Oral preparation containing bepiridic acid and statins and preparation process of oral preparation

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a compound oral preparation containing bepiridic acid, statins and analogues thereof and a process of the compound oral preparation. The compound oral preparation containing the bepiridic acid, the statins and the analogues thereof, provided by the invention, is good in stability, relatively good in dissolution effect and suitable for further clinical popularization and application.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to an oral preparation containing a statin drug and bempedoic acid and a preparation process thereof. Background Art

[0002] Bempedoic acid is an inhibitor of adenosine triphosphate citrate lyase (ACL), which can reduce low-density lipoprotein cholesterol (LDL-C) by inhibiting cholesterol synthesis in the liver, and is used for patients with elevated LDL-C who are intolerant to statin treatment, and patients at high risk of atherosclerotic cardiovascular disease or familial hypercholesterolemia.

[0003] General "statin drugs" are compounds that reduce the cholesterol level in the body by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and concomitantly inhibiting the pathway of cholesterol synthesis in the liver. Compounds included as part of "statins" include, but are not limited to, atorvastatin calcium, simvastatin, rosuvastatin, and pravastatin.

[0004] Patent CN107530308A points out that HMG-CoA reductase inhibition leads to an increase in LDL receptor activity, and the combination of statin drugs and bempedoic acid can lead to synergistic activity and favorable clinical treatment, which can lead to a further reduction in total cholesterol (and especially LDL-C) in patients.

[0005] However, the intake of multiple drugs reduces the compliance of patients to a certain extent. Therefore, on the premise of ensuring safety, it is necessary to provide a stable drug containing multiple active ingredients that can improve the compliance of patients. Summary of the Invention

[0006] The first aspect of the present invention provides an oral pharmaceutical preparation, which is characterized in that it comprises a first component containing 1, 2, or 3 bempedoic acid units, and a second component containing 0.5, 1, 1.5, or 2 statin drug or its analog units; wherein each said bempedoic acid unit contains 100-250 parts by weight of bempedoic acid, and each said statin drug or its analog unit contains 5-100 parts by weight of statin drug or its analog; preferably contains 150-210 parts by weight of bempedoic acid and 10-40 parts by weight of statin drug or its analog; preferably, the preparation is a tablet or a capsule; more preferably, the tablet is a compound double-layer tablet formed by pressing the first component and the second component into tablets respectively and then pressing them together, or a compound single-layer tablet formed by granulating the first component and the second component respectively and then mixing and pressing them, or the capsule is formed by granulating the first component and the second component respectively and then mixing and encapsulating them.

[0007] In one embodiment, each of the bepipidic acid units comprises: 100 - 250 parts by weight of bepipidic acid,

[0008] 40 - 140 parts by weight of a filler,

[0009] 12 - 40 parts by weight of a disintegrant,

[0010] 8 - 30 parts by weight of a binder,

[0011] 5 - 15 parts by weight of a lubricant,

[0012] 1 - 10 parts by weight of a glidant;

[0013] In one embodiment, each of the bepipidic acid units comprises: 150 - 210 parts by weight of bepipidic acid,

[0014] 70 - 110 parts by weight of a filler,

[0015] 15 - 30 parts by weight of a disintegrant,

[0016] 10 - 25 parts by weight of a binder,

[0017] 5 - 15 parts by weight of a lubricant,

[0018] 1 - 10 parts by weight of a glidant; and / or

[0019] Each of the statin or its analogue units comprises:

[0020] 5 - 100 parts by weight of a statin or its analogue,

[0021] 10 - 300 parts by weight of a stabilizer,

[0022] 20 - 400 parts by weight of a filler,

[0023] 2 - 90 parts by weight of a disintegrant,

[0024] 0.2 - 20 parts by weight of a binder,

[0025] 0.1 - 20 parts by weight of a lubricant,

[0026] 0 - 15 parts by weight of a cosolvent,

[0027] In one embodiment, each of the statin or its analogue units comprises:

[0028] 10 - 40 parts by weight of a statin or its analogue,

[0029] 30 - 135 parts by weight of a stabilizer,

[0030] 40 - 200 parts by weight of a filler,

[0031] Disintegrant: 5 - 40 parts by weight,

[0032] Binder: 0.5 - 10 parts by weight,

[0033] Lubricant: 0.1 - 5 parts by weight,

[0034] Solubilizer: 0.1 - 3 parts by weight.

