MR antagonist medicine, preparation method thereof, MR antagonist tablet and preparation method of MR antagonist tablet

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an MR (magnetic resonance) antagonist medicine and a preparation method thereof as well as an MR antagonist tablet and a preparation method thereof. By controlling the particle size of the fenerenone, tablets of different specifications are all dissolved out in vitro and are well fit with a reference preparation in dissolution, and in-vivo bioequivalence is better facilitated; the suspension is prepared from the raw material medicines and at least one of the adhesive and the surfactant, and a fluidized bed process and a liquid spraying adding mode are adopted, so that the flowability of the materials is improved, the mixing uniformity and the content uniformity can meet the requirements, and the content uniformity can be ensured to meet the requirements. And dissolution fitting and in-vivo bioequivalence of preparations with different specifications and an original reference preparation can be realized under various medium conditions.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a MR antagonist drug and a preparation method thereof, and a MR antagonist tablet and a preparation method thereof. Background Art

[0002] Finerenone, chemically known as (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyl-3-carboxamide, is a nonsteroidal selective mineralocorticoid receptor (MR) antagonist developed by Bayer HLTHCARE for use in adult patients with chronic kidney disease associated with type 2 diabetes (estimated glomerular filtration rate [eGFR] ≥25 to <75 mL / min / 1.73 m 2 , with albuminuria), can reduce the risk of continued decline in eGFR and end-stage renal disease.

[0003] In order to ensure high bioavailability, finerenone needs to be micronized. However, the particle size of the API after micronization is small, and there is a risk of uneven mixing during preparation, which in turn reduces the bioavailability of finerenone. Summary of the Invention

[0004] The object of the present invention is to provide a MR antagonist drug and a preparation method thereof, and a MR antagonist tablet and a preparation method thereof. The MR antagonist drug provided by the present invention is uniformly mixed and has good bioavailability.

[0005] In order to achieve the above object, the present invention provides the following technical solutions:

[0006] The present invention provides an MR antagonist drug, comprising the following components by weight: 2 to 10 parts of finerenone, 30 to 80 parts of a diluent, 2 to 6 parts of a disintegrant, 2 to 6 parts of a binder, 0.2 to 1.2 parts of a surfactant, and 0.5 to 2.0 parts of a glidant; the particle size of the finerenone is D 90 ≤15μm.

[0007] Preferably, the particle size of the finerenone is D 90 ≤14μm, average particle size is less than 10μm.

[0008] Preferably, the diluent includes one or more of starch, microcrystalline cellulose, lactose and dextrin; the disintegrant includes one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinyl alcohol, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch; the binder includes one or more of carbomer, povidone K30, hydroxypropyl methylcellulose, high-substituted hydroxypropyl cellulose and sodium carboxymethyl cellulose; the surfactant includes one or more of Tween 20, sodium lauryl sulfate, polysorbate, sodium lauryl sulfate and poloxamer; the glidant includes one or more of talc, magnesium stearate, silicon dioxide and colloidal silicon dioxide.

[0009] Preferably, the particle size of the MR antagonist drug is D 90 ≤10μm, average particle size is less than 5μm.

[0010] The present invention also provides a method for preparing the MR antagonist drug described in the above scheme, comprising the following steps:

[0011] (1) mixing at least one of a portion of a binder and a portion of a surfactant with water and phenelenone to obtain a suspension;

[0012] (2) spraying the suspension into at least one of the remaining binder and the remaining surfactant, a diluent, a disintegrant, and a portion of the glidant in a fluidized bed for granulation to obtain drug particles;

[0013] (3) The drug particles and the remaining part of the glidant are mixed and tableted to obtain the MR antagonist drug.

[0014] Preferably, the mass ratio of the remaining binder to the partial binder is 0-1:1-0; the mass ratio of the remaining surfactant to the partial surfactant is 0-1:1-0; the mass ratio of the remaining flow aid to the partial flow aid is 0.5-1:0-0.5.

[0015] Preferably, the granulation temperature is 30-40°C.

[0016] The present invention also provides an MR antagonist tablet, comprising a drug core and a coating layer coated on the surface of the drug core; the drug core is the MR antagonist drug described in the above scheme or the MR antagonist drug obtained by the preparation method described in the above scheme.

