Bevidelic acid quick-release preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a bepiridic acid quick-release preparation and a preparation method thereof. Compared with the prior art, the preparation method strictly controls the particle size of the bepiridic acid, greatly reduces the types of used auxiliary materials, does not need to add an organic solvent in the preparation process, and is safe and pollution-free; the preparation process belongs to a continuous process and has fewer process steps, so that the production time is shortened, continuous operation is realized, and the production cost is reduced; according to the present invention, with the preparation method, the particles can be uniformly dispersed, the extrudate content uniformity is good, the good in vitro dissolution uniformity is provided, the compressibility of the effective component is not required, the medication safety of the patient is substantially improved, the dissolution rate is improved, and the high bioavailability is provided.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a bepedic acid rapid-release preparation and a preparation method thereof. Background Art

[0002] Dyslipidemia is an important risk factor for cardiovascular disease. Long-term dyslipidemia can cause lipids to precipitate on the vascular endothelium, forming atherosclerosis, which can lead to diseases such as stroke, myocardial infarction, and heart failure. Therefore, dyslipidemia is called the "silent killer."

[0003] Statins are the cornerstone of lipid-lowering and anti-ASCVD. Although statin therapy is generally safe and effective, and the clinical benefits far outweigh the risk of adverse reactions, muscle-related adverse reactions were observed in 9.1% of statin-treated patients, which weakened the compliance of statins. Bempedoic acid is a new type of non-statin oral lipid-lowering drug that can simultaneously reduce LDL-C and the inflammatory marker hs-CRP levels. As a prodrug, muscle-related symptoms rarely occur, and it can be used as a new treatment option for patients with statin intolerance.

[0004] In February 2020, bepedic acid was approved for marketing in the United States and the European Union, respectively, and has exactly the same indications: it is mainly suitable for patients with familial hypercholesterolemia (HeFH) or ASCVD. Bepedic acid is a new lipid-lowering drug, and its mechanism of action is to inhibit adenosine triphosphate citrate lyase (ACL) and reduce cholesterol synthesis, while the mechanism of action of statins is to inhibit HMG-CoA. Therefore, although the mechanisms of bepedic acid and statins are different, they have similar pharmacological effects.

[0005] Bepedic acid is a prodrug that regulates LDL-C receptors. Its action pathway is the same as that of statins, mainly by inhibiting ATP-citrate lyase (ACLY), that is, acting at an earlier site in the enzyme pathway than statins, affecting the later enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The half-life of bepedic acid ranges from 15 to 24 hours. 180 mg is taken orally daily, before or after meals, and a stable concentration is reached within 7 days. More than 70% of the drug is excreted through urine, and the remaining 30% can be excreted through feces.

[0006] Bepedic acid has been shown to be well tolerated and safe. The main reason for its better safety compared to statins is that muscle tissue is not exposed to the active metabolites of the drug. In addition, studies have shown that bepedic acid can reduce TG, glucose or high-sensitivity C-reactive protein (hs-CRP) levels (inflammatory markers). Animal model experiments also suggest that it may have pleiotropic effects such as reducing abdominal fat, atherosclerotic plaques or pro-inflammatory cytokine levels.

[0007] However, currently, bepedic acid tablets are all prepared by wet granulation. However, since bepedic acid is insoluble in water and has poor water solubility, the wet granulation preparation process is complex, the types of auxiliary materials are many, and the cost is high. Summary of the invention

[0008] In view of this, the technical problem to be solved by the present invention is to provide a bepedic acid rapid-release preparation with high solubility and bioavailability and a preparation method thereof.

[0009] The present invention provides a bepedic acid immediate-release preparation, comprising:

[0010]

[0011] The dispersion carrier is selected from copovidone and / or nonionic cellulose ether;

[0012] The plasticizer is selected from one or more of phthalate plasticizers, stearate plasticizers, sodium alkyl sulfate and polyethylene glycol plasticizers.

[0013] Preferably, the dispersion carrier is selected from one or more of copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose and ethyl cellulose;

[0014] And / or, the plasticizer is selected from one or more of dimethyl phthalate, butyl stearate, sodium lauryl sulfate and polyethylene glycol.

[0015] Preferably, the lubricant is selected from one or more of colloidal silicon dioxide, sodium stearate fumarate and magnesium stearate.

[0016] Preferably, it comprises a plain tablet and a coating wrapped on the surface of the plain tablet;

[0017] The plain tablet comprises:

[0018]

[0019] The mass of the coating is 2% to 5% of the mass of the plain tablet.

[0020] Preferably, including:

[0021]

[0022] Or, include:

[0023]

[0024] Or, include:

[0025]

[0026] Or, include:

[0027]

[0028] Or, include:

[0029]

[0030] Preferably, the hardness of the bepedic acid immediate-release preparation is 60 to 120N.

[0031] The present invention also provides a method for preparing the above-mentioned bepedic acid immediate-release preparation, comprising the following steps: S1) crushing bepedic acid to obtain bepedic acid powder;

[0032] mixing the dispersion carrier and the plasticizer to obtain a mixed auxiliary material;

[0033] S2) mixing the bepedic acid powder with a mixed auxiliary material to obtain a bepedic acid premix;

[0034] S3) hot-melt extruding and crushing the bepedic acid premix to obtain bepedic acid dry particles;

[0035] S4) mixing the bepedic acid dry particles with a lubricant to obtain a bepedic acid total mixture;

[0036] S5) tableting the bepedic acid total mixture to obtain a bepedic acid immediate-release preparation.

