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 composition of the application has good dissolution 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 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. Previous studies have shown that Asian patients with type 2 diabetes mellitus (T2DM) are more prone to proteinuria and have higher levels of urinary protein. This may be related to the prevalence of salt-sensitive genes and high-salt dietary habits in Asian populations. 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 chronic kidney disease (CKD) due to the risks of cross-reactivity with sex steroid receptors and hyperkalemia. 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 and CKD. Long-term use can significantly reduce the urinary albumin-to-creatinine ratio (UACR) and has minimal impact on serum potassium levels. In June 2022, the China National Medical Products Administration (NMPA) approved fenelazol for adult patients with type 2 diabetes mellitus (T2DM)-related chronic kidney disease (CKD) to reduce the risk of persistently declining eGFR and end-stage renal disease. In May 2023, the NMPA updated the indications for fenelazol to include adult patients with T2DM-related CKD (with albuminuria) to reduce the risk of persistently declining eGFR, end-stage renal disease, cardiovascular death, and hospitalization due to heart failure.

[0005]

[0006] The inventors discovered that existing fenelazol formulations dissolve slowly, making it difficult to meet higher drug release requirements. Therefore, there is a need to develop fenelazol formulations with faster release rates and better dissolution. Summary of the Invention

[0007] To address the aforementioned technical problems, the present invention provides a pharmaceutical composition wherein the active ingredient of the pharmaceutical composition comprises phenelzine or a pharmaceutically acceptable salt thereof, and the unimodal particle size distribution D90 of the phenelzine or the 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 the fenelinone or its pharmaceutically acceptable salt 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 the fenelone or its pharmaceutically acceptable salt is 2.93-6.27 μm; preferably, the D50 is 2.93-4.62 μm.

[0010] According to an embodiment of the present invention, the unimodal particle size distribution D90 of the fenelone or its pharmaceutically acceptable salt 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 fenelone 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 fenelone or a pharmaceutically acceptable salt thereof is selected from fenelone crystal form I.

[0018] 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°.

[0019] 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°.

[0020] 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°.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] According to an embodiment of the present invention, the non-nelitone crystalline form I has essentially the following characteristics: Figure 4 The micrograph shown.

[0025] According to embodiments of the present invention, the pharmaceutical composition further comprises at least one selected from diluents, disintegrants, binders, wetting agents, and lubricants.

[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, dicalcium phosphate, dicalcium 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, croscarmellose sodium, croscarmellose polyvinylpyrrolidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, polyvinylpyrrolidone, pregelatinized starch, and alginate.

[0028] 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.

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

[0030] 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.

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

[0032] According to embodiments of the present invention, the weight of fenelinone or its pharmaceutically acceptable salt (such as fenelinone crystal 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%, and 15.15%.

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

[0034] According to embodiments 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%.

[0035] According to an embodiment of the present invention, 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%, and 4.5%.

[0036] According to embodiments 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%, and 1.8%.

[0037] According to embodiments 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%, and 4.5%.

[0038] 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%.

[0039] According to an embodiment of the present invention, the pharmaceutical composition comprises phenelzine crystal form I, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl methylcellulose, sodium dodecyl sulfate, and magnesium stearate.

[0040] According to embodiments of the present invention, the weight of feneline 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%, and 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%, and 55%.

[0042] According to embodiments 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%, and 45%.

[0043] According to an embodiment of the present invention, the weight of croscarmellose sodium 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%.

[0044] According to an embodiment of the present invention, the weight of hydroxypropyl methylcellulose 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%, and 4.5%.

[0045] According to an embodiment of the present invention, the sodium dodecyl 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%, and 1.8%.

[0046] According to an embodiment of the present invention, the 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%, and 4.5%.

[0047] According to an embodiment of the present invention, the pharmaceutical composition further includes a gastrointestinal film-coating premix as a coating; 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%, and 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 phenelzine crystal form I to granules a and sieving; adding a disintegrant and mixing; adding a lubricant and mixing; and compressing the mixture into tablets to obtain the pharmaceutical composition.