[0035] In one embodiment, the disintegrant in the bempedoic acid unit is added in an internal addition and / or external addition manner, and it is selected from one or more of sodium croscarmellose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and crospovidone; preferably, the weight ratio of internal addition to external addition of the disintegrant in the bempedoic acid unit is 1:0 - 2; more preferably, the weight ratio of internal addition to external addition of the disintegrant in the bempedoic acid unit is 1:0.1 - 0.6;

[0036] More preferably, the weight ratio of internal addition to external addition of the disintegrant in the bempedoic acid unit is 1:0.2 - 0.5; further preferably, the weight ratio of internal addition to external addition of the disintegrant in the bempedoic acid unit is 1:0.375;

[0037] and / or

[0038] The binder in the bempedoic acid unit is selected from one or more of hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, and polyvinylpyrrolidone; and / or

[0039] The filler in the bempedoic acid unit is selected from one or more of lactose, starch, dextrin, and microcrystalline cellulose; and / or

[0040] The lubricant in the bempedoic acid unit is magnesium stearate; preferably, the lubricant is added in an external addition manner; and / or

[0041] The glidant in the bempedoic acid unit is silicon dioxide; preferably, the glidant is added in an external addition manner; and / or

[0042] The stabilizer of the statin drug or its analog unit is selected from one or more of calcium carbonate, sodium carbonate, sodium bicarbonate, and magnesium oxide; and / or

[0043] The disintegrant of the statin or its analog unit is added in an internal or external manner, and it is selected from one or more of sodium croscarmellose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and crospovidone; preferably, the weight ratio of the internal addition to the external addition of the disintegrant of the statin or its analog unit is 1:0 - 3; preferably, the weight ratio of the internal addition to the external addition of the disintegrant of the statin or its analog unit is 1:0.5 - 2; preferably, the weight ratio of the internal addition to the external addition of the disintegrant of the statin or its analog unit is 1:0.6 - 1.4; preferably, the weight ratio of the internal addition to the external addition of the disintegrant of the statin or its analog unit is 1:1 - 1.4;

[0044] and / or

[0045] The binder of the statin or its analog unit is selected from one or more of hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, and povidone; and / or

[0046] The filler of the statin or its analog unit is selected from one or more of lactose, starch, dextrin, and microcrystalline cellulose; and / or the lubricant of the statin or its analog unit is magnesium stearate; preferably, the lubricant is added externally; and / or

[0047] The co-solvent of the statin or its analog unit is polysorbate 80.

[0048] In one embodiment, the filler of the bepipatide unit is lactose and microcrystalline cellulose, and the ratio of lactose to microcrystalline cellulose is 1:0 - 2, preferably, the ratio of lactose to microcrystalline cellulose is 1:0.2 - 1.5, preferably, the ratio of lactose to microcrystalline cellulose is 1:0.3 - 0.6; preferably, the ratio of lactose to microcrystalline cellulose is 1:0 - 0.5, preferably, the ratio of lactose to microcrystalline cellulose is 1:0.3 - 0.5, preferably, the ratio of lactose to microcrystalline cellulose is 1:0.3 - 0.4; and / or

[0049] The filler of the statin or its analog unit is lactose and microcrystalline cellulose, and the ratio of lactose to microcrystalline cellulose is 1:0.2 - 4, preferably, the ratio of lactose to microcrystalline cellulose is 1:0.4 - 3, preferably, the ratio of lactose to microcrystalline cellulose is 1:0.5 - 2; preferably, the ratio of lactose to microcrystalline cellulose is 1:1 - 3, preferably, the ratio of lactose to microcrystalline cellulose is 1:1.5 - 2.5, preferably, the ratio of lactose to microcrystalline cellulose is 1:1.5 - 2.

[0050] The second aspect of the present invention provides a preparation method of the oral preparation described in any one of the foregoing, and the preparation method includes the following steps:

[0051] (1) Prepare bempedoic acid mixed granules;

[0052] (2) Prepare atorvastatin calcium mixed granules;

[0053] (3) Prepare a compound double-layer tablet of bempedoic acid and atorvastatin calcium; or

[0054] Prepare a compound single-layer tablet of bempedoic acid and atorvastatin calcium, or

[0055] Prepare a compound capsule of bempedoic acid and atorvastatin calcium.

[0056] In one embodiment, step (1) is as follows: Prepare the binder as a solution; take a mixture of bempedoic acid, sodium carboxymethyl starch filler, and disintegrant in a wet granulator, add the prepared binder solution, and granulate to obtain wet granules; add the wet granules to a fluidized bed for drying to obtain dry granules, take sodium carboxymethyl starch glidant, lubricant, and additional disintegrant, add them to a hopper mixer, and mix with the dry granules to obtain bempedoic acid mixed granules.

