Pharmaceutical compositions of finerenone and methods of making and using the same

Abstract

The application provides a pharmaceutical composition of finerenone and a preparation method and use thereof. The pharmaceutical preparation prepared by the method of the application has good stability and is consistent with the release effect of a reference preparation.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions of fenelazol, their preparation methods and uses, and belongs to the field of pharmaceutical preparations. Background Technology

[0002] Diabetes is a major risk factor for chronic kidney disease (CKD), with approximately 50% of patients with type 2 diabetes mellitus (T2DM) developing CKD. Domestic and international consensus and guidelines emphasize the importance of screening diabetic patients for CKD to achieve early diagnosis and treatment, thereby slowing the progression of CKD and reducing the occurrence of related cardiovascular events.

[0003] Mineralocorticoid receptor (MR) is expressed in the kidneys, heart, and blood vessels. In diabetic CKD patients, MR overactivation mediates the development and progression of renal and cardiac tissue inflammation and fibrosis, further leading to various adverse renal and cardiovascular clinical outcomes. Blocking MR overactivation is crucial for preventing and treating adverse renal and cardiovascular outcomes. One of the main mechanisms by which salt sensitivity and high salt intake lead to kidney damage is MR overactivation.

[0004] Traditional steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone have not been extensively explored in the field of CKD due to the risks of cross-reactivity with sex steroid receptors and hyperkalemia [14-15]. Novel nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs) such as finerenone ((4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide) have been shown to have clear renal and cardiovascular protective effects in patients with diabetes mellitus and CKD. Long-term use can significantly reduce the urinary albumin-to-creatinine ratio (UACR) and has little effect on serum potassium.

[0005] The inventors discovered that existing fenelazol formulations have poor stability. Therefore, there is a need to develop fenelazol drug compositions with better stability and satisfactory release. Summary of the Invention

[0006] To address the aforementioned technical problems, the present invention provides a pharmaceutical composition comprising fenelinone or a pharmaceutically acceptable salt thereof, diluent 1, diluent 2, binder, wetting agent, disintegrant, and lubricant.

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

[0008] The particle 1 comprises a diluent 1 and a binder;

[0009] The particles 2 contain fenelinone or a pharmaceutically acceptable salt thereof, diluent 2, binder and wetting agent.

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

[0011] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the fenelinone 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°, and 22.923±0.20°.

[0012] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the fenelinone 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 the fenelone 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 non-nelitone crystalline form I has essentially the following characteristics: Figure 1 The XRPD spectrum shown.

[0015] According to an embodiment of the present invention, the non-nelitone crystalline form I has essentially the following characteristics: Figure 2 The DSC spectrum shown.

[0016] According to an embodiment of the present invention, the non-nelitone crystalline form I has essentially the following characteristics: Figure 3 The TGA spectrum shown.

[0017] According to an embodiment of the present invention, the non-nelitone crystalline form I has essentially the following characteristics: Figure 4 The micrograph shown.

[0018] According to embodiments of the present invention, the diluent 1 and diluent 2 may be 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, dicalcium phosphate, dicalcium 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 adhesive is selected from at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, and ethyl cellulose.

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

[0021] According to an embodiment of the present invention, the disintegrant is selected from at least one of corn starch, croscarmellose sodium, croscarmellose polyvinylpyrrolidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, polyvinylpyrrolidone, pregelatinized starch, and alginate.

[0022] According to an embodiment of the present invention, the lubricant is selected from at least one of magnesium stearate, stearic acid, silica, fat, calcium stearate, polyethylene glycol, sodium stearate fumarate, talc, and fatty acids.

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

[0024] According to an embodiment of the present invention, in the pharmaceutical composition, fenelinone or a pharmaceutically acceptable salt thereof (such as fenelinone crystal 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% to 60% of the total weight of the pharmaceutical composition, for example 35%, 40%, 45%, 46.25%, 50%, 50.03%, and 55%.

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

[0027] According to an embodiment of the present invention, in the pharmaceutical composition, 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%, and 4.5%.

[0028] According to an embodiment of the present invention, 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%, or 1.8%.