[0049] According to an embodiment of the present invention, the preparation method further includes a step of pulverizing phenelzine crystal form I, wherein the pulverization method may be selected from air jet milling or mechanical milling.

[0050] According to an embodiment of the present invention, the mesh size of the sieve is selected from 20-100 mesh, for example 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 includes: granulating lactose monohydrate, microcrystalline cellulose, hydroxypropyl methylcellulose and sodium dodecyl sulfate together to obtain granules a; adding phenelzine crystal form I to granules a and sieving them; then adding croscarmellose sodium; mixing again; then adding magnesium stearate; mixing again; and compressing to obtain the pharmaceutical composition.

[0052] 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.

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

[0054] (1) Mix phenelzine with methanol to obtain a mixture of phenelzine and methanol;

[0055] (2) Add water to the mixture of phenelzine and methanol obtained in step (1) to obtain a mixture of phenelzine, methanol and water.

[0056] (3) Crystallize the mixture of fenelitonee obtained in step (2) with methanol and water to obtain the fenelitonee crystal form I.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[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 can 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℃ to 80℃, for example 10℃ to 70℃, such as 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃.

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

[0067] 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.

[0068] 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, for example, 1 hour, 2 hours, 3 hours, or 4 hours.

[0069] 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℃.

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

[0071] 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.

[0072] 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.

[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 mixtures thereof.

[0075] 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.

[0076] 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.

[0077] 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℃.

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

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

[0080] The present invention also provides the use of the pharmaceutical composition for the preparation of a medicine.

[0081] According to an embodiment of the present invention, the drug is used for the prevention and / or treatment of diseases or conditions.

[0082] The present invention also provides methods for preventing and / or treating diseases or conditions, including administering a therapeutically effective amount of the pharmaceutical composition to a patient in need.

[0083] According to an embodiment of the present invention, the disease or condition is selected from diseases or symptoms related to mineralocorticoid receptors.

[0084] 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.

[0085] 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.

[0086] According to embodiments of the present invention, examples of the disease or condition are selected from at least one of the following: 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.

[0087] 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.

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

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

[0090] 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;

[0091] 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.

[0092] 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.

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

[0094] Beneficial effects

[0095] The pharmaceutical composition of the present invention exhibits good dissolution in a variety of media, and after formulation, it has good uniformity, tolerability, and particle size, with in vitro release effects consistent with the reference formulation. Attached Figure Description

[0096] Figure 1 XRPD spectrum of phenelzine crystal form I prepared in Example 1

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

[0098] Figure 3 TGA spectrum of phenelzine crystal form I prepared in Example 1

[0099] Figure 4 Micrograph of phenelzine crystal form I prepared in Example 1

[0100] Figure 5 Dissolution curve for test example 2

[0101] Figure 6 Dissolution curve for test example 3

[0102] Figure 7 The dissolution curve of the pH 1.2 medium in Test Example 5.

[0103] Figure 8 The dissolution curve of the pH 4.5 medium in Test Example 5.

[0104] Figure 9 The dissolution curve of the pH 6.8 medium in Test Example 5.

[0105] Figure 10 The dissolution curve of pH 1.2 medium in Test Example 6.

[0106] Figure 11 The dissolution curve of the pH 4.5 medium in Test Example 6.

[0107] Figure 12 The dissolution curve of the pH 6.8 medium in Test Example 6. Detailed Implementation

[0108] 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.

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

[0110] Reference preparation source: Bayer, 10 mg fenelitonee, batch number BXK04F1.

[0111] All temperatures mentioned in this invention refer to the temperature inside the reaction vessel.

[0112] Example 1: Preparation of Finelendone Crystal Form I

[0113] 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.

[0114] Example 2: Formulation containing phenelzine crystal form I

[0115] The formulation is shown in Table 1. Finelendone crystal form I is derived from Example 1, and the active pharmaceutical ingredient has a particle size D90 of 15 μm.