[0057] In one embodiment, step (2) is as follows: Prepare the solubilizer as a solution or prepare the solubilizer and the binder together as a solution; weigh atorvastatin calcium, stabilizer, filler, and disintegrant in a wet granulation pot, add the prepared solubilizer and binder mixed solution for granulation to obtain wet granules, or weigh atorvastatin calcium, stabilizer, filler, disintegrant, and binder in a wet granulation pot, add the prepared solubilizer solution for granulation to obtain wet granules; add the wet granules to a fluidized bed for drying; add additional disintegrant and lubricant and mix evenly to obtain atorvastatin calcium mixed granules; or weigh each raw and auxiliary material according to the formula amount, weigh atorvastatin calcium, stabilizer, filler, disintegrant, and binder for premixing, granulate in a dry granulator, add lubricant after sizing, and mix.

[0058] In one embodiment, step (3) is as follows: Press the bempedoic acid mixed granules and the atorvastatin calcium mixed granules into a compound double-layer tablet; coat the compound double-layer tablet to obtain a compound double-layer tablet of bempedoic acid and atorvastatin calcium; or

[0059] Mix the bempedoic acid mixed granules and the atorvastatin calcium mixed granules evenly according to the target weight ratio, and press them into a compound single-layer tablet; or mix the bempedoic acid mixed granules and the atorvastatin calcium mixed granules evenly according to the target weight ratio, and fill them into a hollow capsule to obtain a capsule.

[0060] The beneficial effects of the present invention are mainly as follows:

[0061] 1. Provide a compound oral preparation of bepipastatin calcium with good dissolution and high stability and its preparation method; 2. To a certain extent, improve the compliance of patients. Detailed implementation manners

[0062] The present invention will be further clarified below in conjunction with specific embodiments. Those skilled in the art should understand that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention. After reading the present invention, various equivalent modifications of the present invention by those skilled in the art fall within the scope defined by the appended claims of this application.

[0063] Definitions and explanations

[0064] Internal addition or internal addition method: Add excipients during the granulation process, and the effects of the excipients occur inside the granules. For example, add the disintegrant cross-linked carboxymethylcellulose sodium (CCNa) during the granulation process, and the disintegration occurs inside the granules.

[0065] External addition or external addition method: Add excipients to the granules before tabletting, and the effects of the excipients occur between the granules. For example, add the disintegrant CCNa to the dry granules before tabletting, and the disintegration occurs between the granules.

[0066] In the present invention, whether or not words such as "about" or "approximately" are used, all the numbers disclosed herein are approximate values. Based on the disclosed numbers, the numerical value of each number may have a difference of less than ±10% or a reasonable difference considered by those skilled in the art, such as a difference of ±1%, ±2%, ±3%, ±4% or ±5%.

[0067] In the present invention, "parts by weight" or "number of parts by weight" can be used interchangeably, and the parts by weight can be any fixed weight expressed in milligrams, grams or kilograms (such as 1 mg, 1 g, 2 g, 5 g, or 1 kg, etc.). For example, a composition composed of 1 part by weight of component a and 9 parts by weight of component b can be 1 gram of component a + 9 grams of component b, or a composition composed of 10 grams of component a + 90 grams of component b, etc. In the said composition, the percentage content of a certain component = (the number of parts by weight of this component / the sum of the number of parts by weight of all components) × 100%. Therefore, in a composition composed of 1 part by weight of component a and 9 parts by weight of component b, the content of component a is 10%, and component b is 90%. Preferably, in the invention, the parts by weight are expressed in "mg" for weight.

[0068] In the present invention, "statins or their analogs" are a class of drugs for regulating blood lipids. By competitively inhibiting the activity of HMG-CoA reductase, they reduce cholesterol synthesis and lower serum cholesterol levels, and are mainly used for the treatment of atherosclerosis and coronary heart disease. These drugs include mevastatin, lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, etc., which have different chemical structures and characteristics. In addition to the effect of regulating blood lipids, statins or their analogs also have non-lipid-lowering effects such as improving vascular endothelial function, inhibiting the proliferation and migration of vascular smooth muscle cells, which are beneficial to preventing the formation of arteriosclerosis or stabilizing and shrinking atherosclerotic plaques.

[0069] Example 1 Preparation of bempedoic acid granules

[0070] Table 1. Composition of bempedoic acid granules, expressed as "per tablet"

[0071]

[0072]

[0073] Preparation of bempedoic acid mixed granules:

[0074] 1> Weighing: Weigh each raw and auxiliary material according to the formula amount.

[0075] 2> Preparation of binder: Weigh hydroxypropyl cellulose and add an appropriate amount of hot water, stir until dissolved.

[0076] 3> Mixing of raw and auxiliary materials: Take the mixture of bempedoic acid, microcrystalline cellulose, monohydrate lactose, and sodium carboxymethyl starch and put it into a wet granulator, mix for 3 min.