[0017] Preferably, the coating layer accounts for 2-6% of the mass of the drug tablet core.

[0018] The present invention also provides a method for preparing the MR antagonist tablets described in the above scheme, comprising the following steps:

[0019] The drug tablet core is coated with the coating liquid to obtain the MR antagonist tablet.

[0020] The present invention provides an MR antagonist drug. By controlling the finerenone particle size, the present invention ensures that tablets of different strengths dissolve uniformly in vitro and closely match the dissolution of a reference preparation, further facilitating in vivo bioequivalence. By formulating the API with at least one of a binder and a surfactant into a suspension and employing a fluidized bed process and a liquid spray addition method to increase material fluidity, the present invention ensures that mixing uniformity and content uniformity meet requirements and facilitates the dissolution of tablets of different strengths to match the original reference preparation under various media conditions, achieving in vivo bioequivalence.

[0021] The present invention also provides a method for preparing the MR antagonist drug of the above scheme. The preparation method provided by the present invention has high durability and stability, good dissolution batch uniformity, high in vitro dissolution similarity with the reference preparation, and good bioavailability and bioequivalence.

[0022] The present invention also provides a MR antagonist tablet. The MR antagonist tablet provided by the present invention is suitable for adult patients with chronic kidney disease associated with type 2 diabetes, and can reduce the risk of sustained decline in eGFR and end-stage renal disease.

[0023] The present invention also provides a method for preparing the MR antagonist tablets described in the above scheme. The preparation method provided by the present invention has simple steps, convenient operation, better feasibility, and is suitable for industrial production. DETAILED DESCRIPTION

[0024] The present invention provides an MR antagonist drug, comprising the following components by weight: 2 to 10 parts of finerenone, 30 to 80 parts of a diluent, 2 to 6 parts of a disintegrant, 2 to 6 parts of a binder, 0.2 to 1.2 parts of a surfactant, and 0.5 to 2.0 parts of a glidant; the particle size of the finerenone is D 90 ≤15μm.

[0025] In the present invention, the weight proportion of finerenone is preferably 3 to 9 parts, specifically 5 parts or 7 parts.

[0026] In the present invention, the particle size of finerenone is preferably D 90 ≤14 μm, specifically 14 μm, 12 μm, 10 μm, 8 μm, 5 μm or 3 μm, the average particle size is preferably less than 10 μm, specifically 8 μm, 5 μm, 3 μm or 1 μm.

[0027] In the present invention, the mass fraction of the diluent is preferably 35 to 75 parts, specifically 45 parts, 55 parts or 65 parts.

[0028] In the present invention, the diluent preferably includes one or more of starch, microcrystalline cellulose, lactose and dextrin; the starch preferably includes one or two of pregelatinized starch and corn starch.

[0029] In the present invention, the mass fraction of the disintegrant is preferably 3 to 5 parts, specifically 3.5 parts or 4.5 parts.

[0030] In the present invention, the disintegrant preferably includes one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch.

[0031] In the present invention, the weight percentage of the adhesive is preferably 3 to 5 parts, specifically 3.5 parts or 4.5 parts.

[0032] In the present invention, the binder preferably includes one or more of carbomer, povidone K30, hydroxypropyl methylcellulose, highly substituted hydroxypropyl cellulose and sodium carboxymethyl cellulose.

[0033] In the present invention, the mass fraction of the surfactant is preferably 0.3 to 1.1 parts, specifically 0.5 part or 0.9 part.

[0034] In the present invention, the surfactant preferably includes one or more of Tween 20, sodium lauryl sulfate, polysorbate, sodium lauryl sulfate and poloxamer.

[0035] In the present invention, the mass fraction of the glidant is preferably 0.7 to 1.8 parts, specifically 1 part or 1.5 parts.

[0036] In the present invention, the glidant preferably includes one or more of talc, magnesium stearate, silicon dioxide and colloidal silicon dioxide.

[0037] In the present invention, the particle size of the MR antagonist drug is preferably D 90 ≤10μm, specifically D 90 =10 μm, 8 μm, 5 μm, 3 μm or 1 μm, the average particle size is preferably less than 5 μm, specifically 4 μm, 3 μm, 2 μm or 1 μm.

