Fnerenone orally disintegrating tablet and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a fenerenone orally disintegrating tablet and a preparation method thereof. The active component of the fenerenone orally disintegrating tablet is fenerenone, and the fenerenone orally disintegrating tablet comprises the following components in percentage by weight: 10-15% of fenerenone, 10-15% of magnesium stearate, 10-15% of magnesium stearate and the balance of 70-80% of a filler; 5.5-10% of a disintegrating agent; 1-4% of a flow aid; and 1-4% of a lubricant. The finerenone orally disintegrating tablet disclosed by the invention is suitable for being taken by diabetics, and has the advantages of high disintegration and dissolution speed, stable finished product quality, no need of being taken with water and strong patient compliance; in addition, the finerenone orally disintegrating tablet disclosed by the invention is simple in preparation process, low in cost and suitable for large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a finerenone orally disintegrating tablet and a preparation method thereof. Background Art

[0002] Finerenone (BAY 94-8862) is a non-steroidal selective mineralocorticoid receptor antagonist developed by Bayer, and its structural formula is as follows:

[0003]

[0004] In July 2021, based on the positive results of the FIDELIO-DKD Phase III clinical study in adult patients with chronic kidney disease and type 2 diabetes, the U.S. FDA approved finerenone ( ) is on the market. In December 2021, the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended approval of the marketing application for the non-steroidal selective mineralocorticoid receptor antagonist finerenone, recommending finerenone (10 mg or 20 mg) for the treatment of adult patients with chronic kidney disease (stages 3 and 4 with albuminuria) and type 2 diabetes. In June 2022, it was approved by the China National Medical Products Administration (NMPA). On May 18, 2023, Bayer announced that the China National Medical Products Administration (NMPA) had approved the The applicable population of fenarezone (finerenone tablets, 10 mg or 20 mg) has been expanded to the early stages of chronic kidney disease associated with type 2 diabetes, and cardiovascular-related benefits (reducing the risk of cardiovascular death and hospitalization for heart failure) have been included in the indications.

[0005] Currently, the marketed finerenone is only available in ordinary tablets, but if the patient is an elderly person or has difficulty swallowing, there may be a risk of swallowing, especially for some chronic kidney disease patients whose water intake is limited, and ordinary tablets need to be taken with water. This is inconvenient for patients who need to control their water intake. For some special patients, such as patients with mental illness, Alzheimer's disease, epilepsy, etc., good medication compliance is crucial. However, so far, there are no documents or patents disclosing finerenone orally disintegrating tablets and related processes.

[0006] Therefore, it is necessary to develop a finerenone orally disintegrating tablet that has good patient compliance, is easy to use, has a rapid onset of action, and is easy to industrialize and produce. Summary of the invention

[0007] The purpose of the present invention is to provide a finerenone orally disintegrating tablet for diabetic patients, which has fast disintegration and dissolution, stable finished product quality, no need for water delivery, and strong patient compliance; in addition, the present invention also provides a preparation method of the finerenone orally disintegrating tablet, which has simple process, low cost and is suitable for large-scale production.

[0008] One of the purposes of the present invention is to provide a finerenone orally disintegrating tablet, which comprises, by weight percentage, 10-15% of finerenone; 70-80% of a filler; 5.5-10% of a disintegrant; 1-4% of a glidant; and 1-4% of a lubricant.

[0009] In some embodiments of the present invention, the disintegrant is at least one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

[0010] In some embodiments of the present invention, the disintegrant is one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose, and the content of the disintegrant is 10%, preferably cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose.

[0011] In some embodiments of the present invention, the disintegrant is a combination of two of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose, and the total content of the two disintegrants is 8%.

[0012] In some embodiments of the present invention, the disintegrant is a combination of two of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

[0013] In some embodiments of the present invention, the disintegrant is a combination of cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose, and the mass ratio of cross-linked polyvinylpyrrolidone to cross-linked sodium carboxymethyl cellulose is 1:3 to 3:1.

