Pharmaceutical composition of fenerenone and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and discloses a pharmaceutical composition of fenerenone, which is prepared from the following components in percentage by weight: 4 to 10 percent of fenerenone, 2 to 15 percent of emulsifier, 60 to 90 percent of filler, 2 to 15 percent of disintegrating agent and 0.5 to 1.5 percent of lubricant. The invention discloses a preparation method of the pharmaceutical composition of the fenerenone, which comprises the following steps: dispersing the fenerenone in a solvent, adding an emulsifier, stirring to obtain a fenerenone dispersion liquid, mixing the fenerenone dispersion liquid with purified water, homogenizing to obtain a nano liquid crystal suspension, dispersing the suspension on a filler and a disintegrating agent, and drying to obtain the pharmaceutical composition of the fenerenone. And carrying out wet granulation to obtain particles, and drying to obtain granulated particles. According to the invention, the fenerenone is dispersed in the emulsifier, so that the raw materials are prevented from being clustered, the solubility of the fenerenone is improved, the fenerenone in the prepared composition is uniformly dispersed and has better stability, and the preparation process is simple and easy for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of finerenone and a preparation method thereof. BACKGROUND

[0002] Finerenone, chemical name: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide, molecular formula: C 21 H 22 N4O3, the structural formula is as follows:

[0003]

[0004] Finerenone is a non-steroidal selective mineralocorticoid receptor (MR) antagonist, which can be used for treating chronic kidney disease (CKD) and existing tablet and heart failure (HF) patients.

[0005] Patent CN116655627A uses a fluidized bed granulation process to disperse finerenone and sodium dodecyl sulfate in an aqueous dispersion medium, uses a fluidized bed top spray granulation method to spread the dispersed drug on a granulation carrier for granulation and further tabletting to obtain tablets, but finerenone has low solubility, and needs to be dispersed in a large amount of aqueous base after spraying and granulating, which has a long granulation time, high energy consumption, and causes the base to be excessively wetted and formed into a mass after using a large amount of aqueous base. If the drug is directly added to a high-shear wet granulation kettle for shearing and stirring, the dispersion uniformity and wettability are poor, which will adversely affect the drug efficacy.

[0006] Therefore, it is necessary to provide a composition capable of reducing the amount of aqueous base and improving the dispersion and dissolution of the drug and a preparation method thereof. SUMMARY

[0007] The present application aims at the shortcomings and deficiencies in the prior art, and provides a finerenone composition and a preparation method thereof. In the preparation method of the finerenone pharmaceutical composition of the present application, the finerenone is dispersed in an emulsifier to avoid the formation of a mass of raw materials, thereby improving the solubility of the finerenone. The composition prepared by the method has uniform dispersion of finerenone, good stability, and simple preparation process, and is easy to industrialize.

[0008] The purpose of the present application is achieved by the following technical scheme:

[0009] A pharmaceutical composition of finerenone is prepared from the following components by weight percentage:

[0010] Finerenone 4% to 10%

[0011] Emulsifier 2% to 15%

[0012] Filler 60% to 90%

[0013] Disintegrant 2% to 15%

[0014] Lubricant 0.5% to 1.5%.

[0015] Preferably, the pharmaceutical composition of finerenone is made from components comprising the following weight percentages:

[0016] Finerenone 4% to 10%

[0017] Emulsifier 4% to 13%

[0018] Filler 68% to 85%

[0019] Disintegrant 4% to 12%

[0020] Lubricant 0.8% to 1%.

[0021] More preferably, the pharmaceutical composition of finerenone is made from components comprising the following weight percentages:

[0022] Finerenone 4.5% to 9%

[0023] Emulsifier 4.5% to 13%

[0024] Filler 68% to 83%

[0025] Disintegrant 4.5% to 9%

[0026] Lubricant 0.8% to 1%.