[0038] The present invention also provides a method for preparing the MR antagonist drug described in the above scheme, comprising the following steps:

[0039] (1) mixing at least one of a portion of a binder and a portion of a surfactant with water and phenelenone to obtain a suspension;

[0040] (2) spraying the suspension into at least one of the remaining binder and the remaining surfactant, a diluent, a disintegrant, and a portion of the glidant in a fluidized bed for granulation to obtain drug particles;

[0041] (3) The drug particles and the remaining part of the glidant are mixed and tableted to obtain the MR antagonist drug.

[0042] In the present invention, at least one of a portion of a binder and a portion of a surfactant is mixed with water and phenerenone (referred to as the first mixing) to produce a suspension. In the present invention, the phenerenone is preferably micronized before use; the micronization equipment is preferably a jet mill. The micronization process ensures that the average particle size of the phenerenone is less than 10 μm, and the particle size control is more stable, further ensuring quality stability.

[0043] In the present invention, the mass fraction of finerenone in the suspension is preferably 10-30%, specifically 20%.

[0044] In the present invention, the first mixing is preferably stirring mixing; the rotation speed of the stirring mixing is preferably 50 to 500 rpm, specifically 200 rpm, and the mixing time is preferably 30 to 120 min, specifically 60 min.

[0045] In the present invention, the first mixing is preferably: premixing the binder, the surfactant and 60-90° C. water to obtain a premixed liquid, then diluting the premixed liquid with room temperature water to obtain a diluted liquid, and then mixing the diluted liquid with fenerenone.

[0046] After obtaining the suspension, the present invention sprays the suspension into at least one of the remaining binder and the remaining surfactant, a diluent, a disintegrant, and a portion of the glidant in a fluidized bed for granulation to obtain pharmaceutical granules. In the present invention, the mass ratio of the remaining binder to the portion of the binder is preferably 0-1:1-0, specifically 0:1, 0.1:0.9, 0.3:0.7, 0.5:0.5, 0.7:0.3, 0.9:0.1, or 1:0.

[0047] In the present invention, the mass ratio of the remaining surfactant to the partial surfactant is preferably 0-1:1-0, specifically 0:1, 0.1:0.9, 0.3:0.7, 0.5:0.5, 0.7:0.3, 0.9:0.1 or 1:0.

[0048] In the present invention, the granulation temperature is preferably 30-40° C., specifically 33° C., 36° C. or 38° C. The present invention ensures that the drug dissolution is similar to that of the reference preparation by controlling the granulation temperature.

[0049] In the present invention, the granulation preferably further comprises drying the obtained granules and then performing granulation; the granulation equipment preferably comprises a screen matched with a rapid finishing machine; the aperture of the screen is preferably 1.0 to 1.5 mm.

[0050] After obtaining the drug granules, the present invention mixes the drug granules with the remaining portion of the glidant (referred to as the second mixing) and then tablets to obtain the MR antagonist drug. In the present invention, the mass ratio of the remaining portion of the glidant to the portion of the glidant is preferably 0.5-1:0-0.5, specifically 0.5:0.5, 0.6:0.4, 0.7:0.3, 0.8:0.2, 0.9:0.1 or 1:0.

[0051] In the present invention, the second mixing is preferably stirring mixing; the stirring mixing speed is preferably 5 to 30 rpm, specifically 10 rpm, and the mixing time is preferably not less than 5 min, specifically 5 min, 8 min, 10 min, 20 min, 30 min or 60 min; the second mixing equipment is preferably a mixer.

[0052] In the present invention, the tableting standard is preferably that the tablet hardness reaches 5 to 10 kg, specifically 7 kg or 8 kg. The present invention obtains a disc-shaped product by tableting.

[0053] The present invention also provides an MR antagonist tablet, comprising a drug core and a coating layer coated on the surface of the drug core; the drug core is the MR antagonist drug described in the above scheme or the MR antagonist drug obtained by the preparation method described in the above scheme.

[0054] In the present invention, the coating layer is preferably a water-soluble coating material; the water-soluble coating material preferably includes one or more of hypromellose, titanium dioxide, talc, red iron oxide and yellow iron oxide.

[0055] In the present invention, the coating layer preferably accounts for 2-6% by mass of the drug tablet core, specifically 3% or 5%.

