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: 3-45% of fenerenone, 1-5% of magnesium stearate, 1-5% of magnesium stearate, 1-5% of 48-70% of a filler; 0.5-2% of an adhesive; 1-4% of a flow aid; 1-4% of a lubricant; the composition comprises the following components in percentage by weight: 0-15% of a first disintegrating agent, 2-6% of a second disintegrating agent and 2-6% of a third disintegrating agent, the first disintegrating agent, the second disintegrating agent and the third disintegrating agent are the same or at least two of the first disintegrating agent, the second disintegrating agent and the third disintegrating agent are different, preferably, the weight content of the fenerenone is 10-15%, and / or the weight content of the filling agent is 59-70%. 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 medicine, and particularly 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. 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, and recommended finerenone (10mg or 20mg) 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 approval of the China National Medical Products Administration (NMPA) will be available. The applicable population of fenarenon (finerenone tablets, 10 mg or 20 mg) has been expanded to include the early stages of chronic kidney disease associated with type 2 diabetes, and the indications include cardiovascular-related benefits (reducing the risk of cardiovascular death and hospitalization for heart failure).

[0005] Currently, the marketed finerenone is mainly in the form of ordinary tablets, but if the patient is elderly or has difficulty swallowing, there may be a risk of swallowing, especially for some patients with chronic kidney disease, 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 to take ordinary tablets. For some special patients, such as those with mental illness, Alzheimer's disease, epilepsy, etc., good medication compliance is crucial. So far, only Chinese patent application CN202311409422.X discloses a preparation process for finerenone orally disintegrating tablets, but the patent application does not disclose a method for determining the disintegration time of the prepared finerenone orally disintegrating tablets. Those skilled in the art cannot determine the method for detecting the disintegration time based on the disclosed content. Therefore, it is impossible to determine whether the disintegration time of the finerenone orally disintegrating tablets disclosed in the patent application meets the requirements of the Chinese Pharmacopoeia.

[0006] Therefore, it is necessary to develop a phenerenol orally disintegrating tablet that has good patient compliance, is easy to use, has a rapid onset of action, is easy to industrialize and produces, and meets the requirements of the Chinese Pharmacopoeia. Summary of the Invention

[0007] The purpose of the present application is to provide a finerenone orally disintegrating tablet, which is for use by diabetic patients and has rapid disintegration and dissolution, stable finished product quality, no need for water administration, and strong patient compliance. In addition, the present application also provides a method for preparing the finerenone orally disintegrating tablet, which is simple and feasible, low-cost, and suitable for large-scale industrial production.

[0008] One of the purposes of the present application is to provide a finerenone orally disintegrating tablet, which comprises, by weight percentage, 3-45% finerenone; 48-70% filler; 0.5-2% binder; 1-4% glidant; 1-4% lubricant; 0-15% first disintegrant; 2-6% second disintegrant; and 2-6% third disintegrant, wherein the first disintegrant, the second disintegrant, and the third disintegrant are the same or at least two of them are different.

[0009] In one or more embodiments, a finerenone orally disintegrating tablet of the present application comprises, by weight percentage, 10-15% finerenone; 59-70% filler; 0.5-2% binder; 1-4% glidant; 1-4% lubricant; 0-15% first disintegrant; 2-6% second disintegrant; and 2-6% third disintegrant, wherein the first disintegrant, the second disintegrant, and the third disintegrant are the same or at least two of them are different.

[0010] In one or more embodiments, the first disintegrant, the second disintegrant and the third disintegrant are each independently selected from cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose.

[0011] In one or more embodiments, the first disintegrant and the second disintegrant are each independently selected from low-substituted hydroxypropyl cellulose and croscarmellose sodium, and the third disintegrant is cross-linked polyvinylpyrrolidone.

[0012] In one or more embodiments, the first disintegrant is low-substituted hydroxypropyl cellulose, the second disintegrant is croscarmellose sodium, and the third disintegrant is cross-linked polyvinylpyrrolidone.

[0013] In one or more embodiments, the first disintegrant is croscarmellose sodium, the second disintegrant is low-substituted hydroxypropyl cellulose, and the third disintegrant is crospovidone.

[0014] In one or more embodiments, the weight ratio of the first disintegrant, the second disintegrant and the third disintegrant is 12.5-15:2-6:2-6, preferably 12.5-15:2:6.

[0015] In one or more embodiments, the binder is ethyl cellulose or polyacrylic acid resin.

[0016] In one or more embodiments, the filler is at least one of microcrystalline cellulose, mannitol, starch, lactose, sucrose, sorbitol, xylitol, and maltodextrin, preferably mannitol, lactose, or a combination of mannitol and lactose.

