Pharmaceutical composition of fenerenone as well as preparation method and application of pharmaceutical composition

Abstract

The invention provides a pharmaceutical composition of fenerenone as well as a preparation method and application of the pharmaceutical composition. The pharmaceutical composition disclosed by the invention has better dissolution rate in various media, and a preparation prepared from the pharmaceutical composition has better uniformity, tolerance and particle size, and the in-vitro release effect of the pharmaceutical composition is consistent with that of a reference preparation.

Description

Technical Field

[0001] The invention relates to a finerenone pharmaceutical composition and a preparation method and application thereof, belonging to the field of pharmaceutical preparations. Background Art

[0002] Diabetes is the main risk factor for chronic kidney disease (CKD), and about 50% of patients with type 2 diabetes mellitus (T2DM) will develop CKD. Domestic and international consensus and guidelines have proposed that attention should be paid to the screening of CKD in diabetic patients, so as to achieve early diagnosis and early treatment to delay the progression of CKD and reduce the occurrence of related cardiovascular events.

[0003] Mineralocorticoid receptors (MR) are expressed in the kidneys, heart, and blood vessels. Overactivation of MR in diabetic CKD patients mediates the occurrence and development of inflammation and fibrosis in renal and cardiac tissues, further leading to the occurrence of a variety of adverse renal and cardiac clinical outcomes. Blocking MR overactivation is crucial for preventing and treating adverse renal and cardiovascular outcomes. Previous studies have shown that Asian T2DM patients are more likely to have proteinuria and higher levels of urinary protein, which may be related to the salt-sensitive gene background and high-salt diet habits of the Asian population. One of the main mechanisms for salt sensitivity and high salt intake to cause kidney damage is MR overactivation.

[0004] The traditional steroid mineralocorticoid receptor antagonist (MRA) spironolactone has not been explored in depth in the field of CKD due to the risk of sex steroid receptor cross-reactivity and hyperkalemia. The new nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone ((4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide) has been proven to have a clear renal and cardiovascular protective effect on patients with diabetes and CKD. Long-term use can significantly reduce the urine albumin-to-creatinine ratio (UACR) level of patients, and has little effect on blood potassium. In June 2022, China's National Medical Products Administration approved finerenone for use in adult patients with CKD associated with T2DM to reduce the risk of sustained decline in eGFR and end-stage renal disease. In May 2023, the National Medical Products Administration updated the indications for finerenone to be used in adult patients with CKD associated with T2DM (with albuminuria) to reduce the risk of sustained decline in eGFR, end-stage renal disease, cardiovascular death, and hospitalization for heart failure.

[0005]

[0006] The inventors have found that the existing finerenone preparations have slow dissolution and are difficult to meet higher drug release requirements. Therefore, it is necessary to develop finerenone preparations with faster release speed and better dissolution. Summary of the invention

[0007] To improve the above technical problems, the present invention provides a pharmaceutical composition, wherein the active ingredient of the pharmaceutical composition comprises finerenone or a pharmaceutically acceptable salt thereof, and the unimodal particle size distribution D90 of the finerenone or a pharmaceutically acceptable salt thereof is less than 22 μm.

[0008] According to an embodiment of the present invention, the unimodal particle size distribution D10 of finerenone or a pharmaceutically acceptable salt thereof is 1.54-2.07 μm; preferably, D10 is 1.54-1.73 μm.

[0009] According to an embodiment of the present invention, the unimodal particle size distribution D50 of finerenone or a pharmaceutically acceptable salt thereof is 2.93-6.27 μm; preferably, D50 is 2.93-4.62 μm.

[0010] According to an embodiment of the present invention, the unimodal particle size distribution D90 of finerenone or a pharmaceutically acceptable salt thereof is 4-22 μm; preferably, D90 is 4.95-16.2 μm; preferably, D90 is 4.95-5.4 μm.

[0011] According to an embodiment of the present invention, the finerenone or a pharmaceutically acceptable salt thereof has a particle size distribution selected from the following:

[0012] D10 is selected from the following particle sizes (μm) 2.07 1.72 1.67 1.73 2.04 1.71 1.54

[0013] and / or

[0014]

[0015] and / or

[0016] D90 is selected from the following particle sizes (μm) 7.63 5.40 4.95 4.96 22.0 16.2 6.37

[0017] According to an embodiment of the present invention, the finerenone or a pharmaceutically acceptable salt thereof is selected from finerenone crystalline form I.

[0018] According to an embodiment of the present invention, the X-ray powder diffraction pattern of finerenone or a pharmaceutically acceptable salt thereof has characteristic peaks at the following 2θ angles: 8.519±0.20°, 15.358±0.20°, 19.001±0.20°, 19.737±0.20°, 22.923±0.20°.

[0019] According to an embodiment of the present invention, the X-ray powder diffraction pattern of finerenone or a pharmaceutically acceptable salt thereof has characteristic peaks at the following 2θ angles: 8.519±0.20°, 14.020±0.20°, 15.358±0.20°, 19.001±0.20°, 19.737±0.20°, 22.923±0.20°, 23.877±0.20°, and 25.531±0.20°.