[0116] Table 1. Formulation of 10mg fenelinone preparation

[0117]

[0118] Preparation method:

[0119] Lactose monohydrate and microcrystalline cellulose were added to a fluidized bed, and a binder made of hydroxypropyl methylcellulose and sodium dodecyl sulfate was sprayed in. The mixture was then granulated, dried, and passed through a 20-mesh sieve to obtain granules a.

[0120] After pulverizing phenelzine crystal form I, it was added to granules a and passed through a 40-mesh sieve. It was then transferred to a mixing tank along with croscarmellose sodium and mixed thoroughly. Magnesium stearate was added to the above mixture and mixed for 5 minutes to obtain total granules. These granules were then compressed into tablets with a weight of 132 mg and a hardness of 8–12 kg. Opadry was then used for film coating.

[0121] Example 3: Formulation 2 containing phenelzine crystal form I

[0122] The formulation is shown in Table 2. Finelendone crystal form I is derived from Example 1. The particle size of the active pharmaceutical ingredient is D90: 15 μm. The formulation preparation method is as described in Example 2.

[0123] Table 2. Formulation of 20mg fenelinone preparation

[0124]

[0125] Example 4: Investigation of Particle Size of Active Pharmaceutical Ingredient

[0126] The following API particle sizes were obtained by air jet milling and mechanical milling of phenelzine crystal form I:

[0127] Table 3. Particle size of raw materials by different pulverization methods

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

[0129] Finelone crystal form I was derived from Example 1.

[0130] Referring to the formulation and preparation method of Example 2, the above-mentioned active pharmaceutical ingredients with different particle sizes were used to prepare formulations, resulting in formulations of Examples 4-1, 4-2, 4-3, 4-4, 4-5, and 4-6, respectively.

[0131] Comparative Example 1

[0132] The formulation is the same as in Example 2. Finelendone crystal form I is derived from Example 1. The particle size of the active pharmaceutical ingredient is 15 μm.

[0133] 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. The mixture was then placed in a wet granulator and mixed evenly. 30% purified water was added to make a soft material. The mixture was then passed through a 20-mesh sieve for wet granulation, dried, and passed through a 20-mesh sieve for dry granulation.

[0134] The granulated material was added to the total mixture, along with 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 using Opadry.

[0135] Comparative Example 2

[0136] The formulation is the same as in Example 2. Finelendone crystal form I is derived from Example 1. The particle size of the active pharmaceutical ingredient is 15 μm.

[0137] 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 added and mixed for 5 minutes to obtain total granules. These granules were then compressed into tablets with a weight of 132 mg and a hardness of 8–12 kg. Opadry was then used for film coating.

[0138] Comparative Example 3

[0139] The formulation is the same as in Example 2. Finelendone crystal form I is derived from Example 1. The particle size of the active pharmaceutical ingredient is 15 μm.

[0140] Finelynone crystal form I, lactose monohydrate, croscarmellose sodium, hydroxypropyl methylcellulose, and sodium dodecyl sulfate were mixed evenly in a wet granulator. Then, 30% purified water was added to form a soft mass, which was wet-granulated through a 20-mesh sieve, dried, and then dry-granulated through another 20-mesh sieve. The granulated particles were added to a mixing tank, microcrystalline cellulose was added and mixed evenly, and then magnesium stearate was added and mixed for 5 minutes to obtain the final mixed granules. These 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.

[0141] Test Example 1: Solubility Test

[0142] Solubility experiments were conducted on phenelzine crystal form I prepared in Example 1 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 pH 4.5 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 fenelone crystal form I raw material gradually decreased with increasing pH. In a pH 6.8 medium, the solubility of 20 mg specification could not reach the sink condition and could not be completely dissolved.

[0147] Test Example 2: Dissolution Tests for Different Preparation Processes

[0148] According to the United States Pharmacopeia dissolution method and the Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II, using a pH 4.5 acetate solution, 900 mL as the dissolution medium, and a rotation speed of 75 r / min, online filtration was performed at 5, 10, 15, 20, 30, 45, and 60 min, and 1.8 mL of the solution was collected 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.