[0014] In some embodiments of the present invention, the mass ratio of crospovidone to croscarboxymethyl cellulose sodium is 3:1.

[0015] In some embodiments of the present invention, the finerenone particle size is 50% smaller than 150 μm, and 90% smaller than 210 μm; preferably, the finerenone particle size is 50% smaller than 105 μm, and 90% smaller than 125 μm.

[0016] In some embodiments of the present invention, the filler is at least one of microcrystalline cellulose, mannitol, starch, lactose, sucrose, sorbitol, xylitol, and maltodextrin, preferably mannitol and microcrystalline cellulose.

[0017] In some embodiments of the present invention, the glidant is at least one of gel silicon dioxide, micro-powder silica gel, and talcum powder, preferably gel silicon dioxide.

[0018] In some embodiments of the present invention, the lubricant is at least one of calcium stearate, sodium stearate fumarate or magnesium stearate, preferably magnesium stearate.

[0019] In some embodiments of the present invention, the finerenone orally disintegrating tablet comprises, by weight percentage, 10-15% finerenone; 23-30% microcrystalline cellulose; 45-55% mannitol; 2-6% cross-linked polyvinylpyrrolidone; 2-6% cross-linked sodium carboxymethyl cellulose; 1-4% gel silicon dioxide; and 1-4% magnesium stearate.

[0020] In some embodiments of the present invention, the finerenone orally disintegrating tablet comprises, by weight percentage, the following ingredients: 12.5% ​​finerenone; 25.38% microcrystalline cellulose; 50.13% mannitol; 4.00% cross-linked polyvinylpyrrolidone; 4.00% cross-linked sodium carboxymethyl cellulose; 2.00% gel silicon dioxide; and 2.00% magnesium stearate, wherein each finerenone orally disintegrating tablet contains 10 mg or 20 mg of finerenone.

[0021] In some embodiments of the present invention, the finerenone orally disintegrating tablet comprises, by weight percentage, the following ingredients: 12.5% ​​finerenone; 25.38% microcrystalline cellulose; 50.13% mannitol; 6.00% cross-linked polyvinylpyrrolidone; 2.00% cross-linked sodium carboxymethyl cellulose; 2.00% gel silicon dioxide; and 2.00% magnesium stearate, wherein each finerenone orally disintegrating tablet contains 10 mg or 20 mg of finerenone.

[0022] In some embodiments of the present invention, the finerenone orally disintegrating tablet optionally comprises a sweetener, such as at least one of acesulfame potassium, cyclamate, aspartame and artificial flavors.

[0023] Another object of the present invention is to provide a method for preparing finerenone orally disintegrating tablets, which adopts a powder direct tableting process, comprising the following steps: mixing finerenone with a filler, a disintegrant, a glidant, and a lubricant, and optionally adding a sweetener to obtain a mixed powder, and directly tableting the mixed powder to obtain a finerenone orally disintegrating tablet.

[0024] Advantages of the present invention:

[0025] 1) The finerenone orally disintegrating tablets of the present invention have the advantages of stable quality, no need for water, fast disintegration and dissolution, and strong patient compliance.

[0026] 2) The orally disintegrating tablet of the present invention completely disintegrates within 60 seconds without a hard core, which meets the requirements of the Chinese Pharmacopoeia.

[0027] 3) The preparation method of the present invention has the advantages of simple process, conventional production equipment and low cost. DETAILED DESCRIPTION

[0028] The above contents of the present invention are further described in detail below through specific implementation modes, but this should not be construed as limiting the present invention.

[0029] If no specific conditions are specified in the examples of the present invention, the process is carried out under conventional conditions. If no manufacturer is specified for the reagents or instruments used, they can be conventional products purchased from the market.

[0030] The phenerenone used in the present invention is synthesized according to the process of the company, or prepared according to the process reported in the open literature or patents.