[0027] In particular, the pharmaceutical composition of finerenone is made from components comprising the following weight percentages:

[0028] Finerenone 9%

[0029] Emulsifier 9%

[0030] Filler 72.1%

[0031] Disintegrant 9%

[0032] Lubricant 0.9%;

[0033] or

[0034] Finerenone 9%

[0035] Emulsifier 4.5%

[0036] Filler 81.1%

[0037] Disintegrant 4.5%

[0038] Lubricant 0.9%;

[0039] or

[0040] Finasteride 8.62%

[0041] Emulsifier 12.93%

[0042] Filler 68.97%

[0043] Disintegrant 8.62%

[0044] Lubricant 0.86%;

[0045] or

[0046] Finasteride 4.6%

[0047] Emulsifier 6.9%

[0048] Filler 83%

[0049] Disintegrant 4.6%

[0050] Lubricant 0.9%.

[0051] The dosage form of the pharmaceutical composition of finasteride according to the present application is granules, tablets, and capsules.

[0052] Another object of the present application is to provide a preparation method of the pharmaceutical composition of finasteride, comprising: dispersing finasteride in a solvent, adding an emulsifier and stirring to obtain a finasteride dispersion liquid, mixing the finasteride dispersion liquid with purified water, and homogenizing to obtain a nanocrystal suspension liquid, dispersing the suspension liquid in a carrier (filler and disintegrant), and wet granulating to obtain granules, and drying to obtain granulated granules.

[0053] Specifically comprising the following steps:

[0054] Step (1), dispersing finasteride in a solvent, adding an emulsifier, and stirring to obtain a finasteride dispersion liquid;

[0055] Step (2), slowly adding purified water to the finasteride dispersion liquid, and homogenizing to obtain a nanocrystal suspension liquid;

[0056] Step (3), dispersing the nanocrystal suspension liquid in a filler and a disintegrant, wet granulating to obtain granules, and drying to obtain granulated granules.

[0057] The emulsifier is polysorbate 80 or sodium taurocholate.

[0058] The weight ratio of the finerenone to the emulsifier is (1-3):(3-1).

[0059] Preferably, the weight ratio of the finerenone to the emulsifier is 1:0.5-1:1.5.

[0060] The solvent is anhydrous ethanol, 95% ethanol or purified water, preferably anhydrous ethanol or 95% ethanol.

[0061] The weight ratio of the finerenone to the solvent is 1:1-4:1.

[0062] Specifically, the weight ratio of the finerenone to the solvent is 1:1, 2:1, 4:3 or 4:1.

[0063] The weight ratio of the solvent in step (1) to the purified water in step (2) is 1:2.5-1:12. By controlling the proportion of purified water, the present application avoids excessive water from causing the finerenone to form large crystals.

[0064] The homogenization is performed 2-3 times, each time for 3 min at 15000 rpm. The homogenization is performed using a homogenizer.

[0065] The weight ratio of the filler to the disintegrant is 8:1-18:1. The filler is microcrystalline cellulose, and the disintegrant is one or a combination of cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose.

[0066] The wet granulation is performed using a high-shear wet granulator.

[0067] As a preferred technical solution of the preparation method of the finerenone pharmaceutical composition, the granules are sieved through a 40-mesh screen, mixed with a lubricant, and then tableted to obtain tablets or filled into capsules to obtain a capsule.

[0068] The lubricant is magnesium stearate.

[0069] The present application has the following advantages:

[0070] 1. The high-concentration emulsifier and the finerenone are mixed to obtain a nanocrystal suspension, which can be directly mixed with a carrier by a pouring dispersion method to obtain well-dispersed intermediate particles, thereby increasing the dispersion area of the finerenone raw material in the preparation, changing the existing form, and improving the solubility of the finerenone.

[0071] 2. Compared with the existing fluidized bed process, the nanocrystal suspension of the present application can be granulated by a common wet granulation process, thereby effectively shortening the granulation time and energy consumption.