[0056] The present invention also provides a method for preparing the MR antagonist tablets described in the above scheme, comprising the following steps:

[0057] The drug tablet core is coated with the coating liquid to obtain the MR antagonist tablet.

[0058] In the present invention, the coating solution preferably comprises the following components in parts by mass: 5 to 10 parts of a water-soluble coating material and 50 to 100 parts of a coating solvent.

[0059] In the present invention, the coating solvent is preferably water, ethanol or a mixture of water and ethanol.

[0060] In the present invention, the coating solution is preferably sieved before use.

[0061] In the present invention, the coating temperature is preferably 40-50°C, specifically 45°C.

[0062] In order to further illustrate the present invention, the scheme of the present invention is described in detail below with reference to the embodiments, but they should not be understood as limiting the scope of protection of the present invention.

[0063] Unless otherwise specified, the materials and reagents used in the examples of the present invention are commercially available. Unless otherwise specified, the quantitative analysis experiments in the examples of the present invention were repeated three times, and the results were averaged.

[0064] Examples 1 to 3

[0065] The formulations of the drug tablet cores of Examples 1 to 3 are shown in Table 1. The particle sizes of finerenone are different, and the effect of finerenone particle size on mixing uniformity and drug dissolution was investigated.

[0066] Table 1 Prescription of drug cores of Examples 1 to 3

[0067]

[0068] 1000 MR antagonist tablets were prepared according to the prescription in Table 1. The specific steps are as follows:

[0069] (1) Pretreatment of API: Finerenone API was micronized using a jet mill to a corresponding particle size.

[0070] (2) Preparation of suspension: Dissolve hydroxypropyl cellulose and Tween 20 in 100 mL of 75°C water, then add 15 mL of room temperature water to dissolve and cool. After dissolution, add fenarezone and stir until the raw materials are evenly dispersed to obtain a stable suspension.

[0071] (3) Fluidized bed granulation: Add microcrystalline cellulose, dextrin, croscarmellose sodium, and talc into a fluidized bed, control the material temperature at 35°C for granulation and drying, and use a fast finishing machine equipped with a 1.0 mm screen to granulate after drying to obtain drug granules.

[0072] (4) Mixing: Place the drug granules and magnesium stearate in a square cone mixer and mix for 10 min until uniform.

[0073] (5) Tableting and coating: The granules obtained in step (4) were added to a high-speed tablet press for tableting, and the tablet hardness was controlled to 6 kg; a coating solution with a solid content of 10% (aqueous solution of hydroxypropyl methylcellulose) was prepared, and the tablets were sieved through an 80-mesh sieve and then coated, and the mass of the coating layer was controlled to be 4% of the mass of the drug core tablets to obtain MR antagonist tablets.

[0074] Test Example 1: Mixing uniformity, fluidity and dissolution curve testing

[0075] Mixing uniformity detection: The mixing uniformity samples taken from the mixing process of Examples 1 to 3 were detected by HPLC. The qualified standard for mixing uniformity was RSD≤5.0%.

[0076] Fluidity test: Use a powder tester to test the angle of repose of the filler.

[0077] Dissolution curve test: According to the second method of Part IV of the Chinese Pharmacopoeia 2015 edition, 900 mL of pH 4.5 phosphate buffer was used as the dissolution medium, the rotation speed was 50 rpm, and 10 mL of the solution was taken at 5, 10, 15, 30, 45, 60, and 90 minutes. At the same time, the same volume of dissolution medium at the same temperature was added, and the solution was filtered through a microporous membrane. The filtrate was used as the test solution. The test results of each batch are shown in Tables 2 and 3.

[0078] Table 2 Mixing uniformity and fluidity test results of Examples 1 to 3

[0079]

[0080]

[0081] Table 3 Dissolution curve test results of Examples 1 to 3

[0082]

[0083] According to Tables 2 and 3, when finerenone is micronized to an average particle size of less than 10 μm, the material fluidity and mixing uniformity are good, and the dissolution curve is similar to that of the reference preparation. Therefore, when the average particle size of finerenone is less than 10 μm, the dissolution requirements can be met and the dissolution is stable.