[0077] 4> Wet granulation: Spray the prepared binder into the mixed raw and auxiliary materials, granulate for 90 s. Take out.

[0078] 5> Drying: Put the wet granules into a fluidized bed for drying to obtain dry granules.

[0079] 6> Mixing: Mix colloidal silicon dioxide, sodium carboxymethyl starch, and magnesium stearate through a sieve, add them to a hopper mixer, and mix with the dry granules obtained in step 5) for 5 min to obtain bempedoic acid mixed granules.

[0080] Examples 2 - 10 Preparation of atorvastatin calcium granules

[0081] Table 2. Composition of atorvastatin calcium granules in different examples, expressed as "per tablet"

[0082] Example 2 / mg Example 3 / mg Example 4 / mg Example 5 / mg Atorvastatin Calcium 20.0 20.0 20.0 20.0 Calcium Carbonate 66.0 - - - Sodium Carbonate - 66.0 66.0 - Sodium Bicarbonate - - 34.0 - Magnesium Oxide - - - 66.0 Lactose Monohydrate 33.0 33.0 33.0 33.0 Microcrystalline Cellulose 62.0 62.0 28.0 62.0 Hydroxypropyl Cellulose 4.0 4.0 4.0 4.0 Croscarmellose Sodium 18.0 18.0 18.0 18.0 Magnesium Stearate (extra added) 2.0 2.0 2.0 2.0 Tablet Weight 205 205 205 205

[0083] Examples 2 - 5 are prepared by dry granulation

[0084] Preparation of atorvastatin calcium mixed granules by dry granulation:

[0085] 1> Weighing: Weigh each raw and auxiliary material according to the formula amount.

[0086] 2> Premixing: Weigh atorvastatin calcium, calcium carbonate or sodium carbonate or sodium bicarbonate or magnesium oxide, microcrystalline cellulose, monohydrate lactose, croscarmellose sodium, and hydroxypropyl cellulose and mix them in a mixer for 20 minutes.

[0087] 3> Dry granulation: Press the premixed powder into tablets through a dry granulator. Screen the materials with a 1.7 mm sieve for dry sizing. 4> Mixing: Calculate the yield, weigh magnesium stearate, add it to the hopper mixer, and mix it with the granules for 5 minutes.

[0088] Table 4. Composition of atorvastatin calcium granules, expressed as "per tablet"

[0089]

[0090] The atorvastatin calcium mixed granules in Examples 6 - 9 are all prepared by wet granulation:

[0091] 1> Preparation of wetting agent: Weigh polysorbate 80, add an appropriate amount of water and stir until dissolved.

[0092] 2> Mixing of raw and auxiliary materials: Weigh atorvastatin calcium, calcium carbonate, microcrystalline cellulose, monohydrate lactose, croscarmellose sodium, and hydroxypropyl cellulose and mix them in a wet granulation pot for 3 minutes.

[0093] 3> Wet granulation: Spray the prepared aqueous solution of polysorbate 80 into the wet granulator for granulation.

[0094] 4> Drying: Add the wet granules to the fluidized bed for drying.

[0095] 5> Mixing: Add croscarmellose sodium and magnesium stearate and mix evenly to obtain atorvastatin calcium mixed granules.

[0096] The preparation method of atorvastatin calcium mixed granules in Example 10 is as follows:

[0097] 1> Preparation of binder: Weigh polysorbate 80 and hydroxypropyl cellulose, add an appropriate amount of water and stir until dissolved.

[0098] 3> Mixing of raw and auxiliary materials: Weigh atorvastatin calcium, calcium carbonate, microcrystalline cellulose, monohydrate lactose, croscarmellose sodium and mix them in a wet granulation pot for 3 minutes.

[0099] 4> Wet granulation: Spray the prepared binder solution into the wet granulator for granulation.

[0100] 5> Drying: The wet granules are added to a fluidized bed for drying.

[0101] 6> Mixing: Croscarmellose sodium and magnesium stearate are added and mixed evenly to obtain atorvastatin calcium mixed granules.

[0102] Preparation of bempedoic acid atorvastatin calcium tablets in Examples 11 - 18

[0103] Table 5. Composition of bempedoic acid atorvastatin calcium tablets, expressed as "per tablet"

[0104]

[0105] Preparation of bempedoic acid atorvastatin calcium compound bilayer tablets:

[0106] 1> The granules of Examples 1, 2 - 10 are separately pressed into tablets and then into bilayer tablets.

[0107] 2> The bilayer tablets are coated to obtain bempedoic acid atorvastatin calcium compound bilayer tablets.

[0108] Preparation of bempedoic acid atorvastatin calcium compound monolayer tablets:

[0109] 1> The mixed granules of Examples 1 - 10 are separately mixed evenly and pressed into compound bilayer tablets.