[0017] In one or more embodiments, the glidant is at least one of gel silica, micropowder silica, and talc, preferably talc, gel silica, or a combination of talc and gel silica; the lubricant is at least one of calcium stearate, sodium stearyl fumarate, or magnesium stearate, preferably magnesium stearate.

[0018] In one or more embodiments, the finerenone orally disintegrating tablet comprises, by weight, 10-15% finerenone; 59-70% mannitol; 0.5-2% ethyl cellulose or polyacrylic acid resin; 12.5-15% low-substituted hydroxypropyl cellulose; 2-6% cross-linked polyvinyl alcohol; 2-6% cross-linked sodium carboxymethyl cellulose; 1-4% talc; and 1-2% magnesium stearate. Each finerenone orally disintegrating tablet contains 10 mg or 20 mg of finerenone.

[0019] In one or more embodiments, the finerenone orally disintegrating tablet comprises, by weight percentage, 10-15% finerenone; 59-70% lactose; 0.5-2% ethyl cellulose or polyacrylic acid resin; 12.5-15% low-substituted hydroxypropyl cellulose; 2-6% cross-linked polyvinyl alcohol; 2-6% cross-linked sodium carboxymethyl cellulose; 1-2% gel silicon dioxide; 1-2% talc; and 1-2% magnesium stearate, wherein each finerenone orally disintegrating tablet contains 10 mg or 20 mg of finerenone.

[0020] In one or more embodiments, the weight ratio of low-substituted hydroxypropyl cellulose:croscarmellose sodium:crospovidone is 15:2:6.

[0021] In one or more embodiments, the weight ratio of low-substituted hydroxypropyl cellulose: croscarmellose sodium: crospovidone is 15:3:3.5.

[0022] In one or more embodiments, 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 application is to provide a method for preparing a finerenone orally disintegrating tablet, comprising the following steps: (a) mixing a prescribed amount of a first disintegrant, a second disintegrant, a filler, and a glidant to obtain a mixture; (b) dissolving finerenone and a binder in a suitable solvent to obtain a mixed solution, adding the mixed solution to the mixture obtained in step (a) to obtain a slurry, preparing a soft material, and drying to obtain dry granules; (c) uniformly mixing the dry granules obtained in step (b) with a prescribed amount of a third disintegrant and a lubricant, and tableting to obtain a finerenone orally disintegrating tablet.

[0024] The finerenone orally disintegrating tablets prepared by the wet granulation method have uniform API content in each tablet, and other indicators such as friability and disintegration time meet the requirements of orally disintegrating tablets.

[0025] In one or more embodiments, the suitable solvent is 50-80% acetone solution, 50-90% ethanol solution, preferably 80% acetone solution or ethanol solution.

[0026] Using the technical solution of this application, orally disintegrating phenelenone tablets of varying dosages can be prepared. These tablets exhibit sufficient hardness (2.0-6.0 kg) and a short disintegration time (less than 15 seconds). They are non-gritty and easy to swallow, meet dissolution requirements, and exhibit intact tablets with a smooth tablet compression process. Patients do not need to consume the tablets with water, resulting in high compliance. Furthermore, the preparation process employed in this application is simple and feasible, offering promising production prospects. DETAILED DESCRIPTION

[0027] The above contents of the present application are further described in detail below through specific implementation methods, but this should not be construed as limiting the present invention.

[0028] If no specific conditions are specified in the examples of this application, the procedures were carried out under conventional conditions. If the manufacturer of the reagents or instruments is not specified, they can be purchased from commercially available conventional products.

[0029] The phenerenone used in this application is synthesized according to a process independently developed by Puji Biotechnology (Taizhou) Co., Ltd., that is, the applicant, or prepared according to a process reported in public literature or patents.

[0030] Examples of fillers for this application include Mannitol 100SD from Roquette Freres.

[0031] Examples of disintegrants in the present application include cross-linked polyvinylpyrrolidone XL-10 from Chongqing Steckreidenmeier Material Technology Co., Ltd., cross-linked carboxymethyl cellulose sodium from JRS PHARMA, sodium carboxymethyl starch from JRS, and low-substituted hydroxypropyl cellulose from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0032] Examples of the binder of the present application include polyacrylic acid resin IV from Lianyungang Wantai Pharmaceutical Excipients Technology Co., Ltd. and ethyl cellulose from Ashland.

[0033] Examples of glidants for the present application include talc from Imerys Talc Ital SpA.

[0034] Examples of lubricants for the present application include magnesium stearate from Peter Greven Nederland CV.

[0035] Examples of lactose in the present application include lactose (316) from Kerry.INC or anhydrous lactose DTHV from Kerry Inc. Erythritol from Hunan Jiudian Hongyang Pharmaceutical Co., Ltd., povidone K30 from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., and sodium stearate fumarate from Shanghai Fenghong Pharmaceutical Excipients Technology Co., Ltd.