[0084] Example 4

[0085] The formulation of the drug core tablets in this example is the same as that in Example 2 (as shown in Table 4), with the only difference being that the binder is added in a different manner, and the effects of different binder addition methods on mixing uniformity and dissolution effect are investigated.

[0086] Table 4 Prescription of Example 4 Drug Tablet Core

[0087]

[0088] According to the prescription in Table 4, 1000 MR antagonist tablets were prepared. The specific steps are as follows:

[0089] (1) Pretreatment of API: Finerenone API was micronized using a jet mill to a corresponding particle size.

[0090] (2) Preparation of suspension: Dissolve and disperse Tween 20 in 100 mL of 75°C water, then add 15 mL of room temperature water to dissolve and cool. After dissolution, add fenarezone and stir until the raw material is evenly dispersed to obtain a stable suspension.

[0091] (3) Fluidized bed granulation: Microcrystalline cellulose, dextrin, croscarmellose sodium, hypromellose, and talc are added to a fluidized bed, and the material temperature is controlled at 35°C for granulation and drying. After drying, the granules are sized using a fast finishing machine equipped with a 1.0 mm sieve to obtain drug granules.

[0092] (4) Mixing: Place the drug granules and magnesium stearate in a square cone mixer and mix for 10 min until uniform.

[0093] (5) Tableting and Coating: The granules obtained in step (4) were added to a high-speed tablet press for tableting, and the tablet hardness was controlled to 5-7 kg. A coating solution (aqueous solution of talc) with a solid content of 10% was prepared, and the tablets were sieved through an 80-mesh sieve and then coated. The coating layer weight was controlled to be 4% of the drug core weight to obtain MR antagonist tablets.

[0094] Test Example 2: Mixing uniformity, fluidity, and dissolution curve testing

[0095] Mixing uniformity detection: The mixing uniformity samples taken in the mixing process of Examples 2 and 4 were detected by HPLC. The qualified standard of mixing uniformity was RSD≤5.0%.

[0096] Fluidity test: Use a powder tester to test the angle of repose of the filler.

[0097] Dissolution curve testing: According to the second method of Part 0931 of the General Rules of the 2015 Chinese Pharmacopoeia, using 900 mL of pH 4.5 phosphate buffer as the dissolution medium at a rotation speed of 50 rpm, 10 mL of the solution was collected at 5, 10, 15, 30, 45, 60, and 90 minutes. The solution was then supplemented with the same volume of dissolution medium at the same temperature. The solution was filtered through a microporous membrane, and the filtrate was used as the test solution. The test results for each batch are shown in Tables 5 and 6.

[0098] Table 5 Mixing uniformity and fluidity test results of Examples 2 and 4

[0099] Group Mixing uniformity RSD (%) Fluidity test (angle of repose) Example 2 0.45 35 Example 4 3.2 39

[0100] Table 6 Dissolution curve test results of Examples 2 and 4

[0101]

[0102] As can be seen from Tables 5 and 6, the binder and the API were co-formulated into a suspension and added in the form of a spray for fluidized bed granulation. The mixing uniformity was good and the dissolution was significantly similar to that of the reference preparation after the addition of the binder powder, which was beneficial for bioequivalence.

[0103] Examples 5-6

[0104] The formulations of the drug tablet cores of Examples 5 to 6 are the same as those of Example 2 (as shown in Table 7), except that the fluidized bed granulation temperatures are different. The effects of different fluidized bed granulation temperatures on the dissolution curves of the drug tablets were investigated.

[0105] Table 7 Prescription of Examples 2 and 5-6 Drug Tablet Cores

[0106]

[0107] 1000 MR antagonist tablets were prepared according to the prescription in Table 7. The specific steps are as follows:

[0108] (1) Pretreatment of API: Finerenone API was micronized using a jet mill to a corresponding particle size.

[0109] (2) Preparation of suspension: Dissolve and disperse HPMC and Tween 20 in 100 mL of water at 60-90 °C, then add 15 mL of water at room temperature to dissolve and cool. After dissolution, add fenarezone and stir until the raw materials are evenly dispersed to obtain a stable suspension.