[0037] Preferably, the D of the bepedic acid powder is 50 1~10μm, D 90 5~50μm.

[0038] Preferably, the dispersed carrier and the plasticizer are mixed and then passed through a 60-100 mesh sieve to obtain a mixed auxiliary material;

[0039] After the pulverization in step S3), the powder is sieved through a 80-100 mesh sieve to obtain bepedic acid dry particles.

[0040] Preferably, the temperature of the hot melt extrusion is 60° C. to 100° C.; the rotation speed of the hot melt extrusion is 400 to 600 rpm; and the feeding speed of the hot melt extrusion is 5 to 7 kg / h.

[0041] Preferably, the hot melt extrusion comprises 6 to 10 heating zones, the temperature of the first heating zone is room temperature, the temperature of the last heating zone is 60°C to 100°C; the temperature difference between adjacent heating zones is 5°C to 10°C.

[0042] Compared with the prior art, the present invention strictly controls the particle size of bepedic acid, greatly reduces the types of excipients used, does not require the addition of organic solvents during the preparation process, and is safe and pollution-free; the preparation process is a continuous process with fewer process steps, shortens the production time, enables sustainable operation, and reduces production costs; the particles can be evenly dispersed, the content uniformity of the extrudate is better, and has better in vitro dissolution uniformity, has no requirements for the compressibility of the active ingredient, greatly improves the patient's medication safety, and improves the solubility and has a higher bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is a trend chart of the weight difference of bepedic acid tablets obtained in Example 1 of the present invention;

[0044] Figure 2 This is a hardness fluctuation trend diagram of the bepedic acid tablets obtained in Example 1 of the present invention;

[0045] Figure 3 The dissolution curves of the bepedic acid immediate-release preparation obtained in the example of the present invention and the commercially available bepedic acid preparation are shown in FIG. DETAILED DESCRIPTION

[0046] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0047] The present invention provides a bepedic acid immediate-release preparation, comprising:

[0048]

[0049]

[0050] The dispersion carrier is selected from copovidone and / or nonionic cellulose ether;

[0051] The plasticizer is selected from one or more of phthalate plasticizers, stearate plasticizers, sodium alkyl sulfate and polyethylene glycol plasticizers.

[0052] According to the present invention, the content of bepedic acid in the bepedic acid immediate-release preparation is preferably 70 to 88 parts by weight, more preferably 70 to 86 parts by weight, and even more preferably 71 to 85.5 parts by weight; in some embodiments provided by the present invention, the content of bepedic acid in the bepedic acid immediate-release preparation is specifically 75 parts by weight, 71.04 parts by weight, 85.34 parts by weight, 75.47 parts by weight or 72 parts by weight.

[0053] According to the present invention, the content of the dispersed carrier in the bepedic acid immediate-release preparation is preferably 5 to 20 parts by weight, more preferably 7 to 20 parts by weight, more preferably 8 to 20 parts by weight, more preferably 10 to 20 parts by weight, and most preferably 16 to 20 parts by weight; in some embodiments provided by the present invention, the content of the dispersed carrier in the bepedic acid immediate-release preparation is specifically 18.75 parts by weight, 16.39 parts by weight, 7.61 parts by weight, 7.55 parts by weight or 8 parts by weight; the dispersed carrier is preferably one or more of copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose and ethyl cellulose; the copovidone is preferably S-630.

[0054] According to the present invention, the content of the plasticizer in the bepedic acid immediate-release preparation is preferably 1 to 20 parts by weight, more preferably 2 to 18 parts by weight, more preferably 4 to 16 parts by weight, more preferably 4 to 15 parts by weight, and most preferably 4 to 8.2 parts by weight; in some embodiments provided by the present invention, the content of the plasticizer in the bepedic acid immediate-release preparation is specifically 4.17 parts by weight, 8.2 parts by weight, 5.19 parts by weight, 15.09 parts by weight or 16 parts by weight; the plasticizer is preferably one or more of phthalate plasticizers, stearate plasticizers, sodium alkyl sulfates and polyethylene glycol plasticizers, more preferably one or more of dimethyl phthalate, butyl stearate, sodium lauryl sulfate and polyethylene glycol.

[0055] According to the present invention, the content of the lubricant in the bepedic acid immediate-release preparation is preferably 1 to 5 parts by weight, more preferably 1.5 to 4.5 parts by weight; the content of the lubricant in the bepedic acid immediate-release preparation is specifically 2.08 parts by weight, 4.37 parts by weight, 1.86 parts by weight, 1.89 parts by weight or 4 parts by weight; the lubricant is preferably one or more of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate.

[0056] In a specific embodiment provided by the present invention, the bepedic acid rapid-release preparation comprises a plain tablet and a coating wrapped on the surface of the plain tablet; the plain tablet comprises: 70 to 90 parts by weight of bepedic acid; 5 to 20 parts by weight of a dispersion carrier; 0.5 to 20 parts by weight of a plasticizer; 0.5 to 5 parts by weight of a lubricant; the mass of the coating is 2% to 5% of the mass of the plain tablet.