[0031] Examples of fillers of the present invention include microcrystalline cellulose PH113 or microcrystalline cellulose PH113KG-802 manufactured by Jiangsu Xidian Pharmaceutical Excipients Co., Ltd., and mannitol 100SD manufactured by Roquette Freres.

[0032] Examples of disintegrants of the present invention include cross-linked polyvinylpyrrolidone XL-10 from Chongqing Steckreidenmeier Material Technology Co., Ltd., cross-linked sodium carboxymethylcellulose from JRS PHARMA, sodium carboxymethyl starch from JRS, and low-substituted sodium hydroxypropylcellulose from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0033] Examples of the glidant of the present invention include gel silicon dioxide 244FP from Grace GmbH.

[0034] Examples of the lubricant of the present invention include magnesium stearate from Beijing Fengli Company.

[0035] The instruments used in the present invention include a tablet hardness tester (model: YD-20KZ) manufactured by Tianjin Tianda Tianfa Technology Co., Ltd., an orally disintegrating tablet disintegration instrument (KB-1) manufactured by Tianjin Tianda Tianfa Technology Co., Ltd., and a dissolution tester (DS-1206) manufactured by Shenzhen Huarong.

[0036] The method for detecting the disintegration time limit in the specific embodiment of the present invention is as follows:

[0037] The disintegration time limit test method of 0921 in the 2020 edition of the Chinese Pharmacopoeia is adopted, and an orodisintegrating tablet disintegrator is used. In 37℃±1℃ water, the tablets should all disintegrate and pass through the sieve within 60s. If there is a small amount of light floating or adhering to the stainless steel tube or sieve, but no hard core, it can be regarded as compliance with the regulations as known to those skilled in the art. Repeat the measurement of 6 tablets, all of which should meet the regulations. If one tablet does not meet the regulations, another 6 tablets should be retested, and all should meet the regulations.

[0038] In the specific embodiment of the present invention, the dissolution detection method adopts the "Chinese Pharmacopoeia" 2020 edition, 0931 dissolution and release determination method, and the second method (paddle method) is used for detection.

[0039] The present invention investigates the disintegration time, dissolution and friability of finerenone orally disintegrating tablets through experimental research on the type and content of disintegrants.

[0040] Example 1 Prescription Screening

[0041] In this example, the particle size of the disintegrant and the main drug of the orally disintegrating tablet was studied. The following is the experimental research data. The prescription is shown in Table 1, the disintegration time test results are shown in Table 2, the dissolution test results are shown in Table 3, and the main drug particle size screening is shown in Table 4.

[0042] 1. Preparation method of orally disintegrating tablets: Screen out the main drug with a particle size of less than 150 μm through a 100-mesh sieve, weigh the main drug, filler, disintegrant, lubricant, and glidant in the prescribed amount, pre-mix, and then put them into a mixer for mixing evenly, unload, and tablet press to obtain 1,000 orally disintegrating tablets, each weighing 80 mg. During the preparation process, the tableting hardness is controlled at about 25N, 40N, and 60N, respectively, to prepare orally disintegrating tablets with different tableting hardness, and the sample hardness is tested by a tablet hardness tester.

[0043] Table 1 Prescription study of different disintegrants and their contents

[0044]

[0045] Connect to Table 1

[0046]

[0047] 2. Evaluation of disintegration time of different prescriptions

[0048] Table 2 Evaluation of disintegration time of the formulations in Table 1

[0049]

[0050]

[0051] Table 2 Prescriptions 1 to 4, 15 to 18 contain a single disintegrant. When the disintegrant content is 5.5% to 10%, the disintegration time does not exceed 60s. Compared with Prescriptions 2 and 16, when cross-linked carboxymethyl cellulose sodium is used as a single disintegrant, the orally disintegrating tablets with a hardness of about 40N have little effect on the disintegration time, which is between 40 and 50s. However, it can be concluded from Prescriptions 7, 8, 11 to 13 that the disintegration time of the combination of two disintegrants will change with the change of the disintegrant content, and in general, the disintegration time of the combination of two disintegrants is relatively shorter than that of a single disintegrant with the same content.