[0072] 3. The method of the present application has low content difference and high dissolution rate of finerenone tablets compared with conventional wet granulation method. DETAILED DESCRIPTION

[0073] In order to make the technical solutions of the present application more easily and clearly understood, the technical solutions of the present application will be further described in detail below in combination with specific examples, but the examples of the present application do not constitute a limitation on the scope of the present application.

[0074] The crosslinked povidone is PVP K30.

[0075] Table 1. Formulation of Composition 1-Composition 3

[0076]

[0077] Example 1

[0078] The formulation of the finerenone pharmaceutical composition (Composition 1) is shown in Table 1, and the preparation method comprises the following steps:

[0079] Step (1), premixing: disperse finerenone in ethanol, add polysorbate 80, stir evenly to obtain a finerenone dispersion (denoted as material 1);

[0080] Step (2), homogenization: slowly add purified water to material 1, and process 3 times with a homogenizer at 15000 rpm for 3 min each time to obtain a nanocrystal suspension (denoted as material 2). The nanocrystal suspension obtained by homogenization forms a nanocrystal dispersion state with a multi-distribution and an average particle size of not more than 1 μm;

[0081] Step (3), granulation: add material 2, microcrystalline cellulose and crosslinked povidone into a high-shear wet granulator, stir and shear to disperse evenly to obtain granulation particles, and dry;

[0082] Step (4), pass the dried particles through a 40-mesh sieve, then add magnesium stearate and mix evenly;

[0083] Step (5), tabletting to obtain finerenone tablets.

[0084] Example 2

[0085] The formulation of the finerenone pharmaceutical composition (Composition 2) is shown in Table 1, and the preparation method comprises the following steps:

[0086] Step (1), premixing: disperse finerenone in ethanol, add polysorbate 80, stir evenly to obtain a finerenone dispersion (denoted as material 1);

[0087] Step (2), homogenization: purified water was slowly added to material 1, and the mixture was treated by a homogenizer for 3 times, 15000 rpm for 3 min each time, to obtain a nanocrystal suspension (denoted as material 2). The nanocrystal suspension obtained by homogenization formed a nanocrystal dispersion state with a multi-distribution and an average particle size of not more than 1 μm;

[0088] Step (3), granulation: material 2, microcrystalline cellulose and crospovidone were added into a high-shear wet granulator, and stirred and sheared to disperse uniformly, to obtain granulation particles, which were dried;

[0089] Step (4), the dried particles were passed through a 40-mesh sieve, and then magnesium stearate was added and mixed uniformly;

[0090] Step (5), tabletting, to obtain finerenone tablets.

[0091] Example 3

[0092] The prescription of the finerenone pharmaceutical composition (composition 3) is shown in Table 1, and the preparation method comprises the following steps:

[0093] Step (1), premixing: finerenone was dispersed in ethanol, and polysorbate 80 was added and stirred uniformly, to obtain a finerenone dispersion (denoted as material 1);

[0094] Step (2), homogenization: purified water was slowly added to material 1, and the mixture was treated by a homogenizer for 3 times, 15000 rpm for 3 min each time, to obtain a nanocrystal suspension (denoted as material 2). The nanocrystal suspension obtained by homogenization formed a nanocrystal dispersion state with a multi-distribution and an average particle size of not more than 1 μm;

[0095] Step (3), granulation: material 2, microcrystalline cellulose and crospovidone were added into a high-shear wet granulator, and stirred and sheared to disperse uniformly, to obtain granulation particles, which were dried;

[0096] Step (4), the dried particles were passed through a 40-mesh sieve, and then magnesium stearate was added and mixed uniformly;

[0097] Step (5), tabletting, to obtain finerenone tablets.