[0057] According to the present invention, the content of bepedic acid in the plain tablet is preferably 70 to 88 parts by weight, more preferably 70 to 86 parts by weight, and even more preferably 71 to 85.5 parts by weight; in some embodiments provided by the present invention, the content of bepedic acid in the bepedic acid immediate-release preparation is specifically 75 parts by weight, 71.04 parts by weight, 85.5 parts by weight, 75.47 parts by weight or 72 parts by weight.

[0058] According to the present invention, the content of the dispersed carrier in the plain tablet is preferably 5 to 20 parts by weight, more preferably 7 to 20 parts by weight, more preferably 8 to 20 parts by weight, more preferably 10 to 20 parts by weight, and most preferably 16 to 20 parts by weight; in some embodiments provided by the present invention, the content of the dispersed carrier in the bepedic acid immediate-release preparation is specifically 18.75 parts by weight, 16.39 parts by weight, 7.43 parts by weight, 7.55 parts by weight or 8 parts by weight; the dispersed carrier is preferably one or more of copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose and ethyl cellulose; the copovidone is preferably S-630.

[0059] According to the present invention, the content of the plasticizer in the plain tablet is preferably 1 to 20 parts by weight, more preferably 2 to 18 parts by weight, more preferably 4 to 16 parts by weight, more preferably 4 to 15 parts by weight, and most preferably 4 to 8.2 parts by weight; in some embodiments provided by the present invention, the content of the plasticizer in the bepedic acid immediate-release preparation is specifically 4.17 parts by weight, 8.2 parts by weight, 5.2 parts by weight, 15.09 parts by weight or 16 parts by weight; the plasticizer is preferably one or more of phthalate plasticizers, stearate plasticizers, sodium alkyl sulfates and polyethylene glycol plasticizers, more preferably one or more of dimethyl phthalate, butyl stearate, sodium lauryl sulfate and polyethylene glycol.

[0060] According to the present invention, the content of the lubricant in the plain tablet is preferably 1 to 5 parts by weight, more preferably 1.5 to 4.5 parts by weight; the content of the lubricant in the bepedic acid immediate-release preparation is specifically 2.08 parts by weight, 4.37 parts by weight, 1.86 parts by weight, 1.89 parts by weight or 4 parts by weight; the lubricant is preferably one or more of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate.

[0061] In a specific embodiment provided by the present invention, the plain tablet comprises:

[0062]

[0063] In a specific embodiment provided by the present invention, the plain tablet comprises:

[0064]

[0065]

[0066] In a specific embodiment provided by the present invention, the plain tablet comprises:

[0067]

[0068] In a specific embodiment provided by the present invention, the plain tablet comprises:

[0069]

[0070] In a specific embodiment provided by the present invention, the plain tablet comprises:

[0071]

[0072] According to the present invention, optionally, the mass of the coating is 2%, 3%, 4%, 5% of the mass of the plain tablet or a range between any two of the above values; the coating can be made of coating materials well known to those skilled in the art without any special limitation. In the present invention, preferably one or more of Opadry I (white), Opadry II and Opadry XY are used.

[0073] According to the present invention, the hardness of the bepedic acid immediate-release preparation is preferably 60 to 120N.

[0074] The present invention also provides a method for preparing a bepedic acid immediate-release preparation, comprising the following steps: S1) crushing bepedic acid to obtain bepedic acid powder; mixing a dispersion carrier material with a plasticizer to obtain a mixed excipient; S2) mixing the bepedic acid powder with the mixed excipient to obtain a bepedic acid premix; S3) hot-melt extruding the bepedic acid premix and crushing it to obtain bepedic acid dry granules; S4) mixing the bepedic acid dry granules with a lubricant to obtain a bepedic acid total mixture; S5) tableting the bepedic acid total mixture to obtain a bepedic acid immediate-release preparation.

[0075] The present invention can improve the dissolution state of bepedic acid and thus improve the in vitro dissolution rate of the preparation through designed prescriptions and processes, using advanced preparation processes such as fewer types of excipients, simple preparation processes, safety, no pollution, and lower costs, thereby having higher bioavailability.

[0076] The present invention has no particular limitation on the sources of all raw materials, and any raw materials available on the market can be used.

[0077] Bepedic acid is crushed to obtain bepedic acid powder; the crushing method is well known to those skilled in the art and is not particularly limited. In the present invention, air flow crushing is preferred; the D 50 Preferably 1 to 10 μm, D 90 Preferably, it is 5 to 50 μm; the D50 and D90 are both measured by a Malvern laser diffraction particle size analyzer using a dry method.

[0078] Optionally, the bepedic acid powder D 50is 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm or a range between any two of the above values; in some embodiments provided by the present invention, the D 50 It is 2.231μm, 3.531μm, 5.552μm, 7.635μm or 9.533μm.

[0079] Optionally, the bepedic acid powder D 90 is 5 μm, 10 μm, 15 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm or a range between any two of the above values; in some embodiments provided by the present invention, the D 50 It is 5.768μm, 25.788μm, 30.818μm, 45.798μm or 49.898μm.

[0080] The dispersed carrier and the plasticizer are mixed to obtain a mixed auxiliary material; preferably, the mixed material is dried after mixing; further, after drying, it is preferably sieved through a 60-100 mesh sieve to obtain a mixed auxiliary material; optionally, it is sieved through a 60 mesh sieve, an 80 mesh sieve, a 100 mesh sieve or a range between any two of the above values.