[0110] (3) Fluidized bed granulation: Microcrystalline cellulose, dextrin, and croscarmellose sodium were mixed using a square cone mixer at 10 rpm for 5 min. After uniform mixing, the materials were added to a fluidized bed. The material temperature was controlled at 30-35°C (Example 5) and 35-40°C (Example 6) for granulation and drying. After drying, the granules were sized using a fast finishing machine equipped with a 1.0 mm sieve to obtain drug granules.

[0111] (4) Mixing: The drug granules and magnesium stearate were placed in a square cone mixer and mixed for 10 minutes until uniform.

[0112] (5) Tableting and Coating: The granules obtained in step (4) were added to a high-speed tablet press for tableting, and the tablet hardness was controlled to 6 kg. A coating solution (aqueous solution of red iron oxide) with a solid content of 10% was prepared, and the tablets were passed through an 80-mesh sieve and coated. The coating layer weight was controlled to be 4% of the weight of the drug core tablets to obtain MR antagonist tablets.

[0113] Test Example 3: Mixing uniformity, fluidity and dissolution curve testing

[0114] Mixing uniformity detection: The mixing uniformity samples taken in the mixing process of Examples 5 and 6 were detected by HPLC. The qualified standard of mixing uniformity was RSD≤5.0%.

[0115] Fluidity test: Use a powder tester to test the angle of repose of the filler.

[0116] Dissolution curve testing: According to the second method of Part 0931 of the General Rules of the 2015 Chinese Pharmacopoeia, using 900 mL of pH 4.5 phosphate buffer as the dissolution medium at a rotation speed of 50 rpm, 10 mL of the solution was collected at 5, 10, 15, 30, 45, 60, and 90 minutes. The solution was then supplemented with the same volume of dissolution medium at the same temperature. The solution was filtered through a microporous membrane, and the filtrate was used as the test solution. The test results for each batch are shown in Tables 8 and 9.

[0117] Table 8 Mixing uniformity and fluidity test results of Examples 2 and 5-6

[0118] Group Mixing uniformity RSD (%) Fluidity test (angle of repose) Example 2 0.45 35 Example 5 0.56 36 Example 6 0.54 35

[0119] Table 9 Dissolution curve test results of Examples 2 and 5-6

[0120]

[0121] According to Tables 8 and 9, it can be seen that when the fluidized bed granulation material temperature is controlled at 30-40 °C, the material mixing uniformity and fluidity are good, and the prepared drug tablets and the reference preparation dissolution fitting meet the requirements. Increasing the fluidized bed granulation temperature will reduce the fluidity of the mixture, the mixing uniformity will deteriorate, the dissolution will slow down, and the dissolution similarity with the reference preparation will decrease.

[0122] Examples 7 to 9

[0123] The formulations of the drug core tablets of Examples 7 to 9 are the same as those of Example 2 (as shown in Table 10), except that the coating weight gains are different, and the effects of different coating weight gains on the dissolution curves of the drug tablets are investigated.

[0124] Table 10 Prescription of Examples 2 and 7-9 drug tablet cores

[0125]

[0126]

[0127] Prepare 1000 MR antagonist tablets according to the prescription in Table 10. The specific steps are as follows:

[0128] (1) Pretreatment of API: Finerenone API was micronized using a jet mill to a corresponding particle size.

[0129] (2) Preparation of suspension: Dissolve and disperse HPMC and Tween 20 in 100 mL of 75°C water, then add 15 mL of room temperature water to dissolve and cool. After dissolution, add fenalenone and stir until the raw materials are evenly dispersed to obtain a stable suspension.

[0130] (3) Fluidized bed granulation: Microcrystalline cellulose, dextrin, and croscarmellose sodium were mixed using a square cone mixer at 10 rpm for 5 min. After uniform mixing, the materials were added to a fluidized bed and the material temperature was controlled at 30-40°C for granulation and drying. After drying, the granules were sized using a fast finishing machine equipped with a 1.0 mm sieve to obtain drug granules.

[0131] (4) Mixing: The drug granules and magnesium stearate were placed in a square cone mixer and mixed for 10 minutes until uniform.

[0132] (5) Tableting and Coating: The granules obtained in step (4) were added to a high-speed tablet press for tableting, and the tablet hardness was controlled to be 5-7 kg. A coating solution (aqueous solution of yellow iron oxide) with a solid content of 10% was prepared, and the tablets were sieved through an 80-mesh sieve and then coated. The coating layer weight was controlled to be 2% (Example 7), 4% (Example 8), and 6% (Example 9) of the drug core weight to obtain MR antagonist tablets.