[0098] Table 2. Prescription of compositions 4-6

[0099]

[0100] Example 4

[0101] The prescription of the finerenone pharmaceutical composition (composition 4) is shown in Table 2, and the preparation method comprises the following steps:

[0102] Step (1), premixing: disperse finerenone in ethanol, add sodium taurocholate, stir evenly to obtain a finerenone dispersion (denoted as material 1);

[0103] Step (2), homogenization: slowly add purified water to material 1, use a homogenizer to process 3 times, 15000 rpm each time for 3 min, to obtain a nanocrystal suspension (denoted as material 2), the nanocrystal suspension obtained by homogenization forms a nanocrystal dispersion state with a multi-distribution and an average particle size of not more than 1 μm;

[0104] Step (3), granulation: add material 2, microcrystalline cellulose and crospovidone to a high-shear wet granulator, stir and shear to disperse evenly, to obtain granulation particles, dry;

[0105] Step (4), pass the dried particles through a 40-mesh sieve, then add magnesium stearate, mix evenly;

[0106] Step (5), tabletting, to obtain finerenone tablets.

[0107] Example 5

[0108] The prescription of the finerenone pharmaceutical composition (composition 4) is shown in Table 2, and the preparation method comprises the following steps:

[0109] Step (1), premixing: disperse finerenone in ethanol, add sodium taurocholate, stir evenly to obtain a finerenone dispersion (denoted as material 1);

[0110] Step (2), homogenization: slowly add purified water to material 1, use a homogenizer to process 3 times, 15000 rpm each time for 3 min, to obtain a nanocrystal suspension (denoted as material 2), the nanocrystal suspension obtained by homogenization forms a nanocrystal dispersion state with a multi-distribution and an average particle size of not more than 1 μm;

[0111] Step (3), granulation: add material 2, microcrystalline cellulose and crospovidone to a high-shear wet granulator, stir and shear to disperse evenly, to obtain granulation particles, dry;

[0112] Step (4), pass the dried particles through a 40-mesh sieve, then add magnesium stearate, mix evenly;

[0113] Step (5), tabletting, to obtain finerenone tablets.

[0114] Example 6

[0115] The prescription of the finerenone pharmaceutical composition (composition 4) is shown in Table 2, and the preparation method comprises the following steps:

[0116] Step (1), premixing: disperse finerenone in ethanol, add sodium taurocholate, stir evenly to obtain a finerenone dispersion, denoted as material 1;

[0117] Step (2), homogenization: slowly add purified water to material 1, and process 3 times with a homogenizer at 15000 rpm for 3 min each time to obtain a nanocrystal suspension (denoted as material 2). The nanocrystal suspension obtained by homogenization forms a nanocrystal dispersion state with a multi-distribution and an average particle size of not more than 1 μm;

[0118] Step (3), granulation: add material 2, microcrystalline cellulose and crospovidone to a high-shear wet granulator, and stir and shear to disperse evenly to obtain granulation particles, and dry;

[0119] Step (4), pass the dried granules through a 40-mesh sieve, and then add magnesium stearate and mix evenly;

[0120] Step (5), tabletting to obtain finerenone tablets.

[0121] Comparative Example 1

[0122] The prescription of the finerenone pharmaceutical composition is shown in Table 3, and the preparation method is as follows: disperse finerenone in the prescribed amount of ethanol, add purified water to obtain a finerenone dispersion; mix and disperse microcrystalline cellulose and crospovidone in a wet granulation kettle, then add the finerenone dispersion to granulate, obtain granulation particles, dry, mix the dried granules with magnesium stearate, and tablet to obtain finerenone tablets.

[0123] Table 3. Prescription of finerenone pharmaceutical composition of Comparative Example 1

[0124]

[0125] Example 7

[0126] The stability test of the accelerated condition was carried out on the sample of the example and the sample of the comparative example, the accelerated condition: 40℃±2℃, 75%RH±5%RH, the oxidative degradation impurity 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-formamide was investigated, and the investigation results are shown in Table 4. It can be seen that the oxidative impurity of the tablet prepared by the method is lower than that of the comparative example.