[0081] The bepedic acid powder is mixed with the mixed auxiliary materials to obtain a bepedic acid premix; the mixing rotation speed is preferably 5-50 rpm, more preferably 5-30 rpm, more preferably 10-20 rpm, and most preferably 15 rpm; the mixing time is preferably 5-20 min, more preferably 5-15 min, and more preferably 10 min.

[0082] The bepedic acid premix is ​​subjected to hot-melt extrusion and crushed to obtain bepedic acid dry particles; the temperature of the hot-melt extrusion is preferably 60°C to 100°C, more preferably 70°C to 100°C, more preferably 80°C to 100°C, and most preferably 90°C to 100°C; the rotation speed of the hot-melt extrusion is preferably 400 to 600 rpm; the feeding rate of the hot-melt extrusion is preferably 5 to 7 kg / h; the strips obtained by hot-melt extrusion are preferably cooled and crushed to obtain bepedic acid dry particles; further, after crushing, they are sieved through an 80-100 mesh sieve to obtain bepedic acid dry particles.

[0083] In a specific embodiment provided by the present invention, the hot melt extrusion preferably includes 6 to 10 heating zones, the temperature of the first heating zone is room temperature, and the temperature of the last heating zone is 60°C to 100°C; more preferably, it includes 8 heating zones, the temperature of the first heating zone is room temperature, and the temperature of the last heating zone is 60°C to 100°C; more preferably, it includes 8 heating zones, the temperature of the first heating zone is room temperature, and the temperature of the last heating zone is 80°C to 100°C; the temperature difference between adjacent heating zones is preferably 5°C to 10°C.

[0084] In a specific embodiment provided by the present invention, hot melt extrusion includes 8 heating zones, the temperature of the first heating zone is room temperature, the temperature of the second heating zone is 50°C, the temperature of the third heating zone is 55°C, the temperature of the fourth heating zone is 60°C, the temperature of the fifth heating zone is 70°C, the temperature of the sixth heating zone is 80°C, the temperature of the seventh heating zone is 90°C, and the temperature of the eighth heating zone is 100°C. The technology adopted in the present invention is hot melt extrusion technology (HME), the principle of which is to transport excipients such as solid drugs and carriers into the equipment, and undergo heating and melting, shear mixing, exhaust homogenization, melt conveying, extrusion molding and many other unit operations, that is, under the action of strong shear force and heat energy provided by the sleeve, the particle size of the multi-component material is continuously reduced, fully mixed, and the drug is promoted to be more evenly dispersed in the carrier to form an amorphous solid dispersion (ASD), and then extruded at a certain pressure and speed, shaped through the die hole at the outlet, and cooled to shape, that is, a solid dispersion (SD) with a certain shape is obtained. The hot melt extrusion process has the advantages of continuous process, fewer process steps, safety, pollution-free and high repeatability.

[0085] The bepedic acid dry particles are mixed with a lubricant to obtain a bepedic acid total blend.

[0086] The bepedic acid total mixture is tableted to obtain a bepedic acid immediate-release preparation; the tableting hardness is preferably controlled within a range of 60 to 120N.

[0087] In a specific embodiment provided by the present invention, the bepedic acid total mixture is tableted to obtain a plain tablet; the plain tablet is coated to obtain a bepedic acid immediate-release preparation; the coating method can be a method well known to those skilled in the art, without any special limitation, and spray coating is preferred in the present invention; the weight gain of the coating treatment is preferably 2% to 5%, and optionally, the weight gain is 2%, 3%, 4%, 5% or a range between any two of the above values; the coating material used for the coating treatment can be a coating material well known to those skilled in the art, without any special limitation, and one or more of Opadry I (white), Opadry II and Opadry XY are preferred in the present invention.

[0088] The invention strictly controls the particle size of bepedic acid, greatly reduces the types of auxiliary materials used, does not need to add organic solvents in the preparation process, is safe and pollution-free; the preparation process is a continuous process with fewer process steps, shortens the production time, enables sustainable operation, and reduces production costs; the particles can be evenly dispersed, the content uniformity of the extrudate is better, has good in vitro dissolution uniformity, has no requirements on the compressibility of the active ingredient, greatly improves the safety of patient medication, and improves the solubility and has a higher bioavailability.

[0089] In order to further illustrate the present invention, a bepedic acid rapid-release preparation and a preparation method thereof provided by the present invention are described in detail below in conjunction with examples.

[0090] The materials used in the following examples are all commercially available.

[0091] Example 1

[0092] The formulation of the immediate-release preparation of bepedic acid is shown in Table 1.