[0110] 2> The bilayer tablets are coated to obtain bempedoic acid atorvastatin calcium compound bilayer tablets.

[0111] Test Example 1 Investigation of the dissolution rate of atorvastatin calcium tablets

[0112] The atorvastatin calcium tablets prepared in Examples 2 - 10 are separately taken, and the dissolution rate (average value) test is carried out according to the relevant regulations in the "Chinese Pharmacopoeia 2020 Edition" to investigate their dissolution rate. Control Example 1 is Lipitor (Pfizer) purchased through regular channels, with a specification of 20 mg.

[0113] Table 6. Dissolution rate of atorvastatin calcium

[0114]

[0115] From the results in Table 6, for Examples 2 - 4, the tablets prepared with calcium carbonate, sodium carbonate, and a mixture of sodium carbonate and sodium bicarbonate as stabilizers all have good similarity to the control preparation.

[0116] Table 7. Dissolution rate of atorvastatin calcium

[0117]

[0118]

[0119] From the data in Table 7, it can be seen that the atorvastatin calcium tablets prepared with different dosages of stabilizers, fillers, binders and different addition ratios of disintegrants all have good similarity with the reference preparation.

[0120] Test Example 2 Stability Detection

[0121] The products of Examples 11 - 18 were subjected to accelerated and long-term tests (in total) in accordance with the relevant regulations in the "Chinese Pharmacopoeia 2020 Edition" to investigate their stability. Calculated as atorvastatin calcium, the results are as follows:

[0122] Table 8. Accelerated test stability test, calculated as atorvastatin calcium

[0123]

[0124] Table 9. Long-term test stability test, calculated as atorvastatin calcium

[0125]

[0126] The products of Examples 16, 17, and 18 were subjected to accelerated and long-term tests (in total) in accordance with the relevant regulations in the "Chinese Pharmacopoeia 2020 Edition" to investigate their stability. Calculated as bepipid acid, the results are as follows:

[0127] Table 10. Accelerated test stability test, calculated as bepipid acid

[0128]

[0129] Table 11. Long-term test stability test, calculated as bepipid acid

[0130]

[0131] From the results in Table 8, the levels of related substances of atorvastatin calcium in Examples 11 - 13 are higher than those in Examples 14 and 15. The double-layer tablet pressing process can improve the stability of the compound preparation. The compound preparations using calcium carbonate, sodium carbonate and sodium bicarbonate as stabilizers have better stability than the formulation using sodium carbonate as the stabilizer; the impurity levels of the different specifications of compound tablets prepared by the wet granulation process in Examples 16 - 18 are all below 3% after 6 months of accelerated test, and the stability is good. From the results in Table 9, Examples 16 - 18 all have good stability in the long-term test. From the results in Tables 10 and 11, it can be seen that bepipid acid in the compound tablets of different specifications has good stability.

[0132] Test Example 3 Dissolution rate investigation of the double-layer tablets obtained in the present invention

[0133] Take the double-layer tablets obtained in Examples 16, 17, and 18, and conduct dissolution rate (average value) tests in accordance with the relevant regulations in the "Chinese Pharmacopoeia 2020 Edition" to investigate their dissolution rate. The results are shown in Table 12:

[0134] Table 12 Dissolution Test

[0135] Bezafibrate Dissolution (20 min) % Atorvastatin Dissolution (45 min) % Sample Ph6.8 Water Example 16 88.22 99.46 Example 17 88.35 96.87 Example 18 96.23 92.25

[0136] The results showed that the samples of all three specifications could achieve a dissolution rate of besipirdine > 80% at 20 min and a dissolution rate of atorvastatin calcium > 80% at 45 min, indicating that the bilayer tablets obtained in this invention had good dissolution rates.

[0137] This invention has been illustrated by the above embodiments. However, it should be understood that the above embodiments are only for the purpose of exemplification and illustration, and are not intended to limit this invention to the scope of the described embodiments. In addition, those skilled in the art can understand that this invention is not limited to the above embodiments, and more variations and modifications can be made according to the teachings of this invention, and these variations and modifications all fall within the scope claimed by this invention. The protection scope of this invention is defined by the appended claims and their equivalent scope.

Claims

1. A pharmaceutical oral preparation, characterized in that: A first component comprising 1, 2, or 3 bepedic acid units, and a second component comprising 0.5, 1, 1.5, or 2 statin or analogue thereof units; wherein each of the bepedic acid units contains 100-250 parts by weight of bepedic acid, and each of the statin or analogue thereof units contains 5-100 parts by weight of statin or analogue thereof; preferably, it contains 150-210 parts by weight of bepedic acid and 10-40 parts by weight of statin or analogue thereof; preferably, the preparation is a tablet or a capsule; more preferably, the tablet is a compound double-layer tablet obtained by pressing the first component and the second component into tablets respectively, or the first component and the second component are granulated respectively and then mixed and compressed into a compound single-layer tablet, or the capsule is a compound double-layer tablet obtained by granulating the first component and the second component respectively and then mixing and encapsulating.

