Fnerenone tablet and preparation method thereof

Abstract

The invention provides a pharmaceutical composition containing fenerenone, which comprises the following components in percentage by weight: 1.0%-30.0% of fenerenone, 1.0%-5.0% of hydroxypropyl methylcellulose, 0.1%-1.0% of lauryl sodium sulfate, 5.0%-15.0% of polyvinylpolypyrrolidone and 0.5%-5.0% of sodium stearyl fumarate. The filler is microcrystalline cellulose and lactose monohydrate, a wet granulation process is adopted, the pharmaceutical composition has the characteristics of stable and rapid dissolution and rapid disintegration of the fenerenone, the process is simple, the production steps are simplified, the production efficiency is improved, and the cost is reduced.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition and a preparation method thereof, and in particular to a finerenone tablet and a preparation method thereof. Background Art

[0002] Finerenone, trade name: Kerendia, was developed by Bayer and approved for marketing in the United States in July 2021. Finerenone is the first non-steroidal selective mineralocorticoid receptor antagonist used to improve renal prognosis in adult patients with chronic kidney disease and type 2 diabetes. Preclinical studies have shown that it can block the harmful effects caused by excessive activation of mineralocorticoid receptors.

[0003] At present, type 2 diabetes and chronic kidney disease (CKD) have become health issues of global concern. It is estimated that by 2045, the number of diabetes patients in my country will reach 175 million, of which type 2 diabetes patients will account for more than 90%, and nearly 40% of type 2 diabetes patients will progress to CKD as the disease progresses. Among the nearly 120 million CKD patients in my country, type 2 diabetes is the leading cause of hospitalization and one of the important causes of end-stage renal disease (ESRD) in my country. Not only that, patients with type 2 diabetes-related CKD often have concomitant cardiovascular disease (CVD), and many patients die of cardiovascular events before entering ESRD.

[0004] Therefore, the clinical management of patients with type 2 diabetes-related CKD should pay attention to both renal and cardiac risks, intervene as early as possible, and thus delay disease progression and improve prognosis. Finerenone, as a new nonsteroidal, highly selective mineralocorticoid receptor antagonist (MRA), can directly and accurately inhibit MR overactivation to reduce the continued decline in eGFR and the risk of ESRD, exert anti-inflammatory and anti-fibrotic effects, and thus bring dual benefits to the kidney and heart. In China, finerenone tablets were approved for marketing by the National Medical Products Administration in June 2022. Kerendia is a rapid-release tablet. At present, there is no liquid preparation of finerenone tablets. For pediatric patients and patients who cannot swallow tablets, there is an urgent need for a rapidly dispersible dosage form, preferably dispersible tablets, which are more stable than liquid preparations and easier to carry.

[0005] At present, the technology used by the commercial product Kerendia is fluidized bed granulation tableting. Bayer's Chinese patent CN110022871A discloses a fluidized bed granulation process. The compound in micronized form, hypromellose, and sodium lauryl sulfate are prepared into a granular solution in water. Microcrystalline cellulose, lactose, and cross-linked sodium carboxymethyl cellulose are mixed in a fluidized bed. The premix and granular solution are granulated in a fluidized bed granulator. After the granules are dried and granulated, a lubricant, magnesium stearate, is added. Tablets are pressed using a rotary tablet press.

[0006] The problems with this preparation method are that the fluidized bed top spray granulation has high energy consumption and many influencing factors, and the fluidized bed granulation is more difficult than the high shear mixing granulation, and is prone to fine powder loss, resulting in reduced content.

[0007] Therefore, the development of finerenone dispersible tablets should have the following advantages:

[0008] 1) Rapid dissolution; 2) Good dispersion uniformity.

[0009] In summary, there is no dispersible tablet of finerenone on the market. Since finerenone itself is poorly soluble in water, it is difficult to have both good dispersion uniformity and high solubility. Therefore, it must be combined with various excipients and a suitable preparation process to obtain a suitable dispersible tablet. Summary of the invention

[0010] The present invention aims to provide a pharmaceutical composition containing finerenone, preferably a dispersible tablet, which has a reasonable prescription design, a simple preparation process, a high solubility, is easy to carry, a simple preparation process, a high solubility and is quickly dispersed in water.