[0093] Table 1 Example 1 Bepedic acid immediate release formulation formulation

[0094] Element Dosage(mg) Proportion(%) Bepedic acid 180 75.00 Copolyvidone (S-630) 45 18.75 Dimethyl phthalate 10 4.17 Sodium stearate fumarate 5 2.08 total 240 100％ Opadry I (white) 7.2 - total 247.2 -

[0095] Preparation method of bepedic acid immediate release preparation:

[0096] 1) Pretreatment of raw materials: The raw material bepedic acid was crushed by a jet mill, and the particle size D of the crushed bepedic acid powder was measured by a Malvern laser diffraction particle size analyzer. 50 2.231μm, D 90 5.768μm, for later use; copolyvidone (S-630) and dimethyl phthalate are weighed according to the prescribed amount and for later use;

[0097] 2) preparing a bepedic acid premix: slowly adding the prescribed amount of dimethyl phthalate to copovidone (S-630) and stirring well, drying and passing through an 80-mesh sieve; placing bepedic acid and the sieved excipients in a hopper mixer and mixing at a speed of 15 rpm for 10 min to obtain a bepedic acid premix;

[0098] 3) Extrusion: Use PHARMA 16 hot melt extruder to make pellets. The temperature settings of the extruder are zone A (room temperature) → zone B (50°C) → zone C (55°C) → zone D (60°C) → zone E (70°C) → zone F (80°C) → zone G (90°C) → zone H (100°C). The bepedic acid premix is ​​evenly added to the hopper. After the temperature rises to the set value, the screw is started. The screw speed is 500 rpm, the feeding rate is 6.0 kg / h, and the extrusion operation is started. After the extrudate state is stable, it is collected in a stainless steel plate and cooled at room temperature;

[0099] 4) Granulation: The cooled extrudate is passed through an 80-mesh sieve of a granulator to obtain bepedic acid dry granules;

[0100] 6) Total mixing: Sodium stearate fumarate and bepedic acid dry granules were weighed according to the prescription ratio, placed in a hopper mixer for mixing, the mixing time was 5 minutes, the speed was 10 rpm, and the bepedic acid total mixture was obtained;

[0101] 7) The bepedic acid total mixture is compressed into tablets according to the theoretical tablet weight and the hardness is controlled within the range of 60 to 120 N to obtain bepedic acid tablets.

[0102] 8) Coating: Dissolve the coating material in purified water to prepare a coating solution for use. Transfer the bepedic acid tablets into a high-efficiency coating machine and start spray coating. The coating layer weight gain is 2% to 5%.

[0103] Example 2

[0104] The formulation of the immediate-release preparation of bepedic acid is shown in Table 2.

[0105] Table 2 Example 2 Bepedic acid immediate release formulation formulation

[0106] Element Dosage(mg) Proportion(%) Bepedic acid 130 71.04 Copolyvidone (S-630) 30 16.39 Dimethyl phthalate 15 8.20 Sodium stearate fumarate 8 4.37 total 183 100％ Opadry I (white) 5.5 - total 188.5 -

[0107] The particle size of the crushed bepedic acid powder was measured by dry method using Malvern laser diffraction particle size analyzer. The particle size D50 was 3.531 μm and D90 was 25.788 μm. The preparation method was the same as that in Example 1.

[0108] Example 3

[0109] The formulation of the immediate-release preparation of bepedic acid is shown in Table 3.

[0110] Table 3 Formulation of Bepedic Acid Immediate Release Formulation of Example 3

[0111]

[0112]

[0113] The particle size of the crushed bepedic acid powder was measured by dry method using Malvern laser diffraction particle size analyzer, and the particle size D50 was 5.552 μm and D90 was 30.818 μm. The preparation method was the same as that in Example 1.

[0114] Example 4

[0115] The formulation of the immediate-release preparation of bepedic acid is shown in Table 4.

[0116] Table 4 Example 4 Bepedic acid immediate release formulation formulation

[0117] Element Dosage(mg) Proportion(%) Bepedic acid 200 75.47 Copolyvidone (S-630) 20 7.55 Dimethyl phthalate 40 15.09 Sodium stearate fumarate 5 1.89 total 265 100％ Opadry I (white) 8 - total 273 -

[0118] The particle size of the crushed bepedic acid powder was measured by dry method using Malvern laser diffraction particle size analyzer, and the particle size D50 was 7.635 μm and D90 was 45.798 μm. The preparation method was the same as that in Example 1.

[0119] Example 5

[0120] The formulation of the immediate-release preparation of bepedic acid is shown in Table 5.

[0121] Table 5 Example 5 Bepedic acid immediate release formulation formulation

[0122] Element Dosage(mg) Proportion(%) Bepedic acid 180 72.00 Copolyvidone (S-630) 20 8.00 Dimethyl phthalate 40 16.00 Sodium stearate fumarate 10 4.00 total 250 100％ Opadry I (white) 7.5 - total 257.5 -

[0123] The particle size of the crushed bepedic acid powder was measured by dry method using Malvern laser diffraction particle size analyzer, and the particle size D50 was 9.533 μm and D90 was 49.898 μm. The preparation method was the same as that in Example 1.

[0124] Particle flowability and compressibility testing:

[0125] According to the prescription process of Example 1, three batches of bepedic acid total mixture were prepared in parallel, and the powder indicators such as angle of repose, bulk density, tap density, and Carr's index of the three batches of total mixture were tested respectively to evaluate the fluidity and compressibility of the particles. The results are shown in Table 6. Among them, the angle of repose, bulk density, and tap density are all methods of the Chinese Pharmacopoeia. Carr's index is calculated by bulk density and tap density.

