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

Abstract

The invention provides a fenerenone pharmaceutical composition as well as a preparation method and application thereof. The pharmaceutical preparation prepared by the method disclosed by the invention has better stability, and the release effect of the pharmaceutical preparation 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. One of the main mechanisms of salt sensitivity and high salt intake leading to 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 [14-15]. 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 shown to have a clear renal and cardiovascular protective effect in 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.

[0005] The inventors have found that the stability of existing finerenone preparations is relatively poor. Therefore, it is necessary to develop a finerenone pharmaceutical composition with better stability and satisfactory release. Summary of the invention

[0006] In order to improve the above technical problems, the present invention provides a pharmaceutical composition, which comprises finerenone or a pharmaceutically acceptable salt thereof, diluent 1, diluent 2, a binder, a wetting agent, a disintegrant and a lubricant.

[0007] According to an embodiment of the present invention, the pharmaceutical composition comprises granules 1, granules 2, a disintegrant and a lubricant, wherein:

[0008] The particles 1 include a diluent 1 and a binder;

[0009] The granules 2 comprise finerenone or a pharmaceutically acceptable salt thereof, a diluent 2, a binder and a wetting agent.

[0010] According to an embodiment of the present invention, the finerenone or a pharmaceutically acceptable salt thereof is selected from finerenone crystalline form I.

[0011] 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°.

[0012] 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°.

[0013] 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°.

[0014] According to an embodiment of the present invention, the finerenone crystalline form I has substantially Figure 1 XRPD spectrum shown.

[0015] According to an embodiment of the present invention, the finerenone crystalline form I has substantially Figure 2 DSC spectrum shown.

[0016] According to an embodiment of the present invention, the finerenone crystalline form I has substantially Figure 3 TGA spectrum shown.

[0017] According to an embodiment of the present invention, the finerenone crystalline form I has substantially Figure 4 Micrographs shown.

[0018] According to an embodiment of the present invention, the diluent 1 and the diluent 2 are the same or different and are independently 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; for example, the diluent 1 is microcrystalline cellulose, and / or the diluent 2 is selected from lactose or its monohydrate.

[0019] According to an embodiment of the present invention, the binder is selected from at least one of hydroxypropyl cellulose, hypromellose, povidone and ethyl cellulose.

[0020] According to an embodiment of the present invention, the wetting agent is selected from sodium dodecyl sulfate.

[0021] 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.

[0022] 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.

[0023] According to an embodiment of the present invention, the pharmaceutical composition further comprises a coating, such as a gastric soluble film coating premix.

[0024] According to an embodiment of the present invention, in the pharmaceutical composition, the weight of finerenone or a pharmaceutically acceptable salt thereof (such as finerenone crystalline form I) 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%.

[0025] According to an embodiment of the present invention, in the pharmaceutical composition, the weight of diluent 1 accounts for 30-60% of the total weight of the pharmaceutical composition, for example, 35%, 40%, 45%, 46.25%, 50%, 50.03%, 55%.

[0026] According to an embodiment of the present invention, in the pharmaceutical composition, the weight of the diluent 2 accounts for 20-50% of the total weight of the pharmaceutical composition, for example, 25%, 30%, 30.30%, 34.09%, 35%, 40%, 45%.

[0027] According to an embodiment of the present invention, in the pharmaceutical composition, the weight of the binder 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%.

[0028] According to an embodiment of the present invention, in the pharmaceutical composition, the weight of the wetting agent 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%.

[0029] According to an embodiment of the present invention, in the pharmaceutical composition, the weight of the disintegrant 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%.

[0030] According to an embodiment of the present invention, in the pharmaceutical composition, the weight of the lubricant 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%.

[0031] 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%.

[0032] According to an embodiment of the present invention, the pharmaceutical composition may be in the form of granules, capsules or tablets, preferably tablets.

[0033] The present invention also provides a method for preparing the pharmaceutical composition, wherein the method comprises the following steps:

[0034] (1) mixing and granulating the components of granule 1;

[0035] (2) mixing and granulating the components of granule 2;

[0036] (3) The granules 1 prepared in step (1) and the granules 2 prepared in step (2) are mixed with a disintegrant and a lubricant to obtain the pharmaceutical composition.

[0037] According to an embodiment of the present invention, the granulation in steps (1) and (2) comprises a wet granulation and / or a dry granulation step, for example comprises a wet granulation, a drying and a dry granulation step.

[0038] According to an embodiment of the present invention, in step (3), the granules 1 obtained in step (1) and the granules 2 obtained in step (2) can be first mixed with a disintegrant to obtain a mixture 1; and then the mixture 1 can be mixed with a lubricant to obtain a mixture 2.

[0039] According to an embodiment of the present invention, step (3) may further include a total mixing and tableting step.