[0149] The results showed that, by controlling the particle size D90 of the active pharmaceutical ingredient to 15 μm, the preparation processes of the formulations of Comparative Examples 1, 2, and 3 were different from those of Example 2. The dissolution and release of Example 2 was faster, the dissolution endpoint was higher, and it was closer to the reference.

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

[0151] 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 the formulations of Examples 4-2, 4-3, 4-4, 4-5, and 4-6, as well as the reference formulation, are shown in Table 5. Figure 6 As shown.

[0152] Table 5 Dissolution test results

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

[0154] The data above show that when the particle size of the active pharmaceutical ingredient (API) is less than 22 μm, the formulation sample prepared using phenelzine crystal form I in Example 1 can produce a sample with the same release as the reference.

[0155] Test Example 4: Content Uniformity Examination

[0156] Content uniformity during granulation process:

[0157] The preparation process of Example 2 was followed for scale-up mass production. The formulation and process were confirmed, and the mixing uniformity was investigated. During the final mixing process, two samples of 1.5g each were taken from the upper, middle, and lower positions of the mixing tank. The test results are shown in Table 6.

[0158] Table 6 Results of the uniformity of content in the total blending process

[0159]

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

[0161] Test Example 5: Investigation of Solubility in Different Dissolution Media

[0162] Following the preparation process of Example 2, large-scale production was carried out to confirm the formulation and process, and the release curves of the prepared samples in media at pH 1.2, 4.5 and 6.8 were detected.

[0163] Following the dissolution method of the United States Pharmacopeia and the second method of General Chapter 0931 in Part IV of the 2020 Chinese Pharmacopoeia, 900 mL of hydrochloric acid solution (pH 1.2), acetate solution (pH 4.5), and phosphate solution (pH 6.8) were used as the dissolution medium. The dissolution was performed at a rotation speed of 50 rpm for 5, 10, 15, 20, 30, 45, 60, 75, and 90 min, followed by online filtration. 1.8 mL of each solution was collected as the test solution. The dissolution results in pH 1.2 hydrochloric acid solution are as follows: Figure 7 As shown, the dissolution results in an acetate solution at pH 4.5 are as follows: Figure 8 As shown, the dissolution results in a pH 6.8 phosphate solution are as follows: Figure 9 As 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 media, the dissolution rate was greater than 85% at 15 min, and the in vitro release was consistent with the reference.

[0165] Test Example 6: Dissolution Investigation of 20mg Sample in Different Dissolution Media

[0166] For Example 3, the consistency of dissolution of the 20mg specification product with that of Example 2 was confirmed by measuring its release in media at pH 1.2, 4.5 and 6.8.

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

[0168] Following the dissolution method of the United States Pharmacopeia and the second method of General Chapter 0931 in Part IV of the 2020 Chinese Pharmacopoeia, 900 mL of hydrochloric acid solution (pH 1.2), acetate solution (pH 4.5), and phosphate solution (pH 6.8) were used as the dissolution medium. The dissolution was performed at a rotation speed of 50 rpm for 5, 10, 15, 20, 30, 45, 60, 75, and 90 min, followed by online filtration. 1.8 mL of each solution was collected as the test solution. The dissolution results in pH 1.2 hydrochloric acid solution are as follows: Figure 10 As shown, the dissolution results in an acetate solution at pH 4.5 are as follows: Figure 11 As shown, the dissolution results in a pH 6.8 phosphate solution are as follows: Figure 12 As 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 media, the dissolution rate was greater than 85% at 15 min, 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 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.

[0173] 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.

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

[0175] 4. Sample Solution: The formulation product obtained in Example 2 was placed under high temperature, high humidity, and light conditions. Three tablets each of the 14-day and 30-day samples 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 cooling 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.

[0176] Analytical method: HPLC analysis was performed on blank solution and sample solution.