[0036] The instruments used in this application include a tablet hardness tester (model: YD-20KZ) from Tianjin Tianda Tianfa Technology Co., Ltd., an orally disintegrating tablet disintegration apparatus (KB-1) from Tianjin Tianda Tianfa Technology Co., Ltd., a dissolution tester (DS-1206) from Shenzhen Huarong, and a tablet press (ZP8) from Shanghai Xinyuan Pharmaceutical Machinery Co., Ltd.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the art of this application. The terms used in this application are only for the purpose of describing specific embodiments and are not intended to limit this application. The terms "orally disintegrating tablet" and "orally disintegrating tablet" in this application are interchangeable and represent the same dosage form.

[0038] In the present application, "suitable solvent" includes but is not limited to 50% to 80% acetone (W / W) solution, 50% to 90% (W / W) ethanol solution, and 80% acetone solution is particularly preferred.

[0039] In this application, "W / W" refers to the weight ratio, which refers to the weight of a substance in the total weight of the solution. For example, a 50% acetone solution means that the weight of acetone accounts for 50% of the weight of the solution.

[0040] The solution not specifically mentioned in the present application refers to a solution using water as a solvent.

[0041] The abbreviation "HPMCP" in this application is hypromellose phthalate.

[0042] In this application, “first”, “second”, “third”, etc. are only used for the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

[0043] In this application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0044] In this application, when referring to numerical ranges, unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values of the range is included. In addition, when multiple ranges are provided to describe a feature or characteristic, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges subsumed therein.

[0045] The method for detecting the disintegration time limit in the specific examples of this application is as follows:

[0046] The disintegration time limit test method, 0921, of the 2020 edition of the Chinese Pharmacopoeia was used, using an orally disintegrating tablet disintegrator. In 37°C ± 1°C water, the tablets should completely disintegrate and pass through the sieve within 60 seconds. A small amount of light material floating on top or adhering to the stainless steel tube or sieve, but without a hard core, is considered acceptable to those skilled in the art. Repeat the test for six tablets, and all should meet the requirements. If one tablet does not meet the requirements, retest another six tablets, and all should meet the requirements.

[0047] In the specific embodiments of this application, 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.

[0048] In this application, the BT-1000 powder comprehensive characteristic tester is used to detect the powder properties of the total mixed particles. Angle of repose: add the total mixed particles on a fixed circular bottom plate, detect the angle of the cone formed, and repeat three times. Bulk density: using the fixed volume method, let the total mixed particles flow freely into the stainless steel measuring cup until it overflows, scrape the top of the cup flat, remove the powder attached to the outer wall of the cup, accurately weigh the total mass of the stainless steel measuring cup and the sample in the cup, calculate the bulk density, and test three times in parallel. Tap density: use a covered measuring cup, fill it with loose powder, accurately weigh the total mass of the measuring cup and powder, tap it continuously 400 times, and test three times in parallel. The angle of repose of the total mixed particles is about 39°, the bulk density is ≈0.3g / mL, and the tap density is ≈0.4g / mL, then the compression ratio is about 25%, and the fluidity is good. The hardness of the plain tablets is between 2.0kg-6.0kg, and the tablet weight difference, friability, and disintegration all meet the requirements, and the compressibility is good. At the same time, the content uniformity of the finished product meets the requirements of ChP <0941> Regulation.

[0049] This application investigates the disintegration time, dissolution rate, friability and other indicators of finerenone orally disintegrating tablets through experimental research on the types and contents of disintegrants and binders.

[0050] Example 1

[0051] prescription:

[0052]

[0053]

[0054] Preparation: (a) dry-mix mannitol 100SD, low-substituted hydroxypropylcellulose LH11, croscarmellose sodium, and talc; (b) add finerenone and polyacrylic acid resin IV to 120 g of 80% (w / w) acetone solution to dissolve, add the acetone solution of finerenone and polyacrylic acid resin IV to the mixture obtained in step (a), mix thoroughly, prepare a soft material, and dry to obtain dry granules; (c) mix the dry granules obtained in step (b) with crospovidone XL-10 and magnesium stearate, and compress them in a tablet press to obtain finerenone orally disintegrating tablets.

[0055] Example 2

[0056] prescription:

[0057] Components Feeding amount / g content Finerenone 10 12.50％ Mannitol 100SD 49.6 62.00％ Ethyl cellulose 0.8 1.00％ Low-substituted hydroxypropyl cellulose LH11 10 12.50％ Croscarmellose sodium 1.6 2.00％ Cross-linked polyvinylpyrrolidone XL-10 4.8 6.00％ talcum powder 2.4 3.00％ magnesium stearate 0.8 1.00％ total 80 100％

[0058] Preparation: (a) dry-mix mannitol 100SD, low-substituted hydroxypropylcellulose LH11, croscarmellose sodium, and talc; (b) dissolve finerenone and ethyl cellulose in 120 g of 80% (w / w) acetone solution; add the acetone solution of finerenone and ethyl cellulose to the mixture obtained in step (a), mix thoroughly, prepare a soft material, and dry to obtain dry granules; (c) mix the dry granules obtained in step (b) with crospovidone XL-10 and magnesium stearate, and compress them in a tablet press to obtain finerenone orally disintegrating tablets.