[0052] Prescriptions 5 to 14 are a combination of two disintegrants. Overall, when Prescriptions 7 to 8, and Prescriptions 11 to 13 use cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose as combined disintegrants, the disintegration time is shorter than that of other disintegrant combinations. When the total amount of the two is above 5.5%, the disintegration time can be controlled within 60 seconds. However, if the total amount of the two exceeds 10%, such as Prescription 14, the total amount of the two is 12%, and the disintegration time exceeds 60 seconds, theoretically, the higher the content of the appropriate disintegrant, the shorter the disintegration time of the orodisintegrating tablet, but the opposite is true. The inventors of the present application found that when cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose are used in combination as disintegrants, the content increases, and the viscosity of the surrounding solution of the orodisintegrating tablet increases after the orodisintegrating tablet disintegrates, which increases the resistance to its disintegration, causing the orodisintegrating tablet to disintegrate more slowly.

[0053] 3. Evaluation of dissolution of different prescriptions

[0054] Table 3 Evaluation of the average dissolution amount at each time point of the formulation with different disintegrant contents

[0055]

[0056]

[0057] Prescription 2, Prescription 3, Prescription 6 to Prescription 13, Prescription 17 and Prescription 18 were selected, and the tablet hardness was about 40N. The dissolution in the pH 4.5 acetate buffer was investigated, and the results are shown in the table above. It can be seen that the dissolution effect of the prescriptions with a disintegration time of no more than 60s is good, and the dissolution effect of the prescriptions with a disintegration time of more than 60s is relatively poor.

[0058] 4. Evaluation of the disintegration time of different particle sizes of main drugs

[0059] Table 4 Effect of different particle sizes of main drugs on disintegration time

[0060]

[0061] In this embodiment, prescription 8 is prepared into an orally disintegrating tablet with a hardness of about 40N. When more than 90% of the particle sizes of the main drug finerenone are less than 150μm and more than 50% are less than 90μm, the disintegration time is 25 to 40s. The particle sizes of the main drug of prescription 8 in this embodiment are replaced with the particle sizes of prescription 8-0, prescription 8-1, prescription 8-2, and prescription 8-3 in Table 4, and the disintegration time results are shown in Table 4. It is shown that the particle size of finerenone d(0.9) of the main drug of the prescription of the present invention is 125μm and d(0.5) is 105μm, which makes the disintegration effect of the prescription orally disintegrating tablet relatively good. Further reducing the particle size of the main drug does not significantly reduce the disintegration time. For example, the disintegration time of prescription 8-0 and prescription 8-3 is not much different from that of prescription 8-1.

[0062] 5. Friability inspection

[0063] The orally disintegrating tablets of prescription 8 in this embodiment were selected for friability inspection: the 2020 edition of the Chinese Pharmacopoeia, 0923 tablet friability inspection method, using a tablet hardness tester (manufacturer and model: Tianjin Tianda Tianfa, FT-2000SE), taking a sample and blowing off the powder from the tablet with a hair dryer, accurately weighing 6.80g, placing it in a cylinder, rotating 100 times, taking it out, blowing off the powder with a hair dryer, accurately weighing it, and calculating that the weight loss does not exceed 1%, and no broken, cracked or crushed tablets were detected. It shows that the friability index of the orally disintegrating tablets of prescription 8 of the present invention meets the requirements of the Chinese Pharmacopoeia.

[0064] According to the friability detection method of orally disintegrating tablets in Prescription 8, the orally disintegrating tablets of Prescriptions 6 to 13, Prescription 8-0, Prescription 8-1, and Prescription 8-3 in this example were tested for friability, and the weight loss was no more than 1%, which met the requirements of the Chinese Pharmacopoeia.