2. The oral pharmaceutical preparation according to claim 1, characterized in that Each of the bepedic acid units comprises: 100-250 parts by weight of bepedic acid, Filler 40-140 parts by weight, Disintegrant 12-40 parts by weight, 8-30 parts by weight of adhesive, 5-15 parts by weight of lubricant, 1-10 parts by weight of a glidant; Preferably, each of the bepedic acid units comprises: 150-210 parts by weight of bepedic acid, Filler 70-110 parts by weight, Disintegrant 15-30 parts by weight, 10-25 parts by weight of adhesive, 5-15 parts by weight of lubricant, 1-10 parts by weight of a glidant; and / or Each of the statins or their analogs units comprises: 5-100 parts by weight of statins or their analogs, Stabilizer 10-300 parts by weight, Filler 20-400 parts by weight, Disintegrant 2-90 parts by weight, 0.2-20 parts by weight of adhesive, Lubricant 0.1-20 parts by weight, Solvent 0-15 parts by weight, Preferably, each of the statins or their analogs units comprises: 10-40 parts by weight of statins or their analogs, Stabilizer 30-135 parts by weight, Filler 40-200 parts by weight, 5-40 parts by weight of disintegrant, 0.5-10 parts by weight of adhesive, Lubricant 0.1-5 parts by weight, Co-solvent 0.1-3 parts by weight.

3. The oral pharmaceutical preparation according to any one of claims 1 to 2, characterized in that: The disintegrant in the bepedic acid unit is added internally and / or externally, and is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone; preferably, the weight ratio of the internal and external disintegrant in the bepedic acid unit is 1:0-2; more preferably, the weight ratio of the internal and external disintegrant in the bepedic acid unit is 1:0.1-0.6; More preferably, the weight ratio of the internal disintegrant to the external disintegrant in the bepedic acid unit is 1:0.2-0.5; further preferably, the weight ratio of the internal disintegrant to the external disintegrant in the bepedic acid unit is 1:0.375; and / or The binder in the bepedic acid unit is selected from one or more of hydroxypropyl cellulose, methyl cellulose, ethyl cellulose and povidone; and / or The filler of the bepedic acid unit is selected from one or more of lactose, starch, dextrin and microcrystalline cellulose; and / or The lubricant of the bepedic acid unit is magnesium stearate; preferably, the lubricant is added externally; and / or The glidant of the bepedic acid unit is silicon dioxide; preferably, the glidant is added externally; and / or The stabilizer of the statin or its analogue unit is selected from one or more of calcium carbonate, sodium carbonate, sodium bicarbonate and magnesium oxide; and / or The disintegrant of the statin or its analogue unit is added internally or externally, and is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrrolidone; preferably, the weight ratio of the disintegrant added internally to the disintegrant added externally of the statin or its analogue unit is 1:0-3; preferably, the weight ratio of the disintegrant added internally to the disintegrant added externally of the statin or its analogue unit is 1:0.5-2; preferably, the weight ratio of the disintegrant added internally to the disintegrant added externally of the statin or its analogue unit is 1:0.6-1.4; preferably, the weight ratio of the disintegrant added internally to the disintegrant added externally of the statin or its analogue unit is 1:1-1.4; and / or The binder of the statin or its analogue unit is selected from one or more of hydroxypropyl cellulose, methyl cellulose, ethyl cellulose and povidone; and / or The filler of the statin or its analogue unit is selected from one or more of lactose, starch, dextrin and microcrystalline cellulose; and / or The lubricant of the statin or its analogue unit is magnesium stearate; preferably, the lubricant is added externally; and / or The cosolvent of the statin or its analogue unit is polysorbate 80.

4. The oral pharmaceutical preparation according to any one of claims 1 to 3, characterized in that: The filler of the bepedic acid unit is lactose and microcrystalline cellulose, and the ratio of lactose to microcrystalline cellulose is 1:0-2, preferably, the ratio of lactose to microcrystalline cellulose is 1:0.2-1.5, preferably, the ratio of lactose to microcrystalline cellulose is 1:0.3-0.6; preferably, the ratio of lactose to microcrystalline cellulose is 1:0-0.5, preferably, the ratio of lactose to microcrystalline cellulose is 1:0.3-0.5, preferably, the ratio of lactose to microcrystalline cellulose is 1:0.3-0.4; and / or The fillers of the statin or its analogue unit are lactose and microcrystalline cellulose, and the ratio of lactose to microcrystalline cellulose is 1:0.2-4, preferably, the ratio of lactose to microcrystalline cellulose is 1:0.4-3, preferably, the ratio of lactose to microcrystalline cellulose is 1:0.5-2; preferably, the ratio of lactose to microcrystalline cellulose is 1:1-3, preferably, the ratio of lactose to microcrystalline cellulose is 1:1.5-2.5, preferably, the ratio of lactose to microcrystalline cellulose is 1:1.5-2.