[0020] According to an embodiment of the present invention, the X-ray powder diffraction pattern of finerenone or a pharmaceutically acceptable salt thereof has characteristic peaks at the following 2θ angles: 8.519±0.20°, 11.365±0.20°, 14.020±0.20°, 15.358±0.20°, 17.161±0.20°, 19.001±0.20°, 19.737±0.20°, 22.923±0.20°, 23.877±0.20°, 25.531±0.20°, and 26.467±0.20°.

[0021] According to an embodiment of the present invention, the finerenone crystalline form I has substantially Figure 1 XRPD spectrum shown.

[0022] According to an embodiment of the present invention, the finerenone crystalline form I has substantially Figure 2 DSC spectrum shown.

[0023] According to an embodiment of the present invention, the finerenone crystalline form I has substantially Figure 3 TGA spectrum shown.

[0024] According to an embodiment of the present invention, the finerenone crystalline form I has substantially Figure 4 Micrographs shown.

[0025] According to an embodiment of the present invention, the pharmaceutical composition further comprises at least one selected from the group consisting of a diluent, a disintegrant, a binder, a wetting agent and a lubricant.

[0026] According to an embodiment of the present invention, the diluent is selected from at least one of starch, sucrose, hydroxypropyl cellulose, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium carbonate, sodium carbonate, lactose, lactose monohydrate, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, mannitol and tricalcium phosphate.

[0027] According to an embodiment of the present invention, the disintegrant is selected from at least one of corn starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, polyvinylpyrrolidone, pregelatinized starch and alginic acid.

[0028] According to an embodiment of the present invention, the binder is selected from at least one of hydroxypropyl cellulose, hypromellose, povidone and ethyl cellulose.

[0029] According to an embodiment of the present invention, the wetting agent is selected from sodium dodecyl sulfate.

[0030] According to an embodiment of the present invention, the lubricant is selected from at least one of magnesium stearate, stearic acid, silicon dioxide, fat, calcium stearate, polyethylene glycol, sodium stearyl fumarate, talc and fatty acid.

[0031] According to an embodiment of the present invention, the pharmaceutical composition further comprises a coating, such as a gastric soluble film coating premix.

[0032] According to an embodiment of the present invention, the weight of finerenone or a pharmaceutically acceptable salt thereof (such as finerenone crystalline form I) in the pharmaceutical composition accounts for 6% to 16% of the total weight of the pharmaceutical composition, for example, 7%, 7.58%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15.15%.

[0033] According to an embodiment of the present invention, the weight of the diluent in the pharmaceutical composition accounts for 50-90% of the total weight of the pharmaceutical composition, for example, 55%, 60%, 65%, 70%, 75%, 80%, 85%.

[0034] According to an embodiment of the present invention, the weight of the disintegrant in the pharmaceutical composition accounts for 0.5% to 5.0% of the total weight of the pharmaceutical composition, for example 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%.

[0035] According to an embodiment of the present invention, the weight of the binder in the pharmaceutical composition accounts for 2% to 5% of the total weight of the pharmaceutical composition, for example, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%.

[0036] According to an embodiment of the present invention, the weight of the wetting agent in the pharmaceutical composition accounts for 0.1% to 2.0% of the total weight of the pharmaceutical composition, for example 0.3%, 0.5%, 0.8%, 1.0%, 1.2%, 1.5%, 1.8%.

[0037] According to an embodiment of the present invention, the weight of the lubricant in the pharmaceutical composition accounts for 0.25% to 5% of the total weight of the pharmaceutical composition, for example 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%.

[0038] According to an embodiment of the present invention, the weight of the coating in the pharmaceutical composition accounts for 1%-5% of the total weight of the pharmaceutical composition, for example 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%.

[0039] According to an embodiment of the present invention, the pharmaceutical composition consists of finerenone crystalline form I, microcrystalline cellulose, lactose monohydrate, cross-linked carboxymethyl cellulose sodium, hypromellose, sodium lauryl sulfate, and magnesium stearate.

[0040] According to an embodiment of the present invention, the weight of finerenone crystalline form I in the pharmaceutical composition accounts for 6% to 16% of the total weight of the pharmaceutical composition, for example 7%, 7.58%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15.15%.

[0041] According to an embodiment of the present invention, the weight of microcrystalline cellulose in the pharmaceutical composition accounts for 30% to 60% of the total weight of the pharmaceutical composition, for example, 35%, 40%, 45%, 46.25%, 50%, 50.03%, 55%.

[0042] According to an embodiment of the present invention, the weight of lactose monohydrate in the pharmaceutical composition accounts for 20% to 50% of the total weight of the pharmaceutical composition, for example, 25%, 30%, 30.30%, 34.09%, 35%, 40%, 45%.

[0043] According to an embodiment of the present invention, the weight of cross-linked sodium carboxymethyl cellulose in the pharmaceutical composition accounts for 0.5% to 5.0% of the total weight of the pharmaceutical composition, for example 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%.

[0044] According to an embodiment of the present invention, the weight of the hypromellose in the pharmaceutical composition accounts for 2% to 5% of the total weight of the pharmaceutical composition, for example, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%.

[0045] According to an embodiment of the present invention, the weight of sodium lauryl sulfate in the pharmaceutical composition accounts for 0.1% to 2.0% of the total weight of the pharmaceutical composition, for example 0.3%, 0.5%, 0.8%, 1.0%, 1.2%, 1.5%, 1.8%.