[0029] According to an embodiment of the present invention, 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%, and 4.5%.

[0030] According to an embodiment of the present invention, 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%, and 4.5%.

[0031] According to embodiments of the present invention, 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%, and 4.5%.

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

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

[0034] (1) Mix the components of particle 1 and granulate;

[0035] (2) Mix the components of particle 2 and granulate them;

[0036] (3) Mix the granules 1 obtained in step (1) and the granules 2 obtained in step (2) with the disintegrant and the lubricant to obtain the pharmaceutical composition.

[0037] According to an embodiment of the present invention, the granulation in steps (1) and (2) includes wet granulation and / or dry granulation steps, such as wet granulation, drying and dry granulation steps.

[0038] According to an embodiment of the present invention, in step (3), the particles 1 obtained in step (1) and the particles 2 obtained in step (2) can be mixed with a disintegrant to obtain mixture 1; then mixture 1 can be mixed with a lubricant to obtain 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 includes a step of pulverizing phenelzine crystals or a pharmaceutically acceptable salt thereof, wherein the pulverization method may be selected from air jet milling or mechanical milling.

[0041] According to an embodiment of the present invention, the preparation method includes: granulating microcrystalline cellulose and hydroxypropyl methylcellulose together, followed by wet granulation, drying, and dry granulation to obtain microcrystalline cellulose particles; granulating phenelzine crystal form I, lactose monohydrate, hydroxypropyl methylcellulose, and sodium dodecyl sulfate together, followed by wet granulation, drying, and dry granulation to obtain phenelzine particles; mixing microcrystalline cellulose particles, phenelzine particles, and croscarmellose sodium, then adding magnesium stearate and mixing, and finally compressing the mixture into tablets to obtain the pharmaceutical composition.

[0042] The present invention also provides a method for preparing phenelzine crystal form I, wherein the preparation method includes crystallizing phenelzine in a mixture of methanol and water to obtain phenelzine crystal form I.

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

[0044] (1) Mix phenelzine with methanol to obtain a mixture of phenelzine and methanol;

[0045] (2) Add water to the mixture of phenelzine and methanol obtained in step (1) to obtain a mixture of phenelzine, methanol and water.

[0046] (3) Crystallize the mixture of fenelitonee obtained in step (2) with methanol and water to obtain the fenelitonee crystal form I.

[0047] According to an embodiment of the present invention, in step (1), fenelitonee is mixed and dissolved with methanol to obtain a methanol solution of fenelitonee.

[0048] According to an embodiment of the present invention, step (1) can be performed under heating conditions. Preferably, the temperature at which phenelzine is mixed with methanol can be selected from 30°C to 80°C, for example 50°C to 70°C, such as 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, and 75°C.

[0049] According to an embodiment of the present invention, in step (1), the fenelitonee can be in other forms of fenelitonee besides crystal form I, such as amorphous fenelitonee.

[0050] According to an embodiment of the present invention, in step (2), water is added to the phenelzine methanol solution obtained in step (1) to obtain a mixture of phenelzine, methanol and water.

[0051] According to an embodiment of the present invention, the weight ratio of phenelzine to methanol volume 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 can 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℃ to 80℃, for example 10℃ to 70℃, such as 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃.

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

[0057] According to an embodiment of the present invention, the weight ratio of activated carbon to phenelzine 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, after water is added, the reaction can be kept at a constant temperature for a period of 0.5-5 hours, such as 1 hour, 2 hours, 3 hours, or 4 hours.

[0059] According to an embodiment of the present invention, in step (3), the crystallization temperature can be selected from -15℃ to 50℃, for example -10℃ to 20℃, such as -5℃, 0℃, 5℃, 10℃, 15℃, 20℃.

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

[0061] The present invention also provides a method for preparing phenelzine crystal form I, wherein the preparation method includes mixing phenelzine with an organic solvent, cooling and crystallizing to obtain phenelzine crystal form I.

[0062] According to an embodiment of the present invention, the preparation method includes mixing and dissolving phenelzine with an organic solvent, cooling and crystallizing to obtain phenelzine 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 mixtures thereof.