[0040] According to an embodiment of the present invention, the preparation method further comprises the step of pulverizing the finerenone crystals or a pharmaceutically acceptable salt thereof, and the pulverizing method can be selected from air flow pulverization or mechanical pulverization.

[0041] According to an embodiment of the present invention, the preparation method comprises: granulating microcrystalline cellulose and hypromellose together, followed by wet granulation, drying and dry granulation to obtain microcrystalline cellulose particles; granulating finerenone crystalline form I, lactose monohydrate, hypromellose and sodium lauryl sulfate together, followed by wet granulation, drying and dry granulation to obtain finerenone particles; mixing microcrystalline cellulose particles, finerenone particles and cross-linked sodium carboxymethyl cellulose, adding magnesium stearate to mix, mixing, and tableting to obtain the pharmaceutical composition.

[0042] 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.

[0043] According to an embodiment of the present invention, the preparation method comprises the following steps:

[0044] (1) mixing finerenone with methanol to obtain a mixture of finerenone and methanol;

[0045] (2) adding water to the mixture of finerenone and methanol obtained in step (1) to obtain a mixture of finerenone, methanol and water;

[0046] (3) crystallizing a mixture of the finerenone obtained in step (2) and methanol and water to obtain the finerenone crystalline form I.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] According to an embodiment of the present invention, the water may be added dropwise.

[0054] According to an embodiment of the present invention, the water is purified water.

[0055] 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.

[0056] According to an embodiment of the present invention, step (2) further comprises adding activated carbon before or after adding water.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] According to an embodiment of the present invention, the crystallization time is selected from 0.5-5h, such as 1h, 2h, 3h, 4h.

[0061] 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.

[0062] 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.

[0063] According to an embodiment of the present invention, the organic solvent comprises at least one of methanol and isopropanol.

[0064] According to an embodiment of the present invention, the organic solvent is selected from methanol, isopropanol or a mixture thereof.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] According to an embodiment of the present invention, the crystallization time is selected from 0.5-5h, such as 1h, 2h, 3h, 4h.

[0069] The present invention also provides the use of the pharmaceutical composition as an antagonist of mineralocorticoid receptor.

[0070] The present invention also provides the use of the pharmaceutical composition for preparing medicines.

[0071] According to an embodiment of the present invention, the medicament is for preventing and / or treating a disease or symptom.

[0072] The present invention also provides a method for preventing and / or treating a disease or symptom, comprising administering a therapeutically effective amount of the pharmaceutical composition to a patient in need thereof.

[0073] According to an embodiment of the present invention, the disease or disorder is selected from diseases or symptoms associated with the mineralocorticoid receptor.

[0074] 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.

[0075] 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.

[0076] According to an embodiment of the present invention, the example of the disease or condition is selected from at least one of the following:

[0077] Idiopathic primary aldosteronism, aldosteronism associated with adrenal hyperplasia, adrenal adenoma, and / or adrenal carcinoma, aldosteronism associated with cirrhosis, aldosteronism associated with heart failure, and (relative) aldosteronism associated with essential hypertension;

[0078] 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;

[0079] Diabetes and sequelae of diabetes, such as neuropathy and nephropathy;

[0080] Microalbuminuria (e.g. caused by diabetes or hypertension), proteinuria;

[0081] 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;

[0082] 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.

[0083] 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.

[0084] Beneficial Effects

[0085] The invention provides a finerenone pharmaceutical composition and a preparation method and use thereof. The pharmaceutical preparation prepared by the method of the invention has good stability and is consistent with the release effect of a reference preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1 This is the XRPD spectrum of the phenarezone crystalline form I prepared in Example 1.

[0087] Figure 2 This is the DSC spectrum of the phenarezone crystal form I prepared in Example 1.

[0088] Figure 3 This is the TGA spectrum of the phenaredonide crystal form I prepared in Example 1.

[0089] Figure 4 This is a micrograph of the crystalline form I of phenerenone prepared in Example 1.

[0090] Figure 5 This is the pH 4.5 dissolution result curve of Test Example 1.

[0091] Figure 6 This is the pH 4.5 dissolution result curve of Test Example 2. DETAILED DESCRIPTION

[0092] 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.

[0093] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0094] Example 1 Preparation of Finerenone Crystal Form I

[0095] 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, the DSC spectrum is Figure 2 As shown in the TGA spectrum Figure 3 As shown in the micrographs Figure 4 shown.

[0096] The obtained finerenone crystal form I was used in the following experiments.

[0097] Example 2 Preparation containing finerenone crystalline form I

[0098] Table 1 Prescription composition of 10 mg finerenone preparation

[0099]

[0100]

[0101] Preparation method:

[0102] Mix microcrystalline cellulose and 1 / 2 of hypromellose uniformly, add 30% purified water to make a soft material, sieve through 20 mesh, dry, and granulate through 20 mesh to obtain a granule.