[0126] Table 6 Evaluation results of particle flowability and compressibility of bepedic acid mixture

[0127] batch number ZG-001 ZG-002 ZG-003 Angle of repose° 27 30 32 Bulk density (g / ml) 0.395 0.425 0.403 Tap density(g / ml) 0.486 0.501 0.489 Carl Index % 19 15 18

[0128] The data in the above table show that the repose angles of the three batches of bepedic acid total mixtures are close, and the bulk density data are close. Combined with the evaluation standards of formulation powder science, the total mixture prepared according to the preparation process of the present invention has good fluidity, good reproducibility, and a stable preparation process.

[0129] The above three batches of total mixtures were respectively pressed into tablets according to the theoretical tablet weight, and the tablet weight difference and hardness fluctuation were detected. The weight difference trend diagram of the bepedic acid tablets obtained in Example 1 was obtained as shown in FIG. Figure 1 As shown; the hardness fluctuation trend diagram of the bepedic acid tablets obtained in Example 1 is as shown Figure 2 shown.

[0130] Depend on Figure 1 It can be seen that the differences in tablet weights of the three batches of bepedic acid tablets can be controlled within the range of ±5% of the theoretical tablet weight. The RSD values ​​of the tablet weights of the three batches were 1.57%, 1.36%, and 1.19%, respectively. The fluctuations in the tablet weights of the three batches were stable and controllable.

[0131] Depend on Figure 2It can be seen that the hardness of the three batches of bepedic acid tablets can be controlled within the range of 60 to 120N. The RSD values ​​of the hardness of the three batches are 7.66%, 6.53%, and 9.30%, respectively. The hardness fluctuations of the three batches are relatively close, and they are stable and controllable.

[0132] Comparative Example 1

[0133] The prescription and dosage ratio are the same as in Example 1.

[0134] The original powdered bepedic acid (i.e., the raw material bepedic acid used in Examples 1 to 5) was not processed by a jet mill, i.e., the particle size of the bepedic acid was not controlled. The other preparation methods were the same as in Example 1.

[0135] Comparative Example 2

[0136] The formulation of the immediate-release preparation of bepedic acid is shown in Table 7.

[0137] Table 7 Comparative Example 2 Bepedic Acid Immediate Release Preparation Formulation

[0138] Element Dosage(mg) Proportion(%) Bepedic acid 180 75.00 Microcrystalline Cellulose 45 18.75 Dimethyl phthalate 10 4.17 Sodium stearate fumarate 5 2.08 total 240 100％ Opadry I (white) 7.2 - total 247.2 -

[0139] The preparation method is the same as Example 1.

[0140] Comparative Example 3

[0141] The formulation of the immediate-release preparation of bepedic acid is shown in Table 8.

[0142] Table 8 Comparative Example 3 Bepedic Acid Immediate Release Preparation Formulation

[0143] Element Dosage(mg) Proportion(%) Bepedic acid 180 75.00 Copolyvidone (S-630) 45 18.75 Triethyl citrate 10 4.17 Sodium stearate fumarate 5 2.08 total 240 100％ Opadry I (white) 7.2 - total 247.2 -

[0144] The preparation method is the same as Example 1.

[0145] Comparative Example 4

[0146] The formulation of the immediate-release preparation of bepedic acid is shown in Table 9.

[0147] Table 9 Comparative Example 4 Bepedic Acid Immediate Release Preparation Formulation

[0148]

[0149]

[0150] The preparation method is the same as Example 1.

[0151] Comparative Example 5

[0152] The prescription and dosage ratio are the same as in Example 1.

[0153] The preparation method of the bepedic acid rapid-release preparation:

[0154] 1) Pretreatment of raw materials: The raw material bepedic acid was crushed by a jet mill, and the particle size D of the crushed bepedic acid powder was measured by a Malvern laser diffraction particle size analyzer. 50 2.231μm, D 90 5.768μm, for later use; copolyvidone (S-630) and dimethyl phthalate are weighed according to the prescribed amount and for later use;

[0155] 2) Excipient pretreatment: slowly add the prescribed amount of dimethyl phthalate to copolyvidone (S-630) and stir well, then dry and pass through an 80-mesh sieve;

[0156] 3) Wet granulation: Bepedic acid, the sieved excipients are placed in a wet granulator, purified water is used, granulation is performed at an atomization pressure of 0.5 bar, and then transferred to a boiling dryer, the material temperature is controlled not to exceed 60°C for drying;

[0157] 4) Granulation: The dried granules are passed through an 80-mesh sieve of a granulator to obtain bepedic acid dry granules;

[0158] 6) Total mixing: Sodium stearate fumarate and bepedic acid dry granules were weighed according to the prescription ratio, placed in a hopper mixer for mixing, the mixing time was 5 minutes, the speed was 10 rpm, and the bepedic acid total mixture was obtained;

[0159] 7) The bepedic acid total mixture is compressed into tablets according to the theoretical tablet weight and the hardness is controlled within the range of 60 to 120 N to obtain bepedic acid tablets.

[0160] 8) Coating: Dissolve the coating material in purified water to prepare a coating solution for use. Transfer the bepedic acid tablets into a high-efficiency coating machine and start spray coating. The coating layer weight gain is 2% to 5%.

[0161] Comparative Example 6

[0162] The prescription and dosage ratio are the same as in Example 1.

[0163] Bepedic acid tablets with a hardness lower than 60N and a hardness higher than 120N were respectively pressed; the other preparation methods were the same as those in Example 1.