[0065] According to an embodiment of the present invention, the weight ratio of phenelzine 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 fenelone is mixed with the organic solvent can be selected from 30°C to 90°C, for example 50°C to 85°C, such as 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, and 85°C.

[0067] According to an embodiment of the present invention, the temperature during crystallization can be selected from -15℃ to 50℃, for example -10℃ to 20℃, such as -5℃, 0℃, 5℃, 10℃, 15℃, 20℃.

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

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

[0070] The present invention also provides the use of the pharmaceutical composition for the preparation of a medicine.

[0071] According to an embodiment of the present invention, the drug is used to prevent and / or treat diseases or symptoms.

[0072] The present invention also provides methods for preventing and / or treating diseases or symptoms, including administering a therapeutically effective amount of the pharmaceutical composition to a patient in need.

[0073] According to an embodiment of the present invention, the disease or condition is selected from diseases or symptoms related to mineralocorticoid receptors.

[0074] According to an embodiment of the invention, the disease or symptom is selected from those characterized by an increase or change in plasma aldosterone concentration relative to renin plasma concentration, or those associated with such changes.

[0075] According to an embodiment of the invention, the disease or condition is selected from type 2 diabetes-related chronic kidney disease, for example, an estimated glomerular filtration rate of 25 ≤ [eGFR] < 75 mL / min / 1.73 m 2 Diseases accompanied by albuminuria.

[0076] According to an embodiment of the present invention, the examples of the disease or symptom are 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] Kidney diseases, such as acute and chronic renal failure, hypertensive nephropathy, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal insufficiency and cystic kidney disease, kidney injury (in the case of organ transplantation, it can be caused, for example, by immunosuppressants such as cyclosporine A), and kidney cancer.

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

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

[0081] Conditions associated with increased plasma glucocorticoid concentrations or localized increases in glucocorticoid concentrations in tissues (e.g., the heart), such as: adrenal dysfunction leading to excessive glucocorticoid production (Cushing's syndrome), adrenocortical tumors causing excessive glucocorticoid production, and pituitary tumors that spontaneously produce ACTH (adrenocorticotropic hormone) and thus lead to adrenal hyperplasia that causes Cushing's disease;

[0082] According to embodiments of the present invention, the pharmaceutical composition may contain other active ingredients as needed, particularly pharmaceutical active ingredients known for treating and / or preventing the aforementioned diseases or symptoms.

[0083] According to embodiments of the invention, the pharmaceutical composition can be administered systemically and / or locally, for example via oral, parenteral, pulmonary, nasal, sublingual, tongue, buccal, rectal, dermal, transdermal, conjunctival, or ocular routes, or as an implant or stent. In the case of parenteral administration, the dosage is about 0.001 to 1 mg / kg body weight, preferably about 0.01 to 0.5 mg / kg body weight, to achieve an effective result. In the case of oral administration, the dosage is about 0.01 to 100 mg / kg body weight, preferably about 0.01 to 20 mg / kg body weight, and very particularly preferably 0.1 to 10 mg / kg body weight. Those skilled in the art will understand that the dosage for a particular individual may vary depending on their body weight, route of administration, individual response to the active ingredient, the nature of the formulation, and the time or interval of administration.

[0084] Beneficial effects

[0085] This invention provides a felindone pharmaceutical composition, its preparation method, and its uses. The pharmaceutical preparation prepared by the method of this invention has good stability and release effect consistent with the reference preparation. Attached Figure Description

[0086] Figure 1 The XRPD spectrum of phenelzine crystal form I prepared in Example 1 is shown.

[0087] Figure 2 The DSC spectrum of phenelzine crystal form I prepared in Example 1 is shown.

[0088] Figure 3 The TGA spectrum of phenelzine crystal form I prepared in Example 1.

[0089] Figure 4 Micrograph of phenelzine crystal form I prepared in Example 1.

[0090] Figure 5 The graph shows the dissolution results at pH 4.5 for Test Example 1.