[0065] 6. Investigation of influencing factors

[0066] The orally disintegrating tablets of prescriptions 5 to 13 in this example were sealed and placed at high temperature (60°C) for 10 days, and exposed to light (25°C, exposed to a cool white fluorescent lamp and a near-ultraviolet lamp at 4500lx±500lxd, with the total illumination of the light source not less than 1.2×106lux·hr, and the energy of the near-ultraviolet lamp not less than 200W·hr / m 2 ) for 10 days. The test results show that the maximum single impurity content is less than 0.2% and the total impurity content is less than 1.0%.

[0067] The above purity was determined by high performance liquid chromatography (HPLC), and the data was collected from SHIMADZU LC-20AD / Thermo U3000 (UV / DAD). A C18 chromatographic column, 250mm*4.6mm, column temperature 35°C, wavelength 226nm, flow rate 1.0mL / min, injection volume 10μL, running time 30min. Mobile phase A was 10mmol / L ammonium acetate (pH=4.6): acetonitrile=90:10 (V / V), and mobile phase B was acetonitrile. The gradient is shown in the following table:

[0068] Time min A％ B％ 0 70 30 15 30 70 20 30 70 21 70 30 30 70 30

[0069] Example 2

[0070] Main drugs and excipients Feeding amount Mass percentage Finerenone 10g 12.5％ Microcrystalline cellulose 20.4g 25.5％ Mannitol 41.6g 52％ Crospovidone 2.4g 3％ Croscarmellose Sodium 2.0g 2.5％ Magnesium Stearate 0.8g 1.0％ Gel Silica 2.8g 3.5％ total 80g 100％

[0071] Preparation: Screen out the main drug with d(0.9) of 125 μm and d(0.5) of 105, weigh the prescribed amount of the main drug, microcrystalline cellulose, mannitol, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, magnesium stearate, and gel silicon dioxide, pre-mix them, then put them into a mixer and mix them evenly, discharge the materials, and press them into tablets to obtain 1000 orodisintegrating tablets, each weighing 80 mg.

[0072] Evaluation results of various indicators of finerenone orally disintegrating tablets prepared in this example:

[0073] Evaluation indicators Evaluation results hardness 37～42N Disintegration time 30～45s friability Weight loss less than 1% The influencing factors are complex Less than 1.0%

[0074] Example 3

[0075] Main drugs and excipients Feeding amount Mass percentage Finerenone 10g 12.5％ Microcrystalline cellulose 18.4g 23％ Mannitol 37.6g 47％ Crospovidone 4.0g 5％ Croscarmellose Sodium 4.0g 5％ Magnesium Stearate 2.8g 3.5％ Gel Silica 3.2g 4％ total 80g 100％

[0076] The preparation process is referred to Example 2.

[0077] Evaluation results of various indicators of finerenone orally disintegrating tablets prepared in this example:

[0078] Evaluation indicators Evaluation results hardness 35～44N Disintegration time 30～40s friability Weight loss less than 1% The influencing factors are complex Less than 1.0%

[0079] Example 4

[0080] Main drugs and excipients Feeding amount Mass percentage Finerenone 10g 12.5％ Microcrystalline cellulose 20.8g 26％ Mannitol 43.2g 54％ Crospovidone 2.0g 2.5％ Croscarmellose Sodium 2.4g 3.0％ Magnesium Stearate 0.8g 1％ Gel Silica 0.8g 1％ total 80g 100％

[0081] The preparation process is referred to Example 2.