[0103] Finerenone crystal form I, lactose monohydrate, 1 / 2 of hydroxypropyl methylcellulose and sodium lauryl sulfate are uniformly mixed, 30% purified water is added to prepare a soft material, the mixture is passed through a 20-mesh sieve for wet granulation, and dried to obtain particles B.

[0104] Mix the a particles, b particles and cross-linked carboxymethyl cellulose sodium in a three-dimensional mixer. Then add magnesium stearate and mix for 5 minutes to obtain the total mixed granules, which are compressed into tablets with a tablet weight of 132 mg and a hardness of 8 to 12 kg. Then film-coat with Opadry.

[0105] Comparative Example 1

[0106] The preparation prescription is the same as that in Example 2.

[0107] 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, and the mixture is put into a wet granulator and mixed evenly, 30% purified water is added to prepare a soft material, sieved with a 20-mesh sieve, dried at 55° C. to 65° C., and sieved with a 20-mesh sieve for granulation.

[0108] The granulated material was added to the total mixing tank, and then magnesium stearate was added and mixed for 5 minutes. The total mixed granules were obtained and tablets were compressed to a tablet weight of 132 mg and a hardness of 8 to 12 kg. Opadry was then film-coated.

[0109] Comparative Example 2

[0110] The preparation prescription is the same as that in Example 2.

[0111] 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 then added and mixed for 5 minutes. The total mixed granules were obtained and tableted, with a tablet weight of 132 mg and a hardness of 8 to 12 kg. Opadry was then used for film coating.

[0112] Comparative Example 3

[0113] The preparation prescription is the same as that in Example 2.

[0114] Finerenone crystal form I, lactose monohydrate, cross-linked carboxymethyl cellulose sodium, hypromellose and sodium lauryl sulfate are placed in a wet granulator and mixed evenly, 30% purified water is added to make a soft material, the material is passed through a 20-mesh sieve for wet granulation, dried, and granulated with a 20-mesh sieve.

[0115] The granules after granulation were added to the mixing tank, microcrystalline cellulose was added and mixed evenly, and then magnesium stearate was added and mixed for 5 minutes to obtain the mixed granules, which were compressed into tablets with a tablet weight of 132 mg and a hardness of 8 to 12 kg. Opadry was then film-coated.

[0116] Test Example 1 Dissolution Test of Different Preparation Processes

[0117] 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.

[0118] The results showed that the in vitro release of the sample prepared in Example 2 was consistent with that of the reference preparation, and was able to promote the release well.

[0119] Test Example 2: Investigating the effect of disintegrant dosage on samples

[0120] The preparation method is the same as in Example 2, and the prescription is shown in Table 2.

[0121] Table 2 Composition of different proportions of disintegrants

[0122] Comparative Example 4 Comparative Example 5 Example 2 Comparative Example 6 Finerenone Crystal Form I 7.58％ 7.58％ 7.58％ 7.58％ Microcrystalline Cellulose 52.03％ 51.03％ 50.03％ 49.03％ Lactose Monohydrate 34.09％ 34.09％ 34.09％ 34.09％ Croscarmellose Sodium 1.0％ 2.0％ 3.0％ 4.0％ Hydroxypropyl methylcellulose 4.0％ 4.0％ 4.0％ 4.0％ Sodium Lauryl Sulfate 0.3％ 0.3％ 0.3％ 0.3％ Magnesium Stearate 1.0％ 1.0％ 1.0％ 1.0％ total 100％ 100％ 100％ 100％

[0123] 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 4, Comparative Example 5, Comparative Example 6, Example 2 and the reference preparation are as follows Figure 6 shown.

[0124] Test Example 3: Stability Test

[0125] Solution preparation:

[0126] 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.

[0127] 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.

[0128] 3. Blank solution / diluent: methanol-water (50:50).

[0129] 4. Sample solution: The preparation product prepared in Example 2 was placed under high temperature, high humidity and accelerated conditions, respectively. Three samples were taken under high temperature and high humidity for 14 days, 30 days, and accelerated for 1 month and 2 months, and ground into fine powder with agate. 350 mg of fine powder (equivalent to 26 mg of API) was taken, accurately weighed, placed in a 20 mL volumetric bottle, and an appropriate amount of diluent was added to dissolve by ultrasonic for 10 min. After being placed at room temperature, it was diluted to the scale with a diluent and shaken. 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. 1 mL of the initial filtrate was discarded and the subsequent filtrate was taken as the test solution.

[0130] Analysis method: Take blank solution and sample solution for HPLC analysis.