[0091] Figure 6 The graph shows the dissolution results at pH 4.5 for Test Example 2. Detailed Implementation

[0092] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

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

[0094] Example 1: Preparation of Finelendone Crystal Form I

[0095] Add phenelzine (270 g) and methanol (2430 mL) to a 5 L three-necked flask, heat to 65 °C, reflux and stir until the sample dissolves. Add activated carbon (5.40 g), and stir for 30 min. Filter while hot, rinse the reaction flask and funnel with methanol (270 mL), and transfer the filtrate to a 20 L reactor. Start stirring, heat to 65 °C, add purified water (2700 mL) dropwise, and continue to incubate for crystallization for 1 h after the addition is complete. Slowly cool to 0 °C and incubate for crystallization for 1 h. Filter by suction, rinse the filter cake with a methanol / water mixture (V / V = 1 / 1, 270 mL), and dry under vacuum at 60 °C overnight to obtain phenelzine crystal form I (239.95 g, yield 88.9%). The XRPD spectrum of phenelzine crystal form I is shown below. Figure 1 As shown, the DSC spectrum is as follows Figure 2 As shown, the TGA spectrum is as follows Figure 3 As shown, the micrograph is as follows Figure 4 As shown.

[0096] The obtained phenelzine crystal form I was used in the experiments described below.

[0097] Example 2: Formulation containing phenelzine crystal form I

[0098] Table 1. Formulation of 10mg fenelinone preparation

[0099]

[0100]

[0101] Preparation method:

[0102] Microcrystalline cellulose and 1 / 2 hydroxypropyl methylcellulose were mixed evenly, and 30% purified water was added to make a soft material. The mixture was sieved through a 20-mesh sieve, dried, and granulated through a 20-mesh sieve to obtain particles a.

[0103] Finelone crystal form I, lactose monohydrate, 1 / 2 hydroxypropyl methylcellulose and sodium dodecyl sulfate were mixed evenly, and 30% purified water was added to make a soft material. The mixture was wet-granulated through a 20-mesh sieve and dried to obtain particles b.

[0104] Particles A and B, along with croscarmellose sodium, were mixed uniformly in a three-dimensional mixer. Magnesium stearate was then added and mixed for 5 minutes to obtain the final mixed particles. These particles were then compressed into tablets with a weight of 132 mg and a hardness of 8–12 kg. The tablets were then coated with a film using Opadry.

[0105] Comparative Example 1

[0106] The formulation is the same as in Example 2.

[0107] Finelone crystal form I and microcrystalline cellulose were passed through a 40-mesh sieve. Lactose monohydrate, croscarmellose sodium, hydroxypropyl methylcellulose and sodium dodecyl sulfate were added to the sieved material and mixed evenly in a wet granulator. 30% purified water was added to make a soft material, which was then passed through a 20-mesh sieve, dried at 55℃~65℃, and granulated by passing through a 20-mesh sieve.

[0108] The granulated material was added to the total mixture, followed by magnesium stearate, and mixed for 5 minutes. The resulting granules were then compressed into tablets with a weight of 132 mg and a hardness of 8–12 kg. The tablets were then coated with a film.

[0109] Comparative Example 2

[0110] The formulation is the same as in Example 2.

[0111] Finelendone crystal form I and microcrystalline cellulose were passed through a 40-mesh sieve. The sieved material, lactose monohydrate, croscarmellose sodium, hydroxypropyl methylcellulose, and sodium dodecyl sulfate were added to a mixing tank and mixed thoroughly. Magnesium stearate was then added and mixed for 5 minutes. The resulting granules were compressed into tablets with a weight of 132 mg and a hardness of 8–12 kg. The tablets were then coated with Opadry.

[0112] Comparative Example 3

[0113] The formulation is the same as in Example 2.

[0114] After mixing phenelzine crystal form I, lactose monohydrate, croscarmellose sodium, hydroxypropyl methylcellulose and sodium dodecyl sulfate evenly in a wet granulator, 30% purified water is added to make a soft material, which is then wet-granulated through a 20-mesh sieve, dried, and granulated again through a 20-mesh sieve.