[0011] The technical solution of the present invention is as follows:

[0012] A tablet containing finerenone comprises the following ingredients: by weight percentage, finerenone 1.0%-30.0%, hypromellose 1.0%-5.0%, sodium lauryl sulfate 0.1%-1.0%, cross-linked polyvinylpyrrolidone 5.0%-15.0% and sodium stearyl fumarate 0.5%-5.0%, and the rest is a filler, wherein the filler is microcrystalline cellulose and lactose.

[0013] Furthermore, the present invention provides a tablet, comprising the following ingredients: in terms of weight percentage, 1.5%-25.0% of finerenone, 1.0%-4.0% of hypromellose, 0.2%-0.8% of sodium lauryl sulfate, 6.0%-12.0% of cross-linked polyvinylpyrrolidone and 0.5%-3.0% of sodium stearyl fumarate, and the remainder being a filler, wherein the filler is microcrystalline cellulose and lactose.

[0014] Furthermore, the present invention provides a tablet, comprising the following ingredients: in terms of weight percentage, 1.8%-22.0% of finerenone, 1.5%-3.5% of hypromellose, 0.2%-0.8% of sodium lauryl sulfate, 6.0%-12.0% of cross-linked polyvinylpyrrolidone and 1.1%-2.5% of sodium stearyl fumarate, and the remainder being a filler, wherein the filler is microcrystalline cellulose and lactose.

[0015] Furthermore, the present invention provides a tablet, comprising the following ingredients: in terms of weight percentage, 2.0%-18.0% finerenone, 1.0%-3.0% hypromellose, 0.2%-0.6% sodium lauryl sulfate, 6.0%-10.0% cross-linked polyvinylpyrrolidone and 1.3%-2.2% sodium stearyl fumarate, and the remainder being a filler, wherein the filler is microcrystalline cellulose and lactose.

[0016] In the above tablets, the weight ratio of microcrystalline cellulose and lactose is 1:2-2:1, preferably 1.5:1-1.8:1, and more preferably 1.55:1.

[0017] In view of the above-mentioned internal and external addition structures, the inventors have developed a wet granulation preparation method, which consists of the following steps:

[0018] (1) Weigh the prescribed amount of sodium lauryl sulfate and dissolve it in water which accounts for 30% to 50% of the total weight of the added substances to form a clear granulation liquid for later use;

[0019] (2) Weigh the prescribed amount of finerenone, lactose, and hypromellose and mix them;

[0020] (3) mixing the mixture obtained in step (2) with microcrystalline cellulose and cross-linked polyvinylpyrrolidone;

[0021] (4) spraying the granulation liquid in step (1) onto the mixture, wet granulating, drying, dry granulating, adding sodium stearyl fumarate to the mixture, and tableting to obtain the tablets.

[0022] The present invention has the following beneficial effects:

[0023] 1. The phenerenone dispersible tablets prepared by the method of the present invention have the advantages of fast disintegration and high solubility.

[0024] 2. The phenerenone dispersible tablets prepared by the method of the present invention are easy to take and can be taken as ordinary tablets or taken after being quickly dispersed in water, which greatly improves the compliance of clinical medication.

[0025] 3. The process of preparing the phenerenol dispersible tablets by the method of the present invention is simple, which simplifies the production steps, improves the production efficiency and reduces the cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 1, 2 and 3 are the release curves of finerenone in Examples 1, 2 and 3. DETAILED DESCRIPTION

[0027] The present invention is further explained below with reference to the examples, but the examples do not limit the present invention in any form.

[0028] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are purchased from conventional biochemical reagent stores unless otherwise specified.

[0029] Embodiment 1:

[0030]

[0031] Preparation process:

[0032] (1) Weigh the prescribed amount of sodium dodecyl sulfate and dissolve it in water (40% of the total weight of the internal phase granules) to form a clear granulation liquid for later use;

[0033] (2) weighing the prescribed amount of finerenone, lactose and hypromellose and mixing them in a mixing hopper for 15 minutes at a speed of 15 rpm;

[0034] (3) The above-obtained material was added to a high shear wet granulator, and microcrystalline cellulose and crospovidone were added and mixed for 3 minutes, with the stirring blade rotating at 150 rpm and the cutting blade rotating at 300 rpm;

[0035] (4) Spray the granulation liquid in (1) into the above mixture within 5 minutes and continue bonding for 1 minute;

[0036] (5) wet granulating the wet granules;

[0037] (6) Drying the wet granules in a fluidized bed at a material temperature of 50°C and controlling the moisture content to less than 3.0%;

[0038] (7) performing dry granulation on the dry granules;

[0039] (8) Weigh the amount of the external phase and pass it through a 40-mesh sieve, and mix it with the mixture obtained in (7) at a speed of 15 rpm for 5 minutes;

[0040] (9) After the mixing is completed, the mixture is compressed into tablets using a tablet press to obtain finerenone tablets.

