A non-fenretinide orally disintegrating tablet and a preparation method thereof

Abstract

A method for preparing phenelzine orally disintegrating tablets involves using phenelzine as the main drug, and adding fillers, disintegrants, binders, flavoring agents, and lubricants as excipients. The fillers are at least one of lactose, mannitol, and erythritol; the disintegrants are at least one of croscarmellose sodium, carboxymethyl starch sodium, and croscarmellose; the binders are at least one of hydroxypropyl methylcellulose, carboxymethyl cellulose sodium, and povidone K30; and the lubricant is at least one of silica, magnesium stearate, and sodium stearate fumarate. The phenelzine orally disintegrating tablets prepared by this invention using an extremely simple process do not require water or chewing. They disintegrate rapidly upon contact with saliva when placed on the tongue, aiding in swallowing and allowing the drug to enter the stomach for efficacy. The disintegration rate is as fast as 9 seconds. After disintegration, phenelzine effectively exerts its therapeutic effect after entering the gastrointestinal tract, and the drug has minimal irritation to the digestive tract mucosa.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a fenelazol orally disintegrating tablet and its preparation method. Background Technology

[0002] Fennellone is a nonsteroidal, highly selective mineralocorticoid receptor antagonist. Preclinical studies have shown it can block the harmful effects of excessive mineralocorticoid receptor activation. It is indicated for adult patients with type 2 diabetes-associated chronic kidney disease (with proteinuria) to reduce the risk of persistently declining estimated glomerular filtration rate (eGFR), end-stage renal disease, cardiovascular death, and hospitalization due to heart failure. Fennellone is an effective drug that can improve renal function. It can alleviate hypertension symptoms in patients with chronic kidney disease, mitigate further renal damage by reducing urinary protein excretion, and accelerate sodium and urinary salt excretion, effectively reducing fluid retention and symptoms such as edema while maintaining renal filtration rate.

[0003] Finelerone received marketing approval in the United States in July 2021, in the European Union in February 2022, and in China's NMPA in June 2022. In September 2022, the US FDA approved an update to the finelerone package insert to include the cardiovascular benefits observed in the FIGARO-DKD Phase III study. In February 2023, based on the results of the FIGARO-DKD Phase III study, it was included in the treatment of patients in the early stages of type 2 diabetes-related chronic disease (CKD).

[0004] Currently, fenelazol on the market is only available as a regular oral tablet. However, it is still in phase III clinical trials, which presents significant limitations for patients with swallowing difficulties (such as esophageal cancer patients), patients experiencing nausea and vomiting (cancer chemotherapy patients), and patients who are unwilling or uncooperative with medication (such as young children, the elderly, and bedridden patients). Furthermore, direct administration of fenelazol can cause side effects such as urinary tract infections, hypoglycemia, hyperkalemia, intestinal discomfort, and dizziness. Therefore, we are considering developing it into an orally disintegrating tablet. Summary of the Invention

[0005] Based on the above-mentioned technical problems, the purpose of this invention is to provide a convenient orally administered fenelazol orally disintegrating tablet.

[0006] Another objective of this invention is to provide a method for preparing the above-mentioned fenelazol orally disintegrating tablets. The prepared orally disintegrating tablets have a rapid disintegration rate, high bioavailability, and low irritation to the digestive tract mucosa, thus reducing adverse reactions caused by drug irritation.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] A fenelitonee orally disintegrating tablet, characterized in that it is prepared by mixing and compressing fenelitonee as the main drug with fillers, disintegrants, binders, flavoring agents and lubricants as excipients. The fillers in the excipients are at least one of lactose, mannitol and erythritol; the disintegrants are at least one of croscarmellose sodium, carboxymethyl starch sodium and croscarmellose; the binders are at least one of hydroxypropyl methylcellulose, carboxymethyl cellulose sodium and povidone K30; and the lubricants are at least one of silica, magnesium stearate and sodium stearate fumarate.

[0009] Preferably, in the fenelitonee orally disintegrating tablets, the excipients consist of mannitol and erythritol as fillers, croscarmellose and croscarmellose as disintegrants, povidone K30 as binder, and sodium stearate fumarate as lubricant.

[0010] Furthermore, the orally disintegrating tablet contains, by weight, 15-50 parts feneline, 2500-6000 parts filler, 20-80 parts disintegrant, 5-30 parts binder, 3-20 parts flavoring agent, and 3-15 parts lubricant.

[0011] More preferably, the orally disintegrating tablet contains, by weight, 30-50 parts fenelitonee, 20-30 parts fenelitonee, 3400-5100 parts filler, 30-40 parts disintegrant, 10-15 parts binder, 5-10 parts flavoring agent, and 5-8 parts lubricant.

[0012] The preparation method of the above-mentioned nephenone orally disintegrating tablets is characterized in that: nephenone is used as the main drug, and fillers, disintegrants, binders, flavoring agents and lubricants are added as excipients, and the mixture is compressed into tablets. The fillers in the excipients are at least one of lactose, mannitol and erythritol; the disintegrants are at least one of croscarmellose sodium, carboxymethyl starch sodium and croscarmellose; the binders are at least one of hydroxypropyl methylcellulose, carboxymethyl cellulose sodium and povidone K30; and the lubricant is at least one of silica, magnesium stearate and sodium stearate fumarate.

[0013] Preferably, in the fenelitonee orally disintegrating tablets, the excipients consist of mannitol and erythritol as fillers, croscarmellose and croscarmellose as disintegrants, povidone K30 as binder, and sodium stearate fumarate as lubricant.

[0014] Furthermore, the mass ratio of mannitol to erythritol in the filler is 3:1, and the mass ratio of croscarmellose sodium to croscarmellose in the disintegrant is 1:1.5 to 2.5.

[0015] When phenelzine was prepared into