[0115] The granulated particles were added to a mixing tank, microcrystalline cellulose was added and mixed thoroughly, and then magnesium stearate was added and mixed for 5 minutes to obtain the total granules. The mixture was then compressed into tablets with a weight of 132 mg and a hardness of 8–12 kg. Afterwards, the tablets were coated with a film.

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

[0117] According to the dissolution method of the United States Pharmacopeia and the second method of General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia, using a pH 4.5 acetate solution, 900 mL as the dissolution medium, and a rotation speed of 75 r / min, the solution was filtered online at 5, 10, 15, 20, 30, 45, and 60 min, and 1.8 mL of the solution was taken as the test solution. The dissolution results of Comparative Examples 1, 2, 3, Example 2, and the reference preparation are as follows. Figure 5 As 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 it could effectively promote the release.

[0119] Test Example 2 examines the effect of disintegrant dosage on the sample.

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

[0121] Table 2. Composition of disintegrant formulations with different proportions

[0122] Comparative Example 4 Comparative Example 5 Example 2 Comparative Example 6 Finazine 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％ Cross-linked carboxymethyl cellulose sodium 1.0％ 2.0％ 3.0％ 4.0％ Hydroxypropyl methylcellulose 4.0％ 4.0％ 4.0％ 4.0％ Sodium dodecyl 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 Pharmacopeia and the second method of General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia, using a pH 4.5 acetate solution, 900 mL as the dissolution medium, and a rotation speed of 75 r / min, the solution was filtered online at 5, 10, 15, 20, 30, 45, and 60 min, and 1.8 mL of the solution was taken as the test solution. The dissolution results of Comparative Examples 4, 5, 6, Example 2, and the reference preparation are as follows. Figure 6 As shown.

[0124] Test Example 3 Stability Test

[0125] Solution preparation:

[0126] 1. Mobile phase solution A: Weigh 3.4808 g of dipotassium hydrogen 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 sonicate for 10 min.

[0127] 2. Mobile phase B: Take 1000 mL of methanol and 1000 mL of acetonitrile, place them in a mobile phase bottle, shake well, and sonicate for 10 min.

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

[0129] 4. Sample Solution: The formulation product obtained in Example 2 was placed under high temperature, high humidity, and accelerated conditions, respectively. Three tablets of each of the samples under high temperature and high humidity conditions for 14 days and 30 days, and under accelerated conditions for 1 month and 2 months, were ground into a fine powder using an agate grinder. 350 mg of the fine powder (approximately equivalent to 26 mg of API) was accurately weighed and placed in a 20 mL volumetric flask. An appropriate amount of diluent was added, and the mixture was sonicated for 10 min to dissolve. After being cooled to room temperature, the solution was diluted to the mark with diluent and shaken well. Approximately 9 mL of this solution was centrifuged at 8000 rpm for 5 min. The supernatant was filtered through a 0.22 filter membrane. 1 mL of the initial filtrate was discarded, and the subsequent filtrate was used as the test solution.

[0130] Analytical method: HPLC analysis was performed on blank solution and sample solution.

[0131] Chromatographic conditions:

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

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

[0134] Mobile phase B: Acetonitrile

[0135] Column temperature: 30℃

[0136] Flow rate: 1.0 mL / 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 indicates not detected, NA indicates not applicable.

[0145] The results showed that the total impurities of the fenelazol tablets prepared in this invention remained essentially unchanged after 30 days of storage under high temperature and high humidity conditions and 2 months of storage under accelerated conditions (40℃ / RH 75%), with the increase of individual impurities all within 0.05%, and no significant changes in related substances. This indicates that the formulation of this invention has good stability.

[0146] The above description provides an exemplary account of the implementation methods of the technical solution disclosed herein. It should be understood that the scope of protection of this disclosure is not limited to the above-described embodiments. Any modifications, equivalent substitutions, or improvements made by those skilled in the art within the spirit and principles of this disclosure should be included within the scope of protection of the claims of this application.