[0059] Example 3

[0060] prescription:

[0061] Components Feeding amount / g content Finerenone 10 12.5％ Mannitol 100SD 55.4 69.25％ Low-substituted hydroxypropyl cellulose LH11 4 5％ Polyacrylic Resin IV 1 1.25％ Croscarmellose sodium 1.6 2.00％ Cross-linked polyvinylpyrrolidone XL-10 4.8 6.00％ talcum powder 2.4 3.00％ magnesium stearate 0.8 1.00％ total 80 100％

[0062] Preparation: (a) dry-mixing mannitol 100SD, low-substituted hydroxypropylcellulose LH11, croscarmellose sodium, and talc; (b) adding finerenone and polyacrylic acid resin IV to 120 g of 80% (w / w) acetone solution to dissolve the mixture; adding the acetone solution of finerenone and polyacrylic acid resin IV to the mixture obtained in step (a), mixing uniformly, preparing a soft material, and drying to obtain dry granules; (c) uniformly mixing the dry granules obtained in step (b) with crospovidone XL-10 and magnesium stearate, and compressing the mixture in a tablet press to obtain finerenone orally disintegrating tablets.

[0063] Example 4

[0064] prescription:

[0065] Components Feeding amount / g content Finerenone 10 12.5％ Mannitol 100SD 49 61.25 Low-substituted hydroxypropyl cellulose LH11 12 15％ Polyacrylic Resin IV 1 1.25％ Croscarmellose sodium 2.4 3.00％ Cross-linked polyvinylpyrrolidone XL-10 2.4 3.00％ talcum powder 2.4 3.00％ magnesium stearate 0.8 1.00％ total 80 100％

[0066] Preparation: (a) dry-mix mannitol 100SD, low-substituted hydroxypropylcellulose LH11, croscarmellose sodium, and talc; (b) dissolve finerenone and polyacrylic acid resin IV in 120 g of 80% acetone (w / w) solution, add the acetone solution of finerenone and polyacrylic acid resin IV to the mixture obtained in step (a), mix thoroughly, prepare a soft material, and dry to obtain dry granules; (c) mix the dry granules obtained in step (b) with crospovidone XL-10 and magnesium stearate, and compress them in a tablet press to obtain finerenone orally disintegrating tablets.

[0067] Example 5

[0068] prescription:

[0069] Components Feeding amount / g content Finerenone 10 12.5％ Mannitol 100SD 56 70％ Polyacrylic Resin IV 0.4 0.5％ Croscarmellose sodium 4.8 6.00％ Cross-linked polyvinylpyrrolidone XL-10 4.8 6.00％ talcum powder 0.8 1.00％ magnesium stearate 3.2 4.00％ total 80 100％

[0070] Preparation: (a) dry-mixing mannitol 100SD, croscarmellose sodium, and talc; (b) adding finerenone and polyacrylic acid resin IV to 120 g of 80% acetone (w / w) solution to dissolve the mixture; adding the acetone solution of finerenone and polyacrylic acid resin IV to the mixture obtained in step (a), mixing uniformly, preparing a soft material, and drying to obtain dry granules; (c) uniformly mixing the dry granules obtained in step (b) with crospovidone XL-10 and magnesium stearate, and compressing the mixture in a tablet press to obtain finerenone orally disintegrating tablets.

[0071] Example 6

[0072] prescription:

[0073]

[0074]

[0075] Preparation: (a) dry-mix mannitol 100SD, low-substituted hydroxypropylcellulose LH11, croscarmellose sodium, and talc; (b) dissolve finerenone and polyacrylic acid resin IV in 192 g of 80% (w / w) acetone solution; add the acetone solution of finerenone and polyacrylic acid resin IV to the mixture obtained in step (a), mix thoroughly, and prepare a soft material. Dry the mixture to obtain dry granules; (c) mix the dry granules obtained in step (b) with crospovidone XL-10 and magnesium stearate, and compress the mixture in a tablet press to obtain finerenone orally disintegrating tablets.