[0041] Embodiment 2:

[0042]

[0043] Preparation process:

[0044] (1) Weigh the prescribed amount of sodium dodecyl sulfate and dissolve it in water (40% of the total weight of the internal phase granules) to form a clear granulation liquid for later use;

[0045] (2) weighing the prescribed amount of finerenone, lactose and hypromellose and mixing them in a mixing hopper for 15 minutes at a speed of 15 rpm;

[0046] (3) The above-obtained material was added to a high shear wet granulator, and microcrystalline cellulose and crospovidone were added and mixed for 3 minutes, with the stirring blade rotating at 150 rpm and the cutting blade rotating at 300 rpm;

[0047] (4) Spray the granulation liquid in (1) into the above mixture within 5 minutes and continue bonding for 1 minute;

[0048] (5) wet granulating the wet granules;

[0049] (6) Drying the wet granules in a fluidized bed at a material temperature of 50°C and controlling the moisture content to less than 3.0%;

[0050] (7) performing dry granulation on the dry granules;

[0051] (8) Weigh the amount of the external phase and pass it through a 40-mesh sieve, and mix it with the mixture obtained in (7) at a speed of 15 rpm for 5 minutes;

[0052] (9) After the mixing is completed, the mixture is compressed into tablets using a tablet press to obtain finerenone tablets.

[0053] Embodiment 3:

[0054]

[0055] Preparation process:

[0056] (1) Weigh the prescribed amount of sodium dodecyl sulfate and dissolve it in water (40% of the total weight of the internal phase granules) to form a clear granulation liquid for later use;

[0057] (2) weighing the prescribed amount of finerenone, lactose and hypromellose and mixing them in a mixing hopper for 15 minutes at a speed of 15 rpm;

[0058] (3) The above-obtained material was added to a high shear wet granulator, and microcrystalline cellulose and crospovidone were added and mixed for 3 minutes, with the stirring blade rotating at 150 rpm and the cutting blade rotating at 300 rpm;

[0059] (4) Spray the granulation liquid in (1) into the above mixture within 5 minutes and continue bonding for 1 minute;

[0060] (5) wet granulating the wet granules;

[0061] (6) Drying the wet granules in a fluidized bed at a material temperature of 50°C and controlling the moisture content to less than 3.0%;

[0062] (7) performing dry granulation on the dry granules;

[0063] (8) Weigh the amount of the external phase and pass it through a 40-mesh sieve, and mix it with the mixture obtained in (7) at a speed of 15 rpm for 5 minutes;

[0064] (9) After the mixing is completed, the mixture is compressed into tablets using a tablet press to obtain finerenone tablets.

[0065] Comparative Example 1:

[0066]

[0067] The remaining steps are the same as those described in Examples 1-3.

[0068] Comparative Example 2

[0069]

[0070] The remaining steps are the same as those described in Examples 1-3.

[0071] Experimental example:

[0072] The table summarizes the basic evaluation results of Example 1, Example 2, Example 3, Comparative Example 1, Comparative Example 2 and the commercially available product Kerendia.

[0073] a: According to the disintegration time limit test method (General Rule 0921) of the Chinese Pharmacopoeia 2020 edition, the inner diameter of the stainless steel wire mesh is 710μm, the water temperature is 15-25℃, and 6 tablets of the test sample are taken. They should all disintegrate and pass through the sieve within 3 minutes. If a small amount cannot pass through the sieve, but has softened into a light weight and has no hard core, it meets the requirements.