Claims

1. A pharmaceutical composition comprising particles 1, particles 2, a disintegrant, and a lubricant, wherein: The particle 1 comprises a diluent 1 and a binder; The particle 2 comprises fenelinedone or a pharmaceutically acceptable salt thereof, diluent 2, binder and wetting agent; The phenelzine or a pharmaceutically acceptable salt thereof is selected from phenelzine crystal form I; wherein the phenelzine or a pharmaceutically acceptable salt thereof is obtained by crystallization of phenelzine in a mixture of methanol and water; the phenelzine crystal form I has an XRPD spectrum substantially as shown in Figure 1; The method for preparing the pharmaceutical composition includes the following steps: (1) Mix the components of particle 1 and granulate; (2) Mix the components of particle 2 and granulate them; (3) Mix the granules 1 obtained in step (1) and the granules 2 obtained in step (2) with the disintegrant and the lubricant to obtain the drug composition; The diluent 1 is microcrystalline cellulose; The diluent 2 is lactose monohydrate; The adhesive is hydroxypropyl methylcellulose; The wetting agent is sodium dodecyl sulfonate; The disintegrant is croscarmellose sodium cellulose; The lubricant is magnesium stearate.

2. The pharmaceutical composition according to claim 1, characterized in that, The non-nelinone crystal form I has a DSC spectrum as shown in Figure 2; And / or, the non-nelitone crystalline form I has a TGA spectrum as shown in Figure 3.

3. The pharmaceutical composition according to claim 1, characterized in that, In the pharmaceutical composition, fenelinone or a pharmaceutically acceptable salt thereof accounts for 6% to 16% of the total weight of the pharmaceutical composition; And / or, in the pharmaceutical composition, the weight of diluent 1 accounts for 30-60% of the total weight of the pharmaceutical composition; And / or, in the pharmaceutical composition, the weight of diluent 2 accounts for 20-50% of the total weight of the pharmaceutical composition; And / or, in the pharmaceutical composition, the weight of the binder accounts for 2% to 5% of the total weight of the pharmaceutical composition; And / or, in the pharmaceutical composition, the wetting agent accounts for 0.1% to 2.0% of the total weight of the pharmaceutical composition; And / or, in the pharmaceutical composition, the weight of the disintegrant accounts for 0.5% to 5.0% of the total weight of the pharmaceutical composition; And / or, in the pharmaceutical composition, the weight of the lubricant accounts for 0.25% to 5% of the total weight of the pharmaceutical composition.

4. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition is in the form of granules, capsules, or tablets.

5. The pharmaceutical composition according to claim 1, characterized in that, Granulation in steps (1) and (2) includes wet granulation and / or dry granulation steps; And / or, the preparation method further includes step (3), in which the particles 1 obtained in step (1) and the particles 2 obtained in step (2) are first mixed with a disintegrant to obtain mixture 1; then mixture 1 is mixed with a lubricant to obtain mixture 2; And / or, step (3) also includes a total mixing and tableting step; And / or, the preparation method further includes a step of pulverizing fenelone or a pharmaceutically acceptable salt thereof, wherein the pulverization method may be selected from air jet milling or mechanical milling.

6. The pharmaceutical composition according to claim 1, characterized in that, The preparation method includes: granulating microcrystalline cellulose and hydroxypropyl methylcellulose together, followed by wet granulation, drying, and dry granulation to obtain microcrystalline cellulose particles; granulating phenelzine crystal form I, lactose monohydrate, hydroxypropyl methylcellulose, and sodium dodecyl sulfate together, followed by wet granulation, drying, and dry granulation to obtain phenelzine particles; mixing microcrystalline cellulose particles, phenelzine particles, and croscarmellose sodium, then adding magnesium stearate and mixing, and finally compressing the mixture into tablets to obtain the pharmaceutical composition.

7. Use of the pharmaceutical composition according to any one of claims 1-6 in the preparation of a medicament for the prevention and / or treatment of a disease or symptom; The disease or condition mentioned is selected from kidney disease, type 2 diabetes-related chronic kidney disease.

8. The use according to claim 7, characterized in that, The disease is defined as an estimated glomerular filtration rate (eGFR) of 25 ≤ [eGFR] < 75 mL / min / 1.73 m 2 Diseases accompanied by albuminuria.

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