffer solution; Figure 5 The graph shows the release rate of pemafibrate tablets in phosphate buffer solution at pH 6.8 according to the embodiment. Detailed Implementation

[0030] The technical solutions in some embodiments of this application are clearly and completely described below with reference to specific examples. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments provided in this application are within the scope of protection of this application.

[0031] Unless the context otherwise requires, throughout the specification and claims, the term "comprising" is interpreted as open-ended and encompassing, meaning "including, but not limited to." In the description of the specification, terms such as "one embodiment," "some embodiments," "exemplary embodiment," "exemplary," or "some examples," etc., are intended to indicate that a particular feature, structure, material, or characteristic associated with that embodiment or example is included in at least one embodiment or example of this application. The illustrative representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, a particular feature, material, or characteristic may be included in any suitable manner in any one or more embodiments or examples.

[0032] Hereinafter, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature.

[0033] Unless otherwise defined, all technical terms used herein have the same meaning as commonly known to those skilled in the art. In this application, "at least one" means one or more, and "more than one" means two or more. "At least one of the following" or similar expressions refer to any combination of these items, including any combination of single or multiple items. For example, at least one of a, b, or c can mean: a, b, c, a and b, a and c, b and c, or a, b, and c, where a, b, and c can be single or multiple.

[0034] All the following raw materials mentioned in this application are commercially available products and are intended to fully disclose the raw materials in this application. They should not be construed as limiting the source of the raw materials.

[0035] Example 1

[0036] Example 1 provides a pemafibrate tablet, the preparation method of which includes the following steps: S1: The disintegrant and the glidant are mixed to form a first mixture. The disintegrant is selected from crospovidone and sodium carboxymethyl starch. The glidant is selected from colloidal silica.

[0037] S2: Combine the first mixture, Pemabet, and lubricant to form a second mixture. The lubricant is magnesium stearate.

[0038] S3: Mix the second mixture and the filler to form a mixture. The filler selected is mannitol and microcrystalline cellulose.

[0039] S4: Compress the mixture to obtain the initial Pemabet tablets.

[0040] S5: Coat the initial pemafibrate tablets with a coating material to obtain pemafibrate tablets. The coating material is a film-coating premix (gastric-soluble type).

[0041] The amounts of the above components are: 0.09% pemafibrate, 75.91% mannitol, 10% microcrystalline cellulose, 4% crospovidone, 4% sodium carboxymethyl starch, 4% colloidal silica, 2% magnesium stearate, and 3% film coating premix.

[0042] like Figure 1 As shown, Figure 1The liquid chromatogram of the pemafibrate tablets provided in Example 1 shows that the pemafibrate tablets provided in Example 1 have virtually no impurities and high purity.

[0043] Example 2

[0044] Example 2 provides a pemafibrate tablet, which is prepared in the same way as in Example 1, except that the disintegrant, glidant, pemafibrate, lubricant, filler and coating material are: 0.09% pemafibrate, 74.91% lactose, 11% dicalcium phosphate, 3% dry starch, 5% sodium carboxymethyl starch, 1.1% colloidal silica, 1.9% magnesium stearate and 3% film coating premix.

[0045] Example 3

[0046] Example 3 provides a pemafibrate tablet, which is prepared in the same way as in Example 1, except that the disintegrant, glidant, pemafibrate, lubricant, filler and coating material are: 0.09% pemafibrate, 73.50% starch, 12.41% microcrystalline cellulose, 5% crospovidone, 3% low-substituted hydroxypropyl cellulose, 0.8% talc, 2.2% magnesium stearate and 3% film coating premix.

[0047] Example 4

[0048] Example 4 provides a pemafibrate tablet, which is prepared in the same way as in Example 1, except that the disintegrant, glidant, pemafibrate, lubricant, filler and coating material are: 0.09% pemafibrate, 77.56% dextrin, 8.35% mannitol, 3% dry starch, 5% sodium carboxymethyl starch, 2% colloidal silica, 1% calcium stearate and 3% film coating premix.

[0049] Example 5

[0050] Example 5 provides a pemafibrate tablet, which is prepared in the same way as in Example 1, except that the disintegrant, glidant, pemafibrate, lubricant, filler and coating material are: 0.09% pemafibrate, 80.59% mannitol, 5.32% pregelatinized starch, 8% sodium carboxymethyl starch, 1.6% talc, 1.4% mono- and di-stearyl glycerol and 3% film coating premix.

[0051] Example 6

[0052] Example 6 provides a pemafibrate tablet, which is prepared in the same way as in Example 1, except that the disintegrant, glidant, pemafibrate, lubricant, filler and coating material are: 0.09% pemafibrate, 85.91% mannitol, 4.5% crospovidone, 3.5% dry starch, 1.1% colloidal silica, 1.9% sodium hard fumarate and 3% film coating premix (gastric-soluble type).

[0053] Example 7

[0054] Example 7 provides a pemafibrate tablet, which is prepared in the same way as in Example 1, except that the disintegrant, glidant, pemafibrate, lubricant, filler and coating material are: 0.09% pemafibrate, 85.91% mannitol, 8% sodium carboxymethyl starch, 1% colloidal silica, 2% magnesium stearate and 3% film coating premix (gastric-soluble type).

[0055] Example 8

[0056] Example 8 provides a pemafibrate tablet, which is prepared in the same way as in Example 1, except that the disintegrant, glidant, pemafibrate, lubricant, filler and coating material are 0.09% pemafibrate, 65.91% mannitol, 20% precrosslinked starch, 3% low-substituted hydroxypropyl cellulose, 5% sodium carboxymethyl starch, 2% talc, 1% magnesium stearate and 3% film coating premix (gastric-soluble type).