5. The oral pharmaceutical preparation according to any one of claims 1 to 4, wherein the statin or its analogue is atorvastatin calcium.

6. The pharmaceutical oral formulation according to any one of claims 1 to 5, wherein the bepedic acid unit comprises: About 180 parts by weight of bepedic acid, About 65-70 parts by weight of lactose monohydrate, preferably about 66, about 67, or about 68 parts by weight of lactose monohydrate, About 23-28 parts by weight of microcrystalline cellulose, preferably about 24, about 25, or about 26 parts by weight of microcrystalline cellulose, About 20-25 parts by weight of sodium starch glycolate, preferably about 21, about 22, or about 23 parts by weight of sodium starch glycolate, About 15-20 parts by weight of hydroxypropyl cellulose, preferably about 15, about 16, or about 17 parts by weight of hydroxypropyl cellulose, About 5-10 parts by weight of colloidal silicon dioxide, preferably about 5, about 6, or about 7 parts by weight of colloidal silicon dioxide, and About 5-10 parts by weight of magnesium stearate, preferably about 8, about 9, or about 10 parts by weight of magnesium stearate; The statin or its analogue unit comprises: About 20 parts by weight of atorvastatin calcium, One or more of calcium carbonate, sodium carbonate, sodium bicarbonate, and magnesium oxide totals about 50-100 parts by weight, preferably, calcium carbonate is about 55-77 parts by weight, preferably, calcium carbonate is about 55, about 66, or about 77 parts by weight, About 30-70 parts by weight of lactose monohydrate, preferably, about 33-60.8 parts by weight of lactose monohydrate, preferably, about 33, about 66, or about 60.8 parts by weight of lactose monohydrate, About 25-125 parts by weight of microcrystalline cellulose, preferably, about 28-121.3 parts by weight of microcrystalline cellulose, preferably, about 28, about 33, about 60.8, about 62, or about 121.3 parts by weight of microcrystalline cellulose, About 4-10 parts by weight of hydroxypropyl cellulose, preferably, about 4-6 parts by weight of hydroxypropyl cellulose, preferably, about 4, about 5, or about 6 parts by weight of hydroxypropyl cellulose, About 15-20 parts by weight of cross-linked sodium carboxymethyl cellulose, preferably about 18 parts by weight of cross-linked sodium carboxymethyl cellulose, About 1-5 parts by weight of magnesium stearate, preferably, about 1-2 parts by weight of magnesium stearate, preferably, about 1, about 1.5, or about 2 parts by weight of magnesium stearate, and About 1-1.5 parts by weight of polysorbate 80, preferably, about 1-1.3 parts by weight of polysorbate 80, preferably, about 1, about 1.1, about 1.2, or about 1.3 parts by weight of polysorbate 80; or The statin or its analogue unit comprises: About 20 parts by weight of atorvastatin calcium, One or more of calcium carbonate, sodium carbonate, sodium bicarbonate, and magnesium oxide in an amount of about 50-100 parts by weight, About 30-70 parts by weight of lactose monohydrate, preferably, about 33-60.8 parts by weight of lactose monohydrate; preferably, about 33, about 66, or about 60.8 parts by weight of lactose monohydrate, About 25-125 parts by weight of microcrystalline cellulose, preferably, about 28-121.3 parts by weight of microcrystalline cellulose, preferably, about 28, about 33, about 60.8, about 62, or about 121.3 parts by weight of microcrystalline cellulose, About 4-10 parts by weight of hydroxypropyl cellulose, preferably, about 4-6 parts by weight of hydroxypropyl cellulose, preferably, about 4, about 5, or about 6 parts by weight of hydroxypropyl cellulose, Cross-linked carboxymethyl cellulose sodium 15-20 parts by weight, preferably, cross-linked carboxymethyl cellulose sodium about 18 parts by weight, and magnesium stearate about 1-5 parts by weight, preferably, magnesium stearate about 1-2 parts by weight, preferably, magnesium stearate about 1, about 1.5, or about 2 parts by weight.