[0046] According to an embodiment of the present invention, the weight of magnesium stearate in the pharmaceutical composition accounts for 0.25% to 5% of the total weight of the pharmaceutical composition, for example 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%.

[0047] According to an embodiment of the present invention, the pharmaceutical composition also includes a gastric soluble film coating premix as a coating; the weight of the coating accounts for 1%-5% of the total weight of the pharmaceutical composition, for example 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%.

[0048] The present invention also provides a method for preparing the pharmaceutical composition, comprising the following steps: granulating a diluent, a binder and a wetting agent together to obtain granules a, adding finerenone crystal form I to the granules a material and sieving, adding a disintegrant, mixing, then adding a lubricant, mixing, and tableting to obtain the pharmaceutical composition.

[0049] According to an embodiment of the present invention, the preparation method further comprises the step of pulverizing the finerenone crystal form I, and the pulverizing method can be selected from air flow pulverization or mechanical pulverization.

[0050] According to an embodiment of the present invention, the mesh size of the sieving is selected from 20-100 mesh, such as 30 mesh, 40 mesh, 50 mesh, 60 mesh, 70 mesh, and 80 mesh.

[0051] According to an embodiment of the present invention, the preparation method comprises: granulating lactose monohydrate, microcrystalline cellulose, hypromellose and sodium lauryl sulfate together to obtain granules a, adding finerenone crystalline form I to the granules a material and sieving it, then adding cross-linked sodium carboxymethyl cellulose, mixing, then adding magnesium stearate, mixing, and tableting to obtain the pharmaceutical composition.

[0052] The present invention also provides a method for preparing finerenone crystal form I, wherein the preparation method comprises crystallizing finerenone in a mixture of methanol and water to obtain the finerenone crystal form I.

[0053] According to an embodiment of the present invention, the preparation method comprises the following steps:

[0054] (1) mixing finerenone with methanol to obtain a mixture of finerenone and methanol;

[0055] (2) adding water to the mixture of finerenone and methanol obtained in step (1) to obtain a mixture of finerenone, methanol and water;

[0056] (3) crystallizing a mixture of the finerenone obtained in step (2) and methanol and water to obtain the finerenone crystalline form I.

[0057] According to an embodiment of the present invention, in step (1), finerenone is mixed and dissolved with methanol to obtain a methanol solution of finerenone.

[0058] According to an embodiment of the present invention, step (1) can be carried out under heating conditions. Preferably, the temperature at which finerenone and methanol are mixed can be selected from 30°C to 80°C, such as 50°C to 70°C, such as 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C.

[0059] According to an embodiment of the present invention, in step (1), the finerenone may be in other forms other than crystalline form I, such as amorphous finerenone.

[0060] According to an embodiment of the present invention, in step (2), water is added to the methanol solution of finerenone obtained in step (1) to obtain a mixture of finerenone, methanol and water.

[0061] According to an embodiment of the present invention, the ratio of the weight of finerenone to the volume of methanol can be selected from 1g:(3-20)mL, for example 1g:(5-15)mL, such as 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL, 1g:10mL, 1g:11mL, 1g:12mL.

[0062] According to an embodiment of the present invention, the volume ratio of methanol to water can be selected from 1:(0.2-2), for example 1:(0.5-1.2), such as 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5.

[0063] According to an embodiment of the present invention, the water may be added dropwise.

[0064] According to an embodiment of the present invention, the water is purified water.

[0065] According to an embodiment of the present invention, the temperature of step (2) can be selected from 5°C-80°C, for example 10°C-70°C, such as 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C.

[0066] According to an embodiment of the present invention, step (2) further comprises adding activated carbon before or after adding water.

[0067] According to an embodiment of the present invention, the weight ratio of activated carbon to finerenone is selected from 1:(10-200), for example 1:(20-100), such as 1:40, 1:50, 1:60, 1:70, 1:80.

[0068] According to an embodiment of the present invention, the reaction can be kept warm after the water is added, and the warming time is selected from 0.5-5h, such as 1h, 2h, 3h, 4h.

[0069] According to an embodiment of the present invention, in step (3), the crystallization temperature can be selected from -15°C-50°C, for example, -10°C-20°C, such as -5°C, 0°C, 5°C, 10°C, 15°C, 20°C.

[0070] According to an embodiment of the present invention, the crystallization time is selected from 0.5-5h, such as 1h, 2h, 3h, 4h.

[0071] The present invention also provides a method for preparing the finerenone crystal form I, wherein the preparation method comprises mixing finerenone with an organic solvent, cooling and crystallizing to obtain the finerenone crystal form I.

[0072] According to an embodiment of the present invention, the preparation method comprises mixing and dissolving finerenone with an organic solvent, cooling and crystallizing to obtain the finerenone crystal form I.

[0073] According to an embodiment of the present invention, the organic solvent comprises at least one of methanol and isopropanol.

[0074] According to an embodiment of the present invention, the organic solvent is selected from methanol, isopropanol or a mixture thereof.