[0082] Evaluation results of various indicators of finerenone orally disintegrating tablets prepared in this example:

[0083] Evaluation indicators Evaluation results hardness 38～43N Disintegration time 35～45s friability Weight loss less than 1% The influencing factors are complex Less than 1.0%

[0084] Example 5

[0085] Main drugs and excipients Feeding amount Mass percentage Finerenone 10g 12.5％ starch 20.3g 25.38％ Xylitol 40.1g 50.13％ Crospovidone 4.8g 6％ Croscarmellose Sodium 1.6g 2％ Sodium stearate fumarate 1.6g 2％ talcum powder 1.6g 2％ total 80g 100％

[0086] The preparation process is referred to Example 2.

[0087] Evaluation results of various indicators of finerenone orally disintegrating tablets prepared in this example:

[0088] Evaluation indicators Evaluation results hardness 57～62N Disintegration time 30～40s friability Weight loss less than 1% The influencing factors are complex Less than 1.0%

[0089] Equivalent programs and scope

[0090] Some non-limiting preferred embodiments of the present invention have been described above. Those skilled in the art may make various changes and modifications to the description without departing from the essential scope of the present invention as defined in the claims. These changes and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A finerenone orally disintegrating tablet, characterized in that: In terms of weight percentage, the ingredients include: Finerenone 10-15%; Filler 70-80%; Disintegrant 5.5-10%; Glidant 1-4%; Lubricant 1~4%.

2. The finerenone orally disintegrating tablet according to claim 1, characterized in that: The disintegrant is at least one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

3. The finerenone orally disintegrating tablet according to claim 2, characterized in that: The disintegrant is one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose, with a content of 10%, preferably cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose; or, The disintegrant is a combination of two of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, and the total content of the two disintegrants is 8%.

4. The finerenone orally disintegrating tablet according to claim 3, characterized in that: The disintegrant is a combination of two of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch, preferably a combination of cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose, and the mass ratio of cross-linked polyvinylpyrrolidone to cross-linked sodium carboxymethyl cellulose is 1:3 to 3:1, preferably 3:

1.

5. The finerenone orally disintegrating tablet according to any one of claims 1 to 4, characterized in that: The filler is at least one of microcrystalline cellulose, mannitol, starch, lactose, sucrose, sorbitol, xylitol, and maltodextrin, preferably mannitol and microcrystalline cellulose.

6. The finerenone orally disintegrating tablet according to any one of claims 1 to 5, characterized in that: The glidant is at least one of gel silicon dioxide, micro-powder silica gel and talcum powder, preferably gel silicon dioxide.

7. The finerenone orally disintegrating tablet according to any one of claims 1 to 6, characterized in that: The lubricant is at least one of calcium stearate, sodium stearate fumarate or magnesium stearate, preferably magnesium stearate.

8. The finerenone orally disintegrating tablet according to any one of claims 1 to 7, characterized in that: In terms of weight percentage, the ingredients include: Finerenone 10-15%; Microcrystalline cellulose 23-30%; Mannitol 45-55%; Cross-linked polyvinylpyrrolidone 2-6%; Croscarmellose sodium 2-6%; Gel silicon dioxide 1-4%; Magnesium stearate 1-4%.

9. The finerenone orally disintegrating tablet according to claim 8, characterized in that: In terms of weight percentage, the ingredients include: finerenone 12.5%; Microcrystalline cellulose 25.38%; Mannitol 50.13%; Crospovidone 4.00%; Croscarmellose sodium 4.00%; Gel silica 2.00%; Magnesium stearate 2.00%, or Finerenone 12.5%; Microcrystalline cellulose 25.38%; Mannitol 50.13%; Crospovidone 6.00%; Croscarmellose sodium 2.00%; Gel silica 2.00%; Magnesium stearate 2.00%, Each finerenone orally disintegrating tablet contains 10 mg or 20 mg of finerenone.

10. A method for preparing the finerenone orally disintegrating tablet according to any one of claims 1 to 9, characterized in that: The powder direct tableting process comprises the following steps: mixing finerenone with a filler, a disintegrant, a glidant and a lubricant to obtain a mixed powder, and directly tableting the mixed powder to obtain finerenone orally disintegrating tablets.

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