7. A method for preparing the oral preparation according to any one of claims 1 to 6, comprising the following steps: (1) preparing bepedic acid mixed granules; (2) preparing atorvastatin calcium mixed granules; (3) preparing atorvastatin calcium bepedate compound double-layer tablets; or Preparation of atorvastatin calcium bepedic acid compound single-layer tablets, or Preparation of atorvastatin calcium bepedic acid compound capsules.

8. The preparation method according to claim 7, wherein The step (1) comprises: preparing a binder into a solution; taking a mixture of bepedic acid, sodium starch glycolate filler, and a disintegrant in a wet granulator, adding the prepared binder solution, and granulating to obtain wet granules; adding the wet granules into a fluidized bed for drying to obtain dry granules; taking sodium starch glycolate flow aid, lubricant, and an additional disintegrant, adding them into a hopper mixer, and mixing with the dry granules to obtain bepedic acid mixed granules; Preferably, weigh the formulated amount of hydroxypropyl cellulose, add an appropriate amount of hot water and stir until dissolved; take a mixture of bepedic acid, microcrystalline cellulose, lactose monohydrate and sodium starch glycolate in a wet granulator, turn on the cutter at 200 rpm and the stirring paddle at 150 rpm, and mix for 3 minutes; after turning on the stirring at 250 rpm and the cutter at 1000 rpm, add the configured adhesive solution, granulate for 90 seconds, and granulate to obtain wet granules; add the wet granules to a fluidized bed for drying, take the colloidal silicon dioxide, sodium starch glycolate and magnesium stearate, mix and sieve, add to the hopper mixer, mix with the granules, and mix at 10 rpm for 5 minutes to obtain bepedic acid mixed granules.

9. The preparation method according to claim 7 or 8, wherein the step (2) comprises: preparing a solution with a cosolvent or preparing a solution with a cosolvent and a binder; weighing atorvastatin calcium, a stabilizer, a filler, and a disintegrant, adding the prepared cosolvent and binder mixed solution into a wet granulation pot to granulate to obtain wet granules, or weighing atorvastatin calcium, a stabilizer, a filler, a disintegrant, and a binder, adding the prepared cosolvent solution into a wet granulation pot to granulate to obtain wet granules; adding the wet granules into a fluidized bed for drying; adding an additional disintegrant and a lubricant and mixing evenly to obtain atorvastatin calcium mixed granules; or Weigh all raw materials and auxiliary materials according to the formula amount, weigh atorvastatin calcium, stabilizer, filler, disintegrant, binder, pre-mix, granulate in a dry granulator, add lubricant after granulation, and mix; Preferably, Weigh all the raw materials and excipients according to the formula, weigh polysorbate, add appropriate amount of water and stir until dissolved; weigh atorvastatin calcium and calcium carbonate, pass through a 40-mesh sieve together; pass microcrystalline cellulose, lactose monohydrate, cross-linked carboxymethyl cellulose sodium and hydroxypropyl cellulose through a 40-mesh sieve for later use, and mix in a wet granulation pot at 200*200rpm for 3min; after stirring at 250rpm and cutting at 2000rpm, add the prepared water of polysorbate 80, and take out after granulation is completed; add the wet granules into a fluidized bed for drying; add cross-linked carboxymethyl cellulose sodium and sodium magnesium stearate and mix evenly to obtain atorvastatin calcium mixed granules; or Weigh each raw material and auxiliary material according to the formula amount, weigh atorvastatin calcium and calcium carbonate, and pass them through a 40-mesh sieve together; pass microcrystalline cellulose, lactose monohydrate, cross-linked carboxymethyl cellulose sodium, and hydroxypropyl cellulose through a 40-mesh sieve for later use, mix in a mixer at 10rpm for 20min, set the hydraulic pressure to 80Bar, the screw motor speed to 40rpm, and the roller motor speed to 3rpm for dry granulation, and dry granulate the material with a 1.7mm sieve, weigh magnesium stearate, add it to the hopper mixer, mix it with the granules, and mix it at 10rpm for 5min to obtain atorvastatin calcium mixed granules.

10. The preparation method according to any one of claims 7 to 9, wherein the step (3) comprises: pressing the bepedic acid mixed granules and the atorvastatin calcium mixed granules into a compound double-layer tablet; coating the compound double-layer tablet to obtain a bepedic acid and atorvastatin calcium compound double-layer tablet; or The bepedic acid mixed granules and the atorvastatin calcium mixed granules are uniformly mixed according to the target weight ratio, and a composite single-layer tablet is pressed; preferably, the weight ratio is 325 / 205; or The bepedic acid mixed granules and the atorvastatin calcium mixed granules are uniformly mixed according to the target weight ratio, and filled into hollow capsules to obtain capsules; preferably, the weight ratio is 325 / 205.

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