[0075] According to an embodiment of the present invention, the ratio of the weight of finerenone to the volume of the organic solvent can be selected from 1g:(3-50)mL, for example 1g:(5-35)mL, such as 1g:10mL, 1g:15mL, 1g:20mL, 1g:25mL, 1g:30mL, 1g:35mL.

[0076] According to an embodiment of the present invention, the preparation method can be carried out under heating conditions. Preferably, the temperature at which finerenone is mixed with the organic solvent can be selected from 30°C-90°C, such as 50°C-85°C, such as 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C.

[0077] According to an embodiment of the present invention, the temperature during crystallization can be selected from -15°C-50°C, for example -10°C-20°C, such as -5°C, 0°C, 5°C, 10°C, 15°C, 20°C.

[0078] According to an embodiment of the present invention, the crystallization time is selected from 0.5-5h, such as 1h, 2h, 3h, 4h.

[0079] The present invention also provides the use of the pharmaceutical composition as an antagonist of mineralocorticoid receptor.

[0080] The present invention also provides the use of the pharmaceutical composition for preparing medicines.

[0081] According to an embodiment of the present invention, the medicament is for preventing and / or treating a disease or disorder.

[0082] The present invention also provides a method for preventing and / or treating a disease or condition, comprising administering a therapeutically effective amount of the pharmaceutical composition to a patient in need thereof.

[0083] According to an embodiment of the present invention, the disease or disorder is selected from diseases or symptoms associated with the mineralocorticoid receptor.

[0084] According to an embodiment of the invention, the disease or disorder is selected from disorders characterized by an increased aldosterone concentration in plasma or a change in aldosterone plasma concentration relative to renin plasma concentration, or a disorder associated with these changes.

[0085] According to an embodiment of the present invention, the disease or disorder is selected from chronic kidney disease associated with type 2 diabetes, for example, estimated glomerular filtration rate 25≤[eGFR]<75mL / min / 1.73m 2 , diseases associated with albuminuria.

[0086] According to an embodiment of the present invention, the example of the disease or disorder is selected from at least one of the following: idiopathic primary aldosteronism, aldosteronism associated with adrenal hyperplasia, adrenal adenoma and / or adrenal cancer, aldosteronism associated with cirrhosis of the liver, aldosteronism associated with heart failure, and (relative) aldosteronism associated with essential hypertension;

[0087] Renal disorders, such as acute and chronic renal failure, hypertensive nephropathy, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal insufficiency and cystic kidney disease, renal damage (in the case of organ transplantation, which can be caused, for example, by immunosuppressants such as cyclosporin A), renal cancer;

[0088] Diabetes and sequelae of diabetes, such as neuropathy and nephropathy;

[0089] Microalbuminuria (e.g. caused by diabetes or hypertension), proteinuria;

[0090] Conditions associated with increased plasma glucocorticoid concentrations or with localized increased glucocorticoid concentrations in tissues (e.g., the heart), such as adrenal dysfunction leading to an overproduction of glucocorticoids (Cushing syndrome), adrenocortical tumors leading to an overproduction of glucocorticoids, and pituitary tumors that spontaneously produce ACTH (adrenocorticotropic hormone) and thus lead to adrenal hyperplasia causing Cushing's disease;

[0091] According to an embodiment of the present invention, the pharmaceutical composition may contain other active ingredients as required, in particular, pharmaceutical active ingredients known to be used for treating and / or preventing the above-mentioned diseases or symptoms.

[0092] According to an embodiment of the present invention, the pharmaceutical composition can be systemically and / or topically administered, for example, by oral, parenteral, lung, nose, sublingual, tongue, buccal, rectal, dermal, percutaneous, conjunctival or ear route administration, or as implant or stent administration. In the case of parenteral administration, to achieve effective results, the dosage is about 0.001 to 1mg / kg body weight, preferably about 0.01 to 0.5mg / kg body weight. In the case of oral administration, the dosage is about 0.01 to 100mg / kg body weight, preferably about 0.01 to 20mg / kg body weight and very particularly preferably 0.1 to 10mg / kg body weight. It will be appreciated by those skilled in the art that the dosage of a specific individual may present differences according to its body weight, route of administration, individual response to active ingredient, the nature of the preparation, and administration time or administration interval.

[0093] Unless otherwise specified, the numerical values ​​in the present application should be understood to include the numerical range of ±10% thereof.

[0094] Beneficial Effects

[0095] The pharmaceutical composition of the present invention has good solubility in various media, and has good uniformity, tolerance and particle size after being prepared into a preparation, and is consistent with the in vitro release effect of the reference preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 XRPD spectrum of phenarezone crystalline form I prepared in Example 1

[0097] Figure 2 DSC spectrum of phenarezone crystal form I prepared in Example 1

[0098] Figure 3 TGA spectrum of phenarezone crystalline form I prepared in Example 1

[0099] Figure 4 This is a micrograph of the phenarezone crystal form I prepared in Example 1.

[0100] Figure 5 This is the dissolution curve in Test Example 2

[0101] Figure 6 This is the dissolution curve in Test Example 3

[0102] Figure 7 This is the pH 1.2 medium dissolution curve in Test Example 5

[0103] Figure 8 This is the pH 4.5 medium dissolution curve in Test Example 5

[0104] Fig. 9 This is the pH 6.8 medium dissolution curve in Test Example 5

[0105] Fig.10 This is the pH 1.2 medium dissolution curve in Test Example 6

[0106] Fig.11 This is the pH 4.5 medium dissolution curve in Test Example 6

[0107] Fig.12 This is the pH 6.8 medium dissolution curve in Test Example 6 DETAILED DESCRIPTION

[0108] The technical solution of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included in the scope of protection intended by the present disclosure.