[0177] Chromatographic conditions:

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

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

[0180] Mobile phase B: Acetonitrile

[0181] Column temperature: 30℃

[0182] Flow rate: 1.0 mL / 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. Sample stability test results for Example 2

[0188]

[0189] The results showed that the total impurities of the fenelitonee tablets prepared by the present invention did not change significantly after being placed under high temperature, high humidity and light conditions for 30 days, and the growth of individual impurities was within 0.05%, indicating that the formulation of the present invention has good stability.

[0190] 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 wherein the active ingredient of the pharmaceutical composition comprises phenelzine or a pharmaceutically acceptable salt thereof, wherein the phenelzine or a pharmaceutically acceptable salt thereof has a unimodal particle size distribution D90 of less than 6.37 μm; The phenelzanol or a pharmaceutically acceptable salt thereof is selected from phenelzanol crystal form I; wherein... The phenelzanol or its pharmaceutically acceptable salt is obtained by crystallization of phenelzanol in a mixture of methanol and water; The preparation method of the pharmaceutical composition includes the following steps: granulating a diluent, a binder and a wetting agent together to obtain granules A; adding phenelzine crystal form I to granule A and sieving; adding a disintegrant, mixing; adding a lubricant, mixing; and compressing to obtain the pharmaceutical composition. The diluent is lactose monohydrate and microcrystalline cellulose; The disintegrant is croscarmellose sodium cellulose; The adhesive is hydroxypropyl methylcellulose; The wetting agent is sodium dodecyl sulfonate; The lubricant is magnesium stearate.

2. The pharmaceutical composition according to claim 1, characterized in that, The unimodal particle size distribution D10 of the fenelone or its pharmaceutically acceptable salt is 1.54-2.07 μm; And / or, the unimodal particle size distribution D50 of the fenelone or its pharmaceutically acceptable salt is 2.93-6.27 μm; And / or, the unimodal particle size distribution D90 of the fenelone or its pharmaceutically acceptable salt is 4.95-5.4 μm.

3. The pharmaceutical composition according to claim 1, characterized in that, The unimodal particle size distribution D10 of the fenelone or its pharmaceutically acceptable salt is 1.54-1.73 μm; And / or, the unimodal particle size distribution D50 of the fenelone or its pharmaceutically acceptable salt is 2.93-4.62 μm.

4. The pharmaceutical composition according to claim 1, characterized in that, The weight of feneline or a pharmaceutically acceptable salt thereof in the pharmaceutical composition accounts for 6% to 16% of the total weight of the pharmaceutical composition; And / or, the weight of the diluent in the pharmaceutical composition accounts for 50-90% of the total weight of the pharmaceutical composition; And / or, the weight of the disintegrant in the pharmaceutical composition accounts for 0.5% to 5.0% of the total weight of the pharmaceutical composition; And / or, the binder in the pharmaceutical composition accounts for 2% to 5% of the total weight of the pharmaceutical composition; And / or, the wetting agent in the pharmaceutical composition accounts for 0.1% to 2.0% of the total weight of the pharmaceutical composition; And / or, the weight of the lubricant in the pharmaceutical composition accounts for 0.25% to 5% of the total weight of the pharmaceutical composition.

5. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition comprises phenelzine crystal form I, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl methylcellulose, sodium lauryl sulfate, and magnesium stearate; And / or, the weight of microcrystalline cellulose in the pharmaceutical composition accounts for 30% to 60% of the total weight of the pharmaceutical composition; And / or, the weight of lactose monohydrate in the pharmaceutical composition accounts for 20% to 50% of the total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to claim 1, characterized in that, The preparation method includes: granulating lactose monohydrate, microcrystalline cellulose, hydroxypropyl methylcellulose and sodium dodecyl sulfate together to obtain granules a; adding phenelzine crystal form I to granules a and sieving; then adding croscarmellose sodium; mixing; then adding magnesium stearate; mixing; and compressing 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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