[0131] Chromatographic conditions:

[0132] Chromatographic column: Waters Xbridge C18 4.6×150 mm, 3.5 μm;

[0133] Mobile phase A: Phosphate buffer (pH 4.0)

[0134] Mobile phase B: acetonitrile

[0135] Column temperature: 30°C

[0136] Flow rate: 1.0mL / min

[0137] Detection wavelength: 210nm

[0138] Injection volume: 5 μL

[0139] gradient:

[0140] time Phase A / % Phase B / % 0 95 5 35 10 90 36 95 5 41 95 5

[0141] Table 3 Stability test results of Example 2

[0142]

[0143]

[0144] Note: ND means not detected and NA means not applicable.

[0145] The results show that the total impurities of the phenerenone tablets prepared by the present invention have basically no significant change when placed under high temperature and high humidity conditions for 30 days and under accelerated conditions (40°C / RH75%) for 2 months, the growth of individual impurities is within 0.05%, and there is no significant change in related substances. This shows that the preparation of the present invention has good stability.

[0146] 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 comprising finerenone or a pharmaceutically acceptable salt thereof, a diluent 1, a diluent 2, a binder, a wetting agent, a disintegrant and a lubricant.

2. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition comprises granule 1, granule 2, a disintegrant and a lubricant, wherein: The particles 1 include a diluent 1 and a binder; The granules 2 comprise finerenone or a pharmaceutically acceptable salt thereof, a diluent 2, a binder and a wetting agent.

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; Preferably, the finerenone crystalline form I has an XRPD spectrum substantially as shown in FIG1 ; Preferably, the finerenone crystalline form I has a DSC spectrum substantially as shown in FIG2 ; Preferably, the finerenone crystalline form I has a TGA spectrum substantially as shown in FIG3 .

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The diluent 1 and the diluent 2 are the same or different and are independently 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 diluent 1 is microcrystalline cellulose, and / or the diluent 2 is selected from lactose or its monohydrate; Preferably, the binder is selected from at least one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone and ethyl cellulose. Preferably, the wetting agent is selected from sodium dodecyl sulfate; 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 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.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that In the pharmaceutical composition, the weight of finerenone or its pharmaceutically acceptable salt accounts for 6% to 16% of the total weight of the pharmaceutical composition; Preferably, in the pharmaceutical composition, the weight of the diluent 1 accounts for 30 to 60% of the total weight of the pharmaceutical composition; Preferably, in the pharmaceutical composition, the weight of the diluent 2 accounts for 20 to 50% of the total weight of the pharmaceutical composition; Preferably, in the pharmaceutical composition, the weight of the binder accounts for 2% to 5% of the total weight of the pharmaceutical composition; Preferably, in the pharmaceutical composition, the weight of the wetting agent accounts for 0.1% to 2.0% of the total weight of the pharmaceutical composition; Preferably, in the pharmaceutical composition, the weight of the disintegrant accounts for 0.5% to 5.0% of the total weight of the pharmaceutical composition; Preferably, in the pharmaceutical composition, the weight of the lubricant accounts for 0.25% to 5% of the total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The pharmaceutical composition is in the form of granules, capsules or tablets, preferably tablets.

7. A method for preparing the pharmaceutical composition according to any one of claims 2 to 6, wherein the method comprises the following steps: (1) mixing and granulating the components of granule 1; (2) mixing and granulating the components of granule 2; (3) The granules 1 prepared in step (1) and the granules 2 prepared in step (2) are mixed with a disintegrant and a lubricant to obtain the pharmaceutical composition.

8. The preparation method according to claim 7, characterized in that: The granulation in steps (1) and (2) includes wet granulation and / or dry granulation steps; Preferably, the preparation method further comprises step (3), in which the granules 1 obtained in step (1) and the granules 2 obtained in step (2) are first mixed with a disintegrant to obtain a mixture 1; and then the mixture 1 is mixed with a lubricant to obtain a mixture 2; Preferably, step (3) may also include a total mixing and tableting step; Preferably, the preparation method further comprises the step of pulverizing finerenone or a pharmaceutically acceptable salt thereof, and the pulverizing method can be selected from air flow pulverization or mechanical pulverization; Preferably, the finerenone or a pharmaceutically acceptable salt thereof is obtained by crystallizing finerenone in a mixture of methanol and water.

9. The preparation method according to claim 7 or 8, characterized in that: The preparation method comprises: granulating microcrystalline cellulose and hypromellose together, and then wet granulating, drying and dry granulating to obtain microcrystalline cellulose particles; granulating finerenone crystal form I, lactose monohydrate, hypromellose and sodium lauryl sulfate together, and then wet granulating, drying and dry granulating to obtain finerenone particles; mixing microcrystalline cellulose particles, finerenone particles and cross-linked sodium carboxymethyl cellulose, adding magnesium stearate to mix, mixing, and tableting to obtain the pharmaceutical composition.

10. Use of the pharmaceutical composition according to any one of claims 1 to 6 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.

Images