[0109] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0110] Source of reference preparation: Bayer, 10 mg finerenone, batch number BXK04F1.

[0111] The temperatures described in the present invention are all temperatures inside the reaction container.

[0112] Example 1 Preparation of Finerenone Crystal Form I

[0113] Add phenarenalone (270 g) and methanol (2430 mL) to a 5L three-necked flask, heat to 65°C, reflux and stir until the sample is dissolved. Add activated carbon (5.40 g) and stir for 30 minutes. Filter while hot, rinse the reaction flask and funnel with methanol (270 mL), and transfer the filtrate to a 20L reactor. Turn on stirring, heat to 65°C, add purified water (2700 mL), and continue to keep warm and crystallize for 1 hour after the addition is complete. Slowly cool to 0°C and keep warm and crystallize for 1 hour. Filter by suction, rinse the filter cake with a methanol / water mixed solvent (V / V=1 / 1, 270 mL), and dry it in vacuo at 60°C overnight to obtain phenarenalone form I (239.95 g, yield 88.9%). The XRPD spectrum of phenarenalone form I is shown in the following figure. Figure 1 As shown in the DSC spectrum Figure 2 As shown in the TGA spectrum Figure 3 As shown in the micrographs Figure 4 shown.

[0114] Example 2 Preparation 1 containing finerenone crystalline form I

[0115] The formulation is shown in Table 1. Finerenone Form I is derived from Example 1, and the particle size of the raw material drug D90 is 15 μm.

[0116] Table 1 Prescription composition of 10 mg finerenone preparation

[0117]

[0118] Preparation method:

[0119] Lactose monohydrate and microcrystalline cellulose are added into a fluidized bed, and a binder prepared by hydroxypropyl methylcellulose and sodium lauryl sulfate is sprayed into the fluidized bed. The particles are granulated, dried, and sieved through a 20-mesh sieve to obtain particles a.

[0120] Finerenone crystal form I was crushed and added to the granule a material, passed through a 40-mesh sieve, and transferred to a total mixing tank together with cross-linked sodium carboxymethyl cellulose to mix evenly. Magnesium stearate was added to the above-mentioned mixed material, mixed for 5 minutes, and the total mixed granules were obtained, which were compressed into tablets with a tablet weight of 132 mg and a hardness of 8 to 12 kg. Opadry was film-coated.

[0121] Example 3 Preparation 2 containing finerenone crystalline form I

[0122] The formulation is shown in Table 2. Finerenone Form I is derived from Example 1, the particle size of the raw material D90 is 15 μm, and the preparation method is referenced to Example 2.

[0123] Table 2 Prescription composition of 20 mg finerenone preparation

[0124]

[0125] Example 4 Investigation of the particle size of the raw material

[0126] The finerenone crystal form I was subjected to air flow milling and mechanical milling to obtain API with the following particle size:

[0127] Table 3 Particle size of APIs in different pulverization methods

[0128] serial number Crushing method D10μm D50μm D90μm Example 4-1 Uncrushed 18.8 61.6 134 Example 4-2 Air flow milling 1bar 30rpm 2.07 4.41 7.63 Example 4-3 Air flow milling 2bar 30rpm 1.54 2.93 6.37 Example 4-4 Air flow milling 3bar 30rpm 1.67 3.07 4.95 Embodiment 4-5 Mechanical crushing 15s 2.04 6.27 22.0 Embodiment 4-6 Mechanical crushing 30s 1.71 4.62 16.2

[0129] Finerenone Form I is derived from Example 1.

[0130] With reference to the prescription and preparation method of Example 2, the above-mentioned raw materials of different particle sizes were used to prepare preparations to obtain the preparations of Example 4-1, Example 4-2, Example 4-3, Example 4-4, Example 4-5 and Example 4-6, respectively.

[0131] Comparative Example 1

[0132] The formulation is the same as that of Example 2, the finerenone crystal form I is derived from Example 1, and the particle size of the raw material drug D90: 15 μm.

[0133] Finerenone crystal form I and microcrystalline cellulose are sieved together with a 40-mesh sieve, lactose monohydrate, cross-linked carboxymethyl cellulose sodium, hypromellose and sodium lauryl sulfate are added to the sieved material, the mixture is put into a wet granulator and mixed evenly, 30% purified water is added to make a soft material, the mixture is sieved with a 20-mesh sieve for wet granulation, dried, and sieved with a 20-mesh sieve for dry granulation.

[0134] Add the granulated material to the total mixing tank, add magnesium stearate, and mix for 5 minutes. The total mixed granules are compressed into tablets with a tablet weight of 132 mg and a hardness of 8 to 12 kg. Film coating is performed with Opadry.

[0135] Comparative Example 2

[0136] The formulation is the same as that of Example 2, the finerenone crystal form I is derived from Example 1, and the particle size of the raw material drug D90: 15 μm.