[0076] Example 7

[0077] prescription:

[0078] Components Feeding amount / g content Finerenone 10 3.33％ Mannitol 100SD 205.25 68.41％ Polyacrylic Resin IV 3.75 1.25％ Low-substituted hydroxypropyl cellulose LH11 45 15.00％ Croscarmellose sodium 6 2.00％ Cross-linked polyvinylpyrrolidone XL-10 18 6.00％ talcum powder 9 3.00％ magnesium stearate 3 1.00％ total 300 100％

[0079] Preparation: (a) dry-mix mannitol 100SD, low-substituted hydroxypropylcellulose LH11, croscarmellose sodium, and talc; (b) dissolve finerenone and polyacrylic acid resin IV in 450 g of 80% (w / w) acetone solution; add the acetone solution of finerenone and polyacrylic acid resin IV to the mixture obtained in step (a), mix thoroughly, and prepare a soft material. Dry the mixture to obtain dry granules; (c) mix the dry granules obtained in step (b) with crospovidone XL-10 and magnesium stearate, and compress the mixture in a tablet press to obtain finerenone orally disintegrating tablets.

[0080] Example 8

[0081] prescription:

[0082] Components Feeding amount / g content Finerenone 20 44.44％ Mannitol 100SD 21.6 48％ Low-substituted hydroxypropyl cellulose LH11 0.45 1％ Polyacrylic Resin IV 0.225 0.5％ Croscarmellose sodium 0.9 2.00％ Cross-linked polyvinylpyrrolidone XL-10 0.9 2.00％ talcum powder 0.45 1.00％ magnesium stearate 0.45 1.00％ total 45 100％

[0083] Preparation: (a) dry-mix mannitol 100SD, low-substituted hydroxypropylcellulose LH11, croscarmellose sodium, and talc; (b) add finerenone and polyacrylic acid resin IV to 40 g of 80% (w / w) acetone solution to dissolve the mixture; add the acetone solution of finerenone and polyacrylic acid resin IV to the mixture obtained in step (a), mix thoroughly, and prepare a soft material. Dry the mixture to obtain dry granules; (c) mix the dry granules obtained in step (b) with crospovidone XL-10 and magnesium stearate, and compress the mixture in a tablet press to obtain finerenone orally disintegrating tablets.

[0084] Example 9

[0085] prescription:

[0086]

[0087]

[0088] Preparation: (a) Lactose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, gel silica, and talc are dry-mixed; (b) Finerenone and polyacrylic acid resin IV are added to 120 g of 80% (w / w) acetone solution to dissolve the mixture; the acetone solution of finerenone and polyacrylic acid resin IV is added to the mixture obtained in step (a), mixed uniformly, to prepare a soft material, and dried to obtain dry granules; (c) The dry granules obtained in step (b) are uniformly mixed with crospovidone and magnesium stearate, and compressed on a tablet press to obtain finerenone orally disintegrating tablets.

[0089] Example 10

[0090] prescription:

[0091] Components Feeding amount / g content Finerenone 10 12.5％ anhydrous lactose 48 60.00％ Low-substituted hydroxypropyl cellulose 12 15.00％ Polyacrylic Resin IV 1 1.25％ Croscarmellose sodium 1.6 2.00％ Cross-linked polyvinylpyrrolidone 4.8 6.00％ Gel silica 0.8 1.00％ magnesium stearate 0.8 1.00％ talcum powder 1 1.25％ total 80 100％

[0092] Preparation: (a) dry-mix anhydrous lactose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, gel silica, and talc; (b) add finerenone and polyacrylic acid resin IV to 120 g of 80% (w / w) acetone solution to dissolve the mixture; add the acetone solution of finerenone and polyacrylic acid resin IV to the mixture obtained in step (a), mix thoroughly, and prepare a soft material. Dry the mixture to obtain dry granules; (c) mix the dry granules obtained in step (b) with crospovidone and magnesium stearate, and compress the mixture in a tablet press to obtain finerenone orally disintegrating tablets.

[0093] Comparative Example 1

[0094] prescription:

[0095]

[0096]

[0097] Preparation: (a) dry-mix mannitol 100SD, low-substituted hydroxypropyl cellulose LH11, croscarmellose sodium, and talc; (b) dissolve finerenone and hydroxypropyl cellulose SL in 144 g of 80% acetone solution, add the acetone solution of finerenone and hydroxypropyl cellulose SL to the mixture obtained in step (a), mix thoroughly, prepare a soft material, and dry to obtain dry granules; (c) mix the dry granules obtained in step (b) with crospovidone XL-10 and magnesium stearate, and compress them in a tablet press to obtain finerenone orally disintegrating tablets.

[0098] Comparative Example 2

[0099] prescription:

[0100] Components Feeding amount / g content Finerenone 10 12.50％ Mannitol 100SD 49.2 61.50％ HPMCP 1.2 1.50％ Low-substituted hydroxypropyl cellulose LH11 10 12.50％ Croscarmellose sodium 1.6 2.00％ Cross-linked polyvinylpyrrolidone XL-10 4.8 6.00％ talcum powder 2.4 3.00％ magnesium stearate 0.8 1.00％ total 80 100％

[0101] Preparation: (a) dry-mix mannitol 100SD, low-substituted hydroxypropylcellulose LH11, croscarmellose sodium, and talc; (b) dissolve finerenone and HPMCP in 144 g of 80% acetone solution, add the acetone solution of finerenone and HPMCP to the mixture obtained in step (a), mix thoroughly, prepare a soft material, and dry to obtain dry granules; (c) mix the dry granules obtained in step (b) with crospovidone XL-10 and magnesium stearate, and compress them in a tablet press to obtain finerenone orally disintegrating tablets.