[0127] Table 4. Investigation results of oxidative degradation impurities

[0128]

[0129] The non-aleplon content uniformity of the dried granules was determined, and the results are shown in Table 5. It can be seen that, compared with the conventional wet granulation method, the content RSD of the granules obtained by the present application is smaller, and the content uniformity is better.

[0130] Table 5. Content uniformity test results

[0131]

[0132] Non-aleplon dissolution test

[0133] The dissolution of the samples of Examples 1-6 and the sample of Comparative Example 1 was determined according to the dissolution and release test method (Chinese Pharmacopoeia 2025 edition four general rules 0931 second method). The dissolution test method is as follows: second method paddle method, dissolution medium: 900 mL (pH 4.5 acetic acid buffer salt + 0.1% Tween-20 solution), medium temperature: 37.0℃ ± 0.5℃, rotation speed: 75 rpm, sampling time 30 min. The results are shown in Table 6. It can be seen that the dissolution results of the tablets compressed by the present application in the standard medium are better than those of the comparative example, and meet the set dissolution limit value of 85%.

[0134] Table 6. Dissolution test results

[0135]

Claims

1. A pharmaceutical composition of non-nalestone, characterized by: It is made of components including the following weight percentage: Fenofibrate 4%~10% Emulsifier 2%~15% Filler 60%~90% Disintegrant 2%~15% Lubricant 0.5%~1.5%; Wherein, the emulsifier is polysorbate 80 or sodium taurocholate.

2. The pharmaceutical composition of non-neglitinide according to claim 1, characterized by: It is made of components including the following weight percentage: Fenofibrate 4%~10% Emulsifier 4%~13% Filler 68%~85% Disintegrant 4%~12% Lubricant 0.8~1%.

3. The pharmaceutical composition of non-neglitinide according to claim 2, characterized by: It is made of components including the following weight percentage: Fenofibrate 4.5%~9% Emulsifier 4.5%~13% Filler 68%~83% Disintegrant 4.5%~9% Lubricant 0.8%~1%.

4. The pharmaceutical composition of finerenone according to claim 1, 2 or 3, characterized in that: The dosage form of the fenofibrate pharmaceutical composition is granules, tablets, capsules.

5. The pharmaceutical composition of finerenone according to claim 1, 2 or 3, characterized in that: The weight ratio of the fenofibrate to the emulsifier is (1~3):(3~1), preferably 1:0.5~1:1.

5.

6. The pharmaceutical composition of finerenone according to claim 1, 2 or 3, characterized in that: The filler is microcrystalline cellulose; the disintegrant is one or a combination of cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose; and the lubricant is magnesium stearate.

7. A process for the preparation of a pharmaceutical composition of non- nelineum claimed in claim 1 characterized by: Including the following steps: Step (1), dispersing fenofibrate in a solvent, adding an emulsifier, stirring uniformly to obtain a fenofibrate dispersion; Step (2), slowly adding purified water to the fenofibrate dispersion, homogenizing to obtain a nanometer liquid crystal suspension; Step (3), dispersing the nanometer liquid crystal suspension on the filler and disintegrant, wet granulating to obtain granules, drying to obtain granulated particles.

8. The method of preparing a pharmaceutical composition of non-nailumab according to claim 7, characterized by: In step (1), the solvent is anhydrous ethanol, 95% ethanol or purified water, preferably anhydrous ethanol or 95% ethanol; the weight ratio of the fenofibrate to the solvent is 1:1~4:1; the weight ratio of the solvent in step (1) to the purified water in step (2) is 1:2.5~1:

12.

9. The method of preparing a pharmaceutical composition of non-negligible according to claim 7, characterized in that: The number of homogenization is 2~3 times; each time 15000rpm for 3min.

10. The method of preparing a pharmaceutical composition of non-negligible according to claim 7, characterized in that: Including: Pass the granulated particles through a 40-mesh screen, mix uniformly with the lubricant, and press into tablets to obtain tablets, or fill into capsules to obtain capsules.

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