[0137] Finerenone crystal form I and microcrystalline cellulose were sieved through a 40-mesh sieve, and the sieved materials, lactose monohydrate, cross-linked carboxymethyl cellulose sodium, hypromellose, and sodium lauryl sulfate were added to a mixing tank and mixed evenly. Magnesium stearate was added and mixed for 5 minutes to obtain a total mixed granule, which was compressed into tablets with a tablet weight of 132 mg and a hardness of 8 to 12 kg. Opadry was used for film coating.

[0138] Comparative Example 3

[0139] The formulation is the same as that of Example 2, the finerenone crystal form I is derived from Example 1, and the particle size of the raw material drug D90: 15 μm.

[0140] Finerenone crystal form I, lactose monohydrate, cross-linked carboxymethyl cellulose sodium, hydroxypropyl methylcellulose and sodium lauryl sulfate were placed in a wet granulator and mixed evenly, and then 30% purified water was added to make a soft material, and wet granulation was performed through a 20-mesh sieve, dried, and dry granulation was performed through a 20-mesh sieve. The granulated particles were added to a total mixing tank, microcrystalline cellulose was added and mixed evenly, and then magnesium stearate was added and mixed for 5 minutes to obtain a total mixed granule, which was tableted to a tablet weight of 132 mg and a hardness of 8 to 12 kg. Opadry was film-coated.

[0141] Test Example 1 Solubility Test

[0142] For the phenelenone crystalline form I prepared in Example 1, solubility experiments were carried out at pH 1.0, pH 2.0, pH 4.5, pH 4.5 + 0.1% Tween 20, pH 6.8, and pH 6.8 + 0.1% Tween 20.

[0143] The experimental results are shown in Table 4 below.

[0144] Table 4 Solubility results

[0145] medium Solubility S (mg / mL) pH 1.0 35.720 pH 2.0 2.418 pH4.5 0.058 pH 4.5 + 0.1% Tween 20 0.096 pH 6.8 0.027 pH 6.8 + 0.1% Tween 20 0.060

[0146] The results showed that the solubility of finerenone Form I API decreased gradually with increasing pH. In a pH 6.8 medium, the solubility of the 20 mg strength could not reach the sink condition and could not be completely dissolved.

[0147] Test Example 2 Dissolution Test of Different Preparation Processes

[0148] According to the dissolution method of the United States Pharmacopoeia and the second method of the fourth general rule of the Chinese Pharmacopoeia 2020 edition, pH 4.5 acetate solution, 900mL is used as the dissolution medium, the speed is 75r / min, and at 5, 10, 15, 20, 30, 45, 60min, online filtration is performed, and 1.8mL of the solution is taken as the test solution. The dissolution results of Comparative Example 1, Comparative Example 2, Comparative Example 3, Example 2 and the reference preparation are shown in Figure 5 shown.

[0149] The results show that when the particle size of the raw material drug D90 is controlled at 15 μm, the preparation processes of Comparative Examples 1, 2 and 3 are different from those of Example 2. The dissolution release of Example 2 is faster, the dissolution endpoint is higher, and it is closer to the reference.

[0150] Test Example 3: Dissolution Study of Samples with Different Particle Sizes

[0151] According to the dissolution method of the United States Pharmacopoeia and the second method of the fourth general rule of the Chinese Pharmacopoeia 2020 edition, pH 4.5 acetate solution, 900mL is used as the dissolution medium, the speed is 75r / min, and at 5, 10, 15, 20, 30, 45, 60min, online filtration is performed, and 1.8mL of the solution is taken as the test solution. The dissolution results of the preparations of Example 4-2, Example 4-3, Example 4-4, Example 4-5, Example 4-6 and the reference preparation are shown in Table 5 and Figure 6 shown.

[0152] Table 5 Dissolution test results

[0153] Time / min 0 5 10 15 20 30 45 60 Reference preparation 0 50.8 89.3 98.4 100.5 101.4 101.3 101.2 Example 4-5 (D90: 22 μm) 0 49.8 73.3 81.4 85.7 90.2 93.8 95.7 Example 4-6 (D90: 16.2 μm) 0 50.5 81.3 89.1 92.5 95.6 98.1 99.1 Example 4-2 (D90: 7.63 μm) 0 61.6 83.4 88.5 91.0 93.6 95.6 96.5 Example 4-3 (D90: 6.37 μm) 0 55.6 89.1 95.6 97.2 98.1 98.6 98.9 Example 4-4 (D90: 4.95 μm) 0 55.5 90.7 97.3 99.0 100.0 100.2 100.2

[0154] From the above data, it can be seen that when the particle size of the raw material drug is within the range of D90 less than 22 μm, a sample with a release rate consistent with the reference can be prepared using the preparation sample prepared by finerenone crystal form I in Example 1.

[0155] Test Example 4 Content Uniformity Investigation

[0156] Investigation on content uniformity during granulation process:

[0157] According to the preparation process of Example 2, the batch production was scaled up, the prescription and process were confirmed, and the mixing uniformity was investigated. During the total mixing process, 2 samples were taken from the upper, middle and lower positions of the total mixing tank, each with a sampling amount of 1.5 g. The test results are shown in Table 6.