[0074] b: Use pH 4.5 acetate buffer plus 0.1% Tween 20, 900 ml dissolution medium, paddle method, 75 rpm, and take samples after 30 minutes to measure the dissolution rate:

[0075] Reference preparation Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Whether it is sticky / no no no no no Appearance / Smooth Smooth Smooth Smooth Smooth Compressibility / good good good good good content 99.5％ 98.6％ 98.7％ 99.1％ 95.2％ 97.5％ <![CDATA[Dispersion uniformity a > >3min 57s 77s 85s >3min >3min <![CDATA[30 min dissolution b > 100.1％ 100.2％ 99.5％ 98.4％ 80.1％ 82.6％

[0076] The results show that: from Example 1, Example 2, and Example 3, the smaller the ratio of microcrystalline cellulose to lactose, the slower the dispersion uniformity. When the ratio of microcrystalline cellulose to lactose is 1.55:1, the dispersion uniformity is 57 seconds, when the ratio of microcrystalline cellulose to lactose is 1:1, the dispersion uniformity is 77 seconds, and when the ratio of microcrystalline cellulose to lactose is 1:1.55, the dispersion uniformity is 85 seconds, which are significantly better than the reference preparation and the comparative preparation. Therefore, the preferred ratio of microcrystalline cellulose to lactose in this patent is 1:1-1.78:1, preferably 1.5-1.8:1.

[0077] In Comparative Example 1, when the dosage of the binder hydroxypropyl methylcellulose was 6.15%, the disintegration time was greater than 3 minutes and the dispersion uniformity did not meet the requirements.

[0078] In comparative example 2, when the dosage of the disintegrant cross-linked polyvinylpyrrolidone was 3%, the disintegration time was greater than 3 minutes, and the dispersion uniformity did not meet the requirements. The dissolution rate in 30 minutes was less than 85%. It was preliminarily determined that Example 1 was the prescription under the optimal process.

[0079] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A finerenone tablet, characterized in that: The finerenone tablet comprises, by weight percentage: Finerenone 1.0%-30.0%, hydroxypropyl methylcellulose 1.0%-5.0%, sodium lauryl sulfate 0.1%-1.0%, cross-linked polyvinylpyrrolidone 5.0%-15.0%, sodium stearyl fumarate 0.5%-5.0%, and the rest are fillers, which are microcrystalline cellulose and lactose.

2. The finerenone tablet according to claim 1, characterized in that The finerenone tablet comprises, by weight percentage, 1.5%-25.0% of finerenone, 1.0%-4.0% of hypromellose, 0.2%-0.8% of sodium lauryl sulfate, 6.0%-12.0% of cross-linked polyvinylpyrrolidone, 0.5%-3.0% of sodium stearyl fumarate, and the rest is a filler, which is microcrystalline cellulose and lactose.

3. The finerenone tablet according to claim 1, characterized in that The finerenone tablet comprises, by weight percentage, 1.8%-22.0% of finerenone, 1.5%-3.5% of hypromellose, 0.2%-0.8% of sodium lauryl sulfate, 6.0%-12.0% of cross-linked polyvinylpyrrolidone, 1.1%-2.5% of sodium stearyl fumarate, and the rest is a filler, which is microcrystalline cellulose and lactose.

4. The finerenone tablet according to claim 1, characterized in that The finerenone tablet comprises, by weight percentage, 2.0%-18.0% of finerenone, 1.0%-3.0% of hypromellose, 0.2%-0.6% of sodium lauryl sulfate, 6.0%-10.0% of cross-linked polyvinylpyrrolidone, 1.3%-2.2% of sodium stearyl fumarate, and the rest is a filler, which is microcrystalline cellulose and lactose.

5. The finerenone tablet according to any one of claims 1 to 4, characterized in that The weight ratio of the microcrystalline cellulose to lactose is 1:2-2:1, preferably 1.5:1-1.8:1, and further preferably 1.55:

1.

6. The method for preparing the finerenone tablet according to claim 1, characterized in that: The following steps are involved: (1) Weigh the prescribed amount of sodium lauryl sulfate and dissolve it in water which accounts for 30% to 50% of the total weight of the added substances to form a clear granulation liquid for later use; (2) Weighing the prescribed amount of finerenone, lactose, and hypromellose and mixing; (3) mixing the mixture obtained in step (2) with microcrystalline cellulose and cross-linked polyvinylpyrrolidone; (4) spraying the granulation liquid in step (1) on the above mixture, wet granulating, drying, dry granulating, adding sodium stearyl fumarate to the whole mixture, and tableting to obtain the pharmaceutical composition.

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