[0133] Test Example 4: Dissolution Curve Detection

[0134] Dissolution curve testing: According to the second method of Part 0931 of the fourth chapter of the Chinese Pharmacopoeia (2015 edition), 900 mL of pH 4.5 phosphate buffer was used as the dissolution medium at a rotation speed of 50 rpm. 10 mL of the solution was collected at 5, 10, 15, 30, 45, 60, and 90 minutes, and the same volume of dissolution medium was added at the same temperature. The solution was filtered through a microporous membrane, and the filtrate was used as the test solution. The dissolution results for each batch are shown in Table 11.

[0135] Table 11 Dissolution curve test results of Examples 2 and 7 to 9

[0136]

[0137]

[0138] According to Table 11, it can be seen that when the coating weight gain is controlled at 3-5%, the dissolution fitting of the prepared drug tablets and the reference preparation meets the requirements. Increasing or decreasing the coating weight gain will reduce the dissolution similarity between the drug tablets and the reference.

[0139] It can be seen from the above examples that the MR antagonist tablet API provided by the present invention can be uniformly dispersed and has good mixing uniformity. The in vitro dissolution of different specifications of the drug tablets is well matched with the reference preparation, meeting clinical needs.

[0140] Although the above embodiment provides a detailed description of the present invention, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the scope of protection of the present invention.

Claims

1. A MR antagonist drug, characterized in that: The invention comprises the following components in parts by weight: 2 to 10 parts of finerenone, 30 to 80 parts of diluent, 2 to 6 parts of disintegrant, 2 to 6 parts of binder, 0.2 to 1.2 parts of surfactant, and 0.5 to 2.0 parts of glidant; the particle size of the finerenone is D 90 ≤15μm.

2. The MR antagonist drug according to claim 1, characterized in that The average particle size of finerenone is less than 10 μm.

3. The MR antagonist drug according to claim 1, characterized in that The diluent includes one or more of starch, microcrystalline cellulose, lactose and dextrin; the disintegrant includes one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch; the binder includes one or more of carbomer, povidone K30, hydroxypropyl methylcellulose, high-substituted hydroxypropyl cellulose and sodium carboxymethyl cellulose; the surfactant includes one or more of Tween 20, sodium lauryl sulfate, polysorbate, sodium lauryl sulfate and poloxamer; and the glidant includes one or more of talc, magnesium stearate, silicon dioxide and colloidal silicon dioxide.

4. The MR antagonist drug according to any one of claims 1 to 3, characterized in that Particle size D 90 ≤10μm, average particle size is less than 5μm.

5. The method for preparing the MR antagonist drug according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) mixing at least one of a portion of a binder and a portion of a surfactant with water and phenelenone to obtain a suspension; (2) spraying the suspension into at least one of the remaining binder and the remaining surfactant, a diluent, a disintegrant, and a portion of the glidant in a fluidized bed for granulation to obtain drug particles; (3) The drug particles and the remaining part of the glidant are mixed and tableted to obtain the MR antagonist drug.

6. The preparation method according to claim 5, characterized in that The mass ratio of the remaining binder to the partial binder is 0-1:1-0; the mass ratio of the remaining surfactant to the partial surfactant is 0-1:1-0; the mass ratio of the remaining flow aid to the partial flow aid is 0.5-1:0-0.

5.

7. The preparation method according to claim 5 or 6, characterized in that: The granulation temperature is 30-40°C.

8. A MR antagonist tablet, characterized in that: The invention comprises a drug core and a coating layer coated on the surface of the drug core; the drug core is the MR antagonist drug according to any one of claims 1 to 4 or the MR antagonist drug obtained by the preparation method according to any one of claims 5 to 7.

9. The MR antagonist tablet according to claim 8, characterized in that The coating layer accounts for 2-6% of the mass of the drug tablet core.

10. The method for preparing the MR antagonist tablet according to any one of claims 8 to 9, characterized in that: The following steps are involved: The drug tablet core is coated with the coating liquid to obtain the MR antagonist tablet.

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