[0158] Table 6 Results of the investigation on content uniformity of the total mixing process

[0159]

[0160] The results show that the RSD of mixing uniformity is less than 5%, which meets the requirements.

[0161] Test Example 5: Dissolution Study in Different Dissolution Media

[0162] According to the preparation process of Example 2, scaled-up batch production was carried out, the prescription and process were confirmed, and the release curves of the prepared samples in pH 1.2, 4.5 and 6.8 media were tested.

[0163] According to the dissolution method of the United States Pharmacopoeia and the second method of Part IV of the Chinese Pharmacopoeia 2020, 900 mL of pH 1.2 hydrochloric acid solution, pH 4.5 acetate solution, and pH 6.8 phosphate solution were used as the dissolution medium, the speed was 50 r / min, and 1.8 mL of the solution was taken as the test solution at 5, 10, 15, 20, 30, 45, 60, 75, and 90 min. The dissolution results in pH 1.2 hydrochloric acid solution are as follows: Figure 7 As shown, the dissolution results in pH 4.5 acetate solution are as follows Figure 8 As shown, the dissolution results in pH 6.8 phosphate solution are as follows Fig. 9 shown.

[0164] The results showed that in pH 1.2 and pH 6.8 media, F2 was greater than 50, and the in vitro release was consistent with the reference; in pH 4.5 medium, the 15 min dissolution was greater than 85%, and the in vitro release was consistent with the reference.

[0165] Test Example 6: Dissolution of 20 mg sample in different dissolution media

[0166] For Example 3, the dissolution consistency of the 20 mg product was confirmed to be consistent with that of Example 2, and its release in pH 1.2, 4.5 and 6.8 media was measured respectively.

[0167] According to the Technical Guidelines for Pharmaceutical Change Research of Marketed Chemical Drugs (Trial), based on the solubility results of Test Example 1, the solubility of the 20 mg specification in a pH 6.8 medium could not reach the sink condition and could not be completely dissolved. Therefore, two tablets of 10 mg specification were purchased for comparison with the reference preparation.

[0168] According to the dissolution method of the United States Pharmacopoeia and the second method of Part IV of the Chinese Pharmacopoeia 2020, 900 mL of pH 1.2 hydrochloric acid solution, pH 4.5 acetate solution, and pH 6.8 phosphate solution were used as the dissolution medium, the speed was 50 r / min, and 1.8 mL of the solution was taken as the test solution at 5, 10, 15, 20, 30, 45, 60, 75, and 90 min. The dissolution results in pH 1.2 hydrochloric acid solution are as follows: Fig.10 As shown, the dissolution results in pH 4.5 acetate solution are as follows Fig.11 As shown, the dissolution results in pH 6.8 phosphate solution are as follows Fig.12 shown.

[0169] The results showed that in pH 1.2 and pH 6.8 media, F2 was greater than 50, and the in vitro release was consistent with the reference; in pH 4.5 medium, the 15 min dissolution was greater than 85%, and the in vitro release was consistent with the reference.

[0170] Test Example 7 Investigation of Related Substances

[0171] Solution preparation:

[0172] 1. Mobile phase solution A: Weigh 3.4808 g of potassium dihydrogen phosphate, dissolve and dilute to 2000 mL with ultrapure water, mix well, adjust the pH to 6.51 with phosphoric acid, accurately take 1800 mL of the above buffer solution, add 100 mL of acetonitrile and 100 mL of methanol to the reagent bottle, mix well, and ultrasonicate for 10 min.

[0173] 2. Mobile phase B: Take 1000mL of methanol and 1000mL of acetonitrile respectively, place them in the mobile phase bottle, shake well, and ultrasonicate for 10 minutes.

[0174] 3. Blank solution / diluent: methanol-water (50:50).

[0175] 4. Sample solution: The preparation product prepared in Example 2 was placed under high temperature, high humidity and light conditions, and 3 pieces of 14-day and 30-day samples were taken, ground into fine powder with agate, and 350 mg of fine powder (equivalent to 26 mg of API) was taken, accurately weighed, and placed in a 20 mL volumetric bottle, and an appropriate amount of diluent was added to dissolve it by ultrasonic for 10 min, and then diluted to the scale with a diluent after it was placed at room temperature, and shaken well. About 9 mL of the solution was taken and centrifuged at 8000 rpm for 5 min, and the supernatant was filtered with a 0.22 filter membrane, and 1 mL of the initial filtrate was discarded and the subsequent filtrate was taken as the test solution.

[0176] Analysis method: Take blank solution and sample solution for HPLC analysis.

[0177] Chromatographic conditions:

[0178] Chromatographic column: Waters Xbridge C18 4.6×150 mm, 3.5 μm;

[0179] Mobile phase A: Phosphate buffer (pH 4.0)

[0180] Mobile phase B: acetonitrile

[0181] Column temperature: 30°C

[0182] Flow rate: 1.0mL / min

[0183] Detection wavelength: 210nm

[0184] Injection volume: 5 μL

[0185] gradient:

[0186] time Phase A / % Phase B / % 0 95 5 35 10 90 36 95 5 41 95 5

[0187] Table 7 Example 2 Sample Stability Sample Test Results

[0188]

[0189] The results show that the total impurities of the phenerenone tablets prepared by the present invention are basically unchanged when placed under high temperature, high humidity and light conditions for 30 days, and the growth of individual impurities is within 0.05%, indicating that the preparation of the present invention has good stability.