[0164] Comparative Example 7

[0165] The prescription and dosage ratio are the same as in Example 1.

[0166] The preparation method of the bepedic acid rapid-release preparation:

[0167] 1) Pretreatment of raw materials: The raw material bepedic acid was crushed by a jet mill, and the particle size D of the crushed bepedic acid powder was measured by a Malvern laser diffraction particle size analyzer. 50 2.231μm, D 905.768μm, for later use; copolyvidone (S-630) and dimethyl phthalate are weighed according to the prescribed amount and for later use;

[0168] 2) preparing a bepedic acid premix: slowly adding the prescribed amount of dimethyl phthalate to copovidone (S-630) and stirring well, drying and passing through an 80-mesh sieve; placing bepedic acid and the sieved excipients in a hopper mixer and mixing at a speed of 15 rpm for 10 min to obtain a bepedic acid premix;

[0169] 3) Extrusion: Use PHARMA 16 hot melt extruder to make pellets. The temperature settings of the extruder are zone A (room temperature) → zone B (40°C) → zone C (50°C) → zone D (55°C) → zone E (60°C) → zone F (70°C) → zone G (100°C) → zone H (130°C). The bepedic acid premix is ​​evenly added to the hopper. After the temperature rises to the set value, the screw is started. The screw speed is 300 rpm, the feeding rate is 4.0 kg / h, and the extrusion operation is started. After the extrudate state is stable, it is collected in a stainless steel plate and cooled at room temperature;

[0170] 4) Granulation: The cooled extrudate is passed through an 80-mesh sieve of a granulator to obtain bepedic acid dry granules;

[0171] 6) Total mixing: Sodium stearate fumarate and bepedic acid dry granules were weighed according to the prescription ratio, placed in a hopper mixer for mixing, the mixing time was 5 minutes, the speed was 10 rpm, and the bepedic acid total mixture was obtained;

[0172] 7) The bepedic acid total mixture is compressed into tablets according to the theoretical tablet weight, and the hardness is controlled within the range of 60 to 120 N to obtain bepedic acid tablets.

[0173] 8) Coating: Dissolve the coating material in purified water to prepare a coating solution for use. Transfer the bepedic acid tablets into a high-efficiency coating machine and start spray coating. The coating layer weight gain is 2% to 5%.

[0174] Comparative Example 8

[0175] The prescription and dosage ratio are the same as in Example 1.

[0176] The preparation method of the bepedic acid rapid-release preparation:

[0177] Preparation of bepedic acid premix: Add the prescribed amount of dimethyl phthalate to copovidone (S-630) and bepedic acid in a hopper mixer for mixing at a speed of 15 rpm for 10 min to obtain a bepedic acid premix; other preparation methods are the same as in Example 1.

[0178] According to the dissolution determination method (Appendix XC Method 2 of Part II of the 2020 edition of the Chinese Pharmacopoeia), Examples 1 to 5, Comparative Examples 1 to 8, and commercially available bepedic acid preparations were measured, using 900 mL of phosphate buffer with a pH value of 6.6 as the solvent, the speed was 50 rpm, and the operation was performed according to the law. Samples were taken and measured at 5, 10, 15, 20, 30, 45, and 60 minutes, respectively, to obtain the dissolution curves of the bepedic acid immediate-release preparation and the commercially available bepedic acid preparation (bepedic acid tablets from Esperion, USA) as shown in the figure Figure 3 shown.

[0179] Depend on Figure 3 From the dissolution curve data of Examples 1 to 5, the dissolution of the preparations has good reproducibility, indicating that the dissolution of the rapid-release preparations prepared by the present invention has good reproducibility, and the dissolution trend of the main component bepedic acid is 10% to 15% faster than that of the commercially available samples, indicating that the preparation process and prescription design of the present invention can better improve the dissolution rate.

[0180] According to the in vitro dissolution data of the embodiment and comparative example 1, the in vitro dissolution of the comparative example 1 sample in which the particle size of the raw material drug is not strictly controlled is 5% to 10% slower than that of the embodiment, indicating that strict control of the particle size of the raw material drug in the present invention is beneficial to improving the in vitro dissolution of the new compound preparation.

[0181] According to Comparative Example 2, a new dispersed carrier material was replaced and the hot melt extrusion process parameters of the present invention were adopted. During the preparation process, the material had problems such as dispersion and accumulation, which was not conducive to the preparation processes such as melting and shear mixing. This shows that the dispersed carrier of the present invention is conducive to the hot melt extrusion preparation process of the preparation.

[0182] According to the embodiment and comparative example 3, after replacing other plasticizers, the in vitro dissolution rate is 6% to 15% slower than that of the embodiment, indicating that the plasticizer of the present invention is conducive to the dissolution of the preparation.

[0183] According to Example 4 and Comparative Example 4, after replacing other lubricants, the tablet weight fluctuation during tableting was large (>7.5%), which did not meet the requirements, indicating that the lubricant of the present invention is beneficial to the tableting of the preparation of the present invention.

[0184] According to Example 1 and Comparative Example 5, by using the prescription of the present invention and replacing other preparation processes, the in vitro dissolution is 10% to 15% faster than that of the Example 1, indicating that the preparation process of the present invention is conducive to the dissolution of the active ingredient and accelerates the in vitro dissolution.