[0102] Comparative Example 3

[0103] prescription:

[0104] Components Feeding amount / g content Finerenone 10 12.50％ Mannitol 100SD 49.2 61.50％ Copolyvidone 1.2 1.50％ Low-substituted hydroxypropyl cellulose LH11 10 12.50％ Croscarmellose sodium 1.6 2.00％ Cross-linked polyvinylpyrrolidone XL-10 4.8 6.00％ talcum powder 2.4 3.00％ magnesium stearate 0.8 1.00％ total 80 100％

[0105] Preparation: (a) dry-mix mannitol 100SD, low-substituted hydroxypropylcellulose LH11, croscarmellose sodium, and talc; (b) dissolve finerenone and copovidone in 144 g of 80% acetone solution; add the acetone solution of finerenone and copovidone to the mixture obtained in step (a), mix thoroughly, prepare a soft material, and dry to obtain dry granules; (c) mix the dry granules obtained in step (b) with crospovidone XL-10 and magnesium stearate, and compress them in a tablet press to obtain finerenone orally disintegrating tablets.

[0106] Comparative Example 4

[0107] The prescription and preparation method of Example 2 of CN202311409422.X are as follows:

[0108]

[0109]

[0110] Preparation method:

[0111] Step (1) processing of raw materials and auxiliary materials: finerenone, filler lactose, disintegrant croscarmellose sodium and cross-linked polyvinylpyrrolidone are respectively passed through a 100-mesh sieve for later use; binder polyvinylpyrrolidone K30 and lubricant sodium stearyl fumarate are respectively passed through a 200-mesh sieve for later use; step (2) preparing mixed powder: according to parts by mass, 2500 parts of the sieved filler, 15 parts of finerenone, 20 parts of disintegrant, 5 parts of polyvinylpyrrolidone K30 and 10 parts of sucrose are sequentially added into a three-dimensional motion mixer and mixed for 10 minutes, and then 3 parts of sodium stearyl fumarate are added, and stirring and mixing are continued for 15 minutes to obtain a total mixed powder for later use, wherein the mass ratio of lactose to erythritol in the filler is 3:1, and the mass ratio of cross-linked polyvinylpyrrolidone to cross-linked polyvinylpyrrolidone in the disintegrant is 1:1.5;

[0112] Step (3): Add the total mixed powder into a rotary tablet press, control the tableting speed, and control the hardness at 3 to 8 kg, and then tablets are obtained.

[0113] Comparative Example 5

[0114] The prescription and preparation method of Example 3 of CN202311409422.X are as follows:

[0115] Components content Feeding amount / g Number of copies Mannitol 72.64％ 450 900 erythritol 24.21％ 150 300 Finerenone 0.81％ 5.0 10 Croscarmellose sodium 0.37％ 2.3 4.6 Cross-linked polyvinylpyrrolidone 0.92％ 5.7 11.4 Povidone K 30 0.48％ 2.97 6 Aspartame 0.32％ 1.98 4 Sodium stearyl fumarate 0.24％ 1.48 3 total 100％ 619.5 1239

[0116] Preparation method:

[0117] Step (1) processing of raw materials and auxiliary materials: filtrate fenaretone, fillers mannitol and erythritol, and disintegrant cross-linked polyvinylpyrrol (CPPV) through a 100-mesh sieve for later use; binder polyvinylpyrrolidone K30 and lubricant sodium stearyl fumarate through a 200-mesh sieve for later use;

[0118] Step (2) preparing a mixed powder: adding 6000 parts of the sifted filler, 50 parts of phenerone, 80 parts of the disintegrant, 30 parts of povidone K30, and 20 parts of aspartame in sequence, by mass, into a three-dimensional motion mixer and mixing for 10 minutes; then adding 15 parts of sodium stearyl fumarate, and continuing to stir and mix for 15 minutes to obtain a total mixed powder for later use; wherein the mass ratio of mannitol to erythritol in the filler is 3:1, and the mass ratio of croscarmellose sodium to crospovidone in the disintegrant is 1:2.5;

[0119] Step (3): Add the total mixed powder into a rotary tablet press, control the tableting speed, and control the hardness at 3 to 8 kg, and then tablets are obtained.