[0190] The above is an exemplary description of the implementation of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above-mentioned implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of this application.

Claims

1. A pharmaceutical composition, wherein the active ingredient of the pharmaceutical composition comprises finerenone or a pharmaceutically acceptable salt thereof, and the unimodal particle size distribution D90 of the finerenone or a pharmaceutically acceptable salt thereof is less than 22 μm.

2. The pharmaceutical composition according to claim 1, characterized in that The finerenone or its pharmaceutically acceptable salt has a unimodal particle size distribution D10 of 1.54-2.07 μm; preferably, D10 is 1.54-1.73 μm; Preferably, the finerenone or a pharmaceutically acceptable salt thereof has a unimodal particle size distribution D50 of 2.93-6.27 μm; preferably, D50 is 2.93-4.62 μm; Preferably, the finerenone or a pharmaceutically acceptable salt thereof has a unimodal particle size distribution D90 of 4-22 μm; preferably, D90 is 4.95-16.2 μm; preferably, D90 is 4.95-5.4 μm.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The finerenone or a pharmaceutically acceptable salt thereof is selected from finerenone crystal form I; wherein the finerenone or a pharmaceutically acceptable salt thereof is obtained by crystallizing finerenone in a mixture of methanol and water.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical composition further comprises at least one selected from the group consisting of a diluent, a disintegrant, a binder, a wetting agent and a lubricant.

5. The pharmaceutical composition according to claim 4, characterized in that The diluent is selected from at least one of starch, sucrose, hydroxypropyl cellulose, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium carbonate, sodium carbonate, lactose, lactose monohydrate, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, mannitol and tricalcium phosphate; Preferably, the disintegrant is selected from at least one of corn starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, polyvinylpyrrolidone, pregelatinized starch and alginic acid; Preferably, the binder is selected from at least one of hydroxypropyl cellulose, hypromellose, povidone and ethyl cellulose; Preferably, the wetting agent is selected from sodium dodecyl sulfate; Preferably, the lubricant is selected from at least one of magnesium stearate, stearic acid, silicon dioxide, fat, calcium stearate, polyethylene glycol, sodium stearyl fumarate, talc and fatty acid.

6. The pharmaceutical composition according to claim 4 or 5, characterized in that The weight of finerenone or its pharmaceutically acceptable salt in the pharmaceutical composition accounts for 6% to 16% of the total weight of the pharmaceutical composition; Preferably, the weight of the diluent in the pharmaceutical composition accounts for 50 to 90% of the total weight of the pharmaceutical composition; Preferably, the weight of the disintegrant in the pharmaceutical composition accounts for 0.5% to 5.0% of the total weight of the pharmaceutical composition; Preferably, the weight of the binder in the pharmaceutical composition accounts for 2% to 5% of the total weight of the pharmaceutical composition; Preferably, the weight of the wetting agent in the pharmaceutical composition accounts for 0.1% to 2.0% of the total weight of the pharmaceutical composition; Preferably, the weight of the lubricant in the pharmaceutical composition accounts for 0.25% to 5% of the total weight of the pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that The pharmaceutical composition is composed of finerenone crystal form I, microcrystalline cellulose, lactose monohydrate, cross-linked carboxymethyl cellulose sodium, hypromellose, sodium lauryl sulfate, and magnesium stearate; Preferably, the weight of microcrystalline cellulose in the pharmaceutical composition accounts for 30% to 60% of the total weight of the pharmaceutical composition; Preferably, the weight of lactose monohydrate in the pharmaceutical composition accounts for 20% to 50% of the total weight of the pharmaceutical composition.

8. A method for preparing the pharmaceutical composition according to any one of claims 1 to 7, comprising the following steps: The diluent, binder and wetting agent are granulated together to obtain granules A, finerenone crystal form I is added to the granules A material and sieved, a disintegrant is added, mixed, a lubricant is added, mixed, and tableting is performed to obtain the pharmaceutical composition.

9. The preparation method according to claim 8, characterized in that: The preparation method comprises: granulating lactose monohydrate, microcrystalline cellulose, hypromellose and sodium lauryl sulfate together to obtain granules a, adding finerenone crystal form I to the granules a material and sieving, then adding cross-linked sodium carboxymethyl cellulose, mixing, then adding magnesium stearate, mixing, and tableting to obtain the pharmaceutical composition.

10. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a drug, wherein the drug may be an antagonist of a mineralocorticoid receptor; Preferably, the medicament is used to prevent and / or treat a disease or symptom; Preferably, the disease or condition is selected from diseases or symptoms associated with the mineralocorticoid receptor; Preferably, the disease or disorder is selected from disorders characterized by an increase in the aldosterone concentration in plasma or a change in the aldosterone plasma concentration relative to the renin plasma concentration, or a disorder associated with such changes; Preferably, the disease or disorder is selected from chronic kidney disease associated with type 2 diabetes; Preferably, the disease is estimated glomerular filtration rate 25≤[eGFR]<75mL / min / 1.73m 2 , diseases associated with albuminuria.

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