[0185] According to Comparative Example 6, when the hardness of bepedic acid tablets is less than 60N, the tablet friability is greater than 1%, which does not meet the requirements; when the hardness of bepedic acid tablets is greater than 120N, the in vitro dissolution of Comparative Example 6 is slow, which is lower than the dissolution of the commercially available preparation, indicating that the hardness range of the present invention is conducive to the dissolution of the preparation.

[0186] According to Example and Comparative Example 7, the hot melt extrusion process parameters were adjusted, and the in vitro dissolution was 10% to 18% slower than that of the Example, indicating that the preparation process parameters of the present invention are conducive to the in vitro dissolution of the preparation.

[0187] According to Comparative Example 8, the preparation method of bepedic acid is adjusted, and the in vitro dissolution uniformity of the preparation does not meet the requirements, that is, the dissolution RSD of the 5th minute is greater than 20%, and the dissolution of the 10th minute is greater than 10%. This shows that the preparation method of the bepedic acid premix of the present invention is more conducive to the full integration of the plasticizer, the dispersing carrier and the active ingredient, and is more conducive to in vitro dissolution.

[0188] 40 SD rats weighing 180±10g were randomly divided into 2 groups (Group A and Group B), 20 rats in each group. The preparation of Example 1 was taken, ground into powder and dispersed into a suspension with purified water, and the rats in Group A were gavaged at 5 mg / kg body weight; the commercially available bepedic acid preparation (bepedic acid tablets of Esperion, USA) was taken, ground into powder and dispersed into a suspension with purified water, and the rats in Group B were gavaged at 5 mg / kg body weight; after gavage, venous blood was taken at 15min, 30min, 45min, 60min, 90min, 2h, 3h, 4h, 6h, and 8h, and the concentration of bepedic acid in the blood sample was determined by gas chromatography-mass spectrometry after extraction, and the pharmacokinetic parameters were calculated as shown in Table 10.

[0189] Table 10 Calculation results of pharmacokinetic parameters of bepedic acid immediate release preparation and commercially available bepedic acid preparation

[0190]

[0191] It can be seen from the data in the table that after the preparation of the present invention was administered to rats by gavage, its Tmax was shortened, and Cmax and AUC 0-∞ (h×ng / mL) were greatly increased, indicating that the present invention can greatly improve the oral bioavailability of bepedic acid.

[0192] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A bepedic acid immediate-release preparation, characterized in that: include: The dispersion carrier is selected from copovidone and / or nonionic cellulose ether; The plasticizer is selected from one or more of phthalate plasticizers, stearate plasticizers, sodium alkyl sulfate and polyethylene glycol plasticizers.

2. The bepedic acid immediate-release preparation according to claim 1, characterized in that The dispersion carrier is selected from one or more of copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose and ethyl cellulose; And / or, the plasticizer is selected from one or more of dimethyl phthalate, butyl stearate, sodium lauryl sulfate and polyethylene glycol; And / or, the lubricant is selected from one or more of colloidal silicon dioxide, sodium stearate fumarate and magnesium stearate.

3. The bepedic acid immediate-release preparation according to any one of claims 1 to 3, characterized in that: It includes a plain tablet and a coating wrapped on the surface of the plain tablet; The plain tablet comprises: The mass of the coating is 2% to 5% of the mass of the plain tablet.

4. The bepedic acid immediate-release preparation according to any one of claims 1 to 3, characterized in that: include: Or, include: Or, include: Or, include: Or, include:

5. The bepedic acid immediate-release preparation according to any one of claims 1 to 4, characterized in that: The hardness of the bepedic acid rapid-release preparation is 60-120N.

6. A method for preparing the bepedic acid immediate-release preparation according to any one of claims 1 to 5, characterized in that: The following steps are involved: S1) crushing bepedic acid to obtain bepedic acid powder; mixing the dispersion carrier and the plasticizer to obtain a mixed auxiliary material; S2) mixing the bepedic acid powder with a mixed auxiliary material to obtain a bepedic acid premix; S3) hot-melt extruding and crushing the bepedic acid premix to obtain bepedic acid dry particles; S4) mixing the bepedic acid dry particles with a lubricant to obtain a bepedic acid total mixture; S5) tableting the bepedic acid total mixture to obtain a bepedic acid immediate-release preparation.

7. The preparation method according to claim 6, characterized in that: The bepedic acid powder D 50 1~10μm, D 90 5~50μm.

8. The preparation method according to claim 6, characterized in that: The dispersed carrier and the plasticizer are mixed and passed through a 60-100 mesh sieve to obtain a mixed auxiliary material; After the pulverization in step S3), the powder is sieved through a 80-100 mesh sieve to obtain bepedic acid dry particles.

9. The preparation method according to claim 6, characterized in that: The temperature of the hot melt extrusion is 60° C. to 100° C.; the rotation speed of the hot melt extrusion is 400 to 600 rpm; and the feeding speed of the hot melt extrusion is 5 to 7 kg / h.

10. The preparation method according to claim 6, characterized in that: The hot melt extrusion comprises 6 to 10 heating zones, the temperature of the first heating zone is room temperature, the temperature of the last heating zone is 60° C. to 100° C.; the temperature difference between adjacent heating zones is 5° C. to 10° C.

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