[0120] Test Example 1: Determination of disintegration time (DT) of orally disintegrating tablets

[0121] The disintegration time limit test method of 0921 in the 2020 edition of the Chinese Pharmacopoeia was adopted, and the orally disintegrating tablet disintegration apparatus (KB-1) of Tianjin Tianda Tianfa Technology Co., Ltd. was used. In 37°C ± 1°C water, 6 tablets of the orally disintegrating tablets prepared in Examples 1-10 and Comparative Examples 1-5 were respectively taken and placed in a hanging basket. The timing was started after the tablets were added. The measurement results are shown in the following table:

[0122] Table 1 Disintegration time (DT) determination results of finerenone orally disintegrating tablets

[0123]

[0124] As can be seen from the above table, the average disintegration time of the phenaretone orally disintegrating tablets prepared in Examples 1 to 10 of the present application is between 8 seconds and 17 seconds, while the average disintegration time of the orally disintegrating tablets of Comparative Examples 1 to 3 is over 95 seconds. According to oral tests conducted by volunteers, the time from complete disintegration in the oral cavity to swallowing of the phenaretone orally disintegrating tablets prepared in Examples 1 to 8 of the present application is 15 seconds, indicating that the selection of appropriate disintegrants and binders and their types and amounts have a significant impact on the disintegration time of the disintegrating tablets of the present application.

[0125] Comparative Example 4 repeats the formulation and preparation method of orally disintegrating tablets of Example 2 of CN202311409422.X. During the tableting process, the orally disintegrating tablets had difficulty in ejecting tablets from the tablet press, with unusual noises during ejection, rough tablet sides, and severe scaling of the tablet press turntable and die. Orally disintegrating tablets with hardnesses of approximately 25N, 45N, and 50N were selected for disintegration time testing, and it took more than 3 minutes for the tablets to completely dissolve and pass through the stainless steel sieve.

[0126] Comparative Example 5 The prescription and preparation method of orally disintegrating tablets of Example 3 of CN202311409422.X were repeated, and orally disintegrating tablets with a hardness of approximately 25N and 45N were selected for disintegration time testing. Among them, the orally disintegrating tablet with a hardness of 25N passed through the stainless steel screen for the most part at 1 minute and 54 seconds, and small particles were stuck on the screen mesh; the orally disintegrating tablet with a hardness of 45N was completely dissolved and passed through the stainless steel screen at 2 minutes and 51 seconds.

[0127] The disintegration time of finerenone orally disintegrating tablets prepared according to the prescription and preparation method of CN202311409422.X does not meet the requirements of the 2020 edition of the "Chinese Pharmacopoeia".

[0128] Test Example 2: Determination of dissolution curve of orally disintegrating tablets

[0129] The dissolution and release rate determination method 0931 of the 2020 edition of the Chinese Pharmacopoeia was used, and the second method (paddle method) was used for detection. The dissolution medium was selected as pH 4.5 acetate buffer, the volume was 900 mL, the rotation speed was 75 r / min, and the sampling time was 5, 10, 15, 20, and 30 min. The drug content was determined by ultraviolet detection and the dissolution rate was calculated. The results are shown in the table below:

[0130] Table 2 Dissolution test results of finerenone orally disintegrating tablets

[0131]

[0132]

[0133] As can be seen from the above table, the dissolution amount of the phenerenone orally disintegrating tablets prepared in the present application in pH 4.5 acetate buffer was greater than 85% within 15 minutes, proving that the tablets of the present application can achieve rapid dissolution after disintegration and dispersion.

[0134] The dissolution rate of fenaretone orally disintegrating tablets prepared according to the prescription and preparation method of CN202311409422.X does not meet the requirements of the 2020 edition of the "Chinese Pharmacopoeia".

[0135] Test Example 3: Determination of friability of orally disintegrating tablets

[0136] The 2020 edition of the Chinese Pharmacopoeia, 0923 tablet friability test method, was used with a tablet hardness tester (manufacturer and model: Tianjin Tianda Tianfa, FT-2000SE). Samples were taken and blown away with a hair dryer to remove powder from the tablets. Each time, approximately 6.80 g was accurately weighed, placed in a cylinder, rotated 100 times, taken out, and the powder was blown away with a hair dryer. The tablets were accurately weighed and calculated. The results are shown in the table below:

[0137] Table 3 Finerenone orally disintegrating tablet friability determination results

[0138] Example Appearance Friability / % Example 1 No broken, cracked or crushed pieces 0.2％ Example 2 No broken, cracked or crushed pieces 0.3％ Example 3 No broken, cracked or crushed pieces 0.2％ Example 4 No broken, cracked or crushed pieces 0.2％ Example 5 No broken, cracked or crushed pieces 0.2％ Example 6 No broken, cracked or crushed pieces 0.3％ Example 7 No broken, cracked or crushed pieces 0.2％ Example 8 No broken, cracked or crushed pieces 0.3％ Comparative Example 1 No broken, cracked or crushed pieces 0.1％ Comparative Example 2 No broken, cracked or crushed pieces 0.2％ Comparative Example 3 No broken, cracked or crushed pieces 0.3％

[0139] It can be seen from the above table that the friability index of the orally disintegrating tablets prepared in this application meets the requirements of the Chinese Pharmacopoeia.

[0140] Test Example 4: Investigation of Influencing Factors

[0141] The orally disintegrating tablets prepared in Examples 1 to 10 of the present application were sealed and placed at high temperature (60° C.) for 10 days, and exposed to light (25° C., under a cool white fluorescent lamp and a near-ultraviolet lamp at 4500 lx±500 lxd, with a total illumination of not less than 1.2×106 lux·hr and an energy of not less than 200 W·hr / m 2 ) and left uncovered for 10 days. The test results showed that the maximum single impurity content was less than 0.2% and the total impurity content was less than 1.0%.

[0142] The above purity was determined using high-performance liquid chromatography (HPLC), with data collected from a SHIMADZU LC-20AD / Thermo U3000 (UV / DAD). A C18 column, 150 mm x 4.6 mm, was used at a column temperature of 25°C, a wavelength of 251 nm, a flow rate of 1.0 mL / min, and an injection volume of 5 μL. Mobile phase A consisted of 10 mmol / L ammonium acetate:acetonitrile (90:10, v / v), and mobile phase B was acetonitrile. The gradient is shown in the table below:

[0143] Time (min) Mobile phase A (%) Mobile phase B (%) 0 95 5 10 70 30 20 40 60 50 40 60 55 95 5

[0144] Equivalent schemes and scope

[0145] The foregoing description has described some non-limiting preferred embodiments of the present invention. Those skilled in the art may make various changes and modifications to this description without departing from the true scope of the present invention as defined by the claims. Such changes and modifications should also be considered 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 3-45%; Filler 48-70%; Adhesive 0.5-2%; Glidant 1-4%; Lubricant 1-4%; First disintegrant 0-15%; Second disintegrant 2-6%; The third disintegrant is 2-6%, wherein the first disintegrant, the second disintegrant and the third disintegrant are the same or at least two of them are different, Preferably, the weight content of finerenone is 10-15%, and / or the weight content of the filler is 59-70%.

2. The finerenone orally disintegrating tablet according to claim 1, wherein: The first disintegrant, the second disintegrant and the third disintegrant are each independently selected from cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose.

3. The finerenone orally disintegrating tablet according to claim 2, wherein: The first disintegrant and the second disintegrant are each independently selected from low-substituted hydroxypropyl cellulose and croscarmellose sodium, and the third disintegrant is cross-linked polyvinylpyrrolidone. Preferably, the first disintegrant is low-substituted hydroxypropyl cellulose, and the second disintegrant is croscarmellose sodium.

4. The finerenone orally disintegrating tablet according to claim 3, wherein: The weight ratio of the first disintegrant, the second disintegrant and the third disintegrant is 12.5-15:2-6:2-6, preferably 12.5-15:2:

6.

5. The finerenone orally disintegrating tablet according to any one of claims 1 to 4, characterized in that: The binder is ethyl cellulose or polyacrylic acid resin.

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

7. The finerenone orally disintegrating tablet according to any one of claims 1 to 6, characterized in that: The glidant is at least one of gel silicon dioxide, micropowder silica gel, and talc, preferably talc and / or gel silicon dioxide; the lubricant is at least one of calcium stearate, sodium stearyl 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%; Mannitol 59-70%; Ethyl cellulose or polyacrylic acid resin 0.5-2% Low-substituted hydroxypropyl cellulose 12.5-15% Cross-linked polyvinylpyrrolidone 2-6%; Croscarmellose sodium 2-6%; Talc 1-4%; Magnesium stearate 1-2%, Each finerenone orally disintegrating tablet contains 10 mg or 20 mg of finerenone.

9. 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%; Lactose 59-70%; Ethyl cellulose or polyacrylic acid resin 0.5-2%; Low-substituted hydroxypropyl cellulose 12.5-15%; Cross-linked polyvinylpyrrolidone 2-6%; Croscarmellose sodium 2-6%; Gel silica 1-2%; Talc 1-2%; Magnesium stearate 1-2%, 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 following steps are involved: (a) mixing a prescribed amount of a first disintegrant, a second disintegrant, a filler, and a glidant to obtain a mixture; (b) dissolving finerenone and a binder in a suitable solvent to obtain a mixed solution, adding the mixed solution to the mixture obtained in step (a) to obtain a slurry, preparing a soft material, and drying to obtain dry granules; (c) uniformly mixing the dry granules obtained in step (b) with a prescribed amount of a third disintegrant and a lubricant, and tableting to obtain finerenone orally disintegrating tablets.

Images