[0057] Example 9

[0058] Example 9 provides a pemafibrate tablet, which is prepared in the same way as in Example 1, except that the disintegrant, glidant, pemafibrate, lubricant, filler, and coating material are: 0.09% pemafibrate, 70.16% lactose, 15.75% microcrystalline cellulose, 2% dry starch, 6% sodium carboxymethyl starch, 1.6% colloidal silica, 1.4% sodium hard fumarate, and 3% film coating premix (gastric-soluble type).

[0059] Example 10

[0060] Example 10 provides a pemafibrate tablet, which is prepared in the same way as in Example 1, except that the disintegrant, glidant, pemafibrate, lubricant, filler and coating material are: 0.09% pemafibrate, 80.11% dextrin, 5.80% lactose, 3.5% crospovidone, 4.5% sodium carboxymethyl starch, 2.6% talc, 0.4% magnesium stearate and 3% film coating premix (gastric-soluble type).

[0061] Example 11

[0062] Example 11 provides a pemafibrate tablet, which is prepared in the same way as in Example 1, except that the disintegrant, glidant, pemafibrate, lubricant, filler and coating material are: 0.09% pemafibrate, 62.60% starch, 23.31% microcrystalline cellulose, 3% crospovidone, 5% low-substituted hydroxypropyl cellulose, 1.2% talc, 1.8% calcium stearate and 3% film coating premix (gastric-soluble type).

[0063] Performance testing The release rate of the pemabet tablets obtained in the above examples and comparative examples was determined.

[0064] The specific test method is as follows: the slurry method is used, with 900 mL of 0.1 mol / L hydrochloric acid solution, pH 4.5 acetate buffer solution and pH 6.8 phosphate buffer solution as the dissolution medium, the temperature is 37±0.5℃ and the rotation speed is 50 r / min.

[0065] Dissolution tests were conducted on pemafibrate tablets prepared in Examples 1-11 under the conditions described above. Samples were taken at different time points: 5 min, 10 min, 15 min, 20 min, and 30 min. The concentration of pemafibrate in the samples was determined using high-performance liquid chromatography (HPLC), and the cumulative drug release rate was calculated. Figures 2-5 As shown, the horizontal axis represents time in minutes, and the vertical axis represents the release rate; where, for example... Figure 2 As shown, Figure 2 Example 1 provides a dissolution curve of pemafibrate tablets in different dissolution media. It can be seen that pemafibrate has a relatively fast release time and the dissolution rate of pemafibrate in different dissolution media is relatively similar, indicating that it has stability.

[0066] Figure 3 The release rate of pemafibrate tablets in 0.1 mol / L hydrochloric acid solution is shown in the example diagram. Figure 4 The release rate of pemafibrate tablets in a pH 4.5 acetate buffer solution is shown in the example diagram. Figure 5 The graph shows the release rate of pemafibrate tablets in a pH 6.8 phosphate buffer solution, representing an example. By comparing the release rates of the pemafibrate tablets in different dissolution media, the pemafibrate tablets of Example 1 showed a faster release rate, completely dissolving within 20-30 minutes, with a solubility-to-release ratio approaching 100%. The pemafibrate tablets of other examples showed a solubility-to-release ratio generally below 85% within 30 minutes.

[0067] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A pemafibrate tablet, characterized by, Pemafibrate 0.05-0.1%, filler 70-90%, disintegrant 1-8%, glidant 1-5%, lubricant 1-5% and coating material 2-4% by weight percentage.

2. The pemafibrate tablet according to claim 1, characterized by, The filler is selected from at least one of microcrystalline cellulose, mannitol, lactose, starch, dextrin, glucose and calcium hydrogen phosphate.

3. The pemafibrate tablet according to claim 1, characterized by, The disintegrant is selected from at least one of starch, sodium carboxymethyl starch, hydroxypropyl cellulose and cross-linked polyvidone.

4. The pemafibrate tablet according to claim 1, characterized by, The glidant is selected from at least one of colloidal silicon dioxide and talc.

5. The pemafibrate tablet according to claim 1, characterized by, The lubricant is selected from at least one of magnesium stearate, calcium stearate, sodium sodium fumarate and glycerol mono-diestearate.

6. The pemafibrate tablet according to claim 3, characterized by, The disintegrant is a mixture of the cross-linked polyvidone and the sodium carboxymethyl starch.

7. The pemafibrate tablet according to claim 6, characterized by, The mass ratio between the cross-linked polyvidone and the sodium carboxymethyl starch is 1:

1.

8. A process for the preparation of pemafibrate tablets according to any one of claims 1-7, characterized in that, Comprising: mixing the disintegrant, the glidant, the pemafibrate, the lubricant and the filler to form a mixture; tabletting the mixture to obtain initial pemafibrate tablets; coating the initial pemafibrate tablets with the coating material to obtain the pemafibrate tablets.

9. The method of preparing pemafibrate tablets according to claim 8, characterized by, The mixing the disintegrant, the glidant, the pemafibrate, the lubricant and the filler to form a mixture comprises: mixing the disintegrant and the glidant to form a first mixture; mixing the first mixture, the pemafibrate and the lubricant to form a second mixture; mixing the second mixture and the filler to form a mixture.

10. The method of preparing pemafibrate tablets according to claim 8, characterized by, The mixing the disintegrant, the glidant, the pemafibrate, the lubricant and the filler to form a mixture comprises: sifting the disintegrant, the glidant, the pemafibrate, the lubricant, the filler and the coating material through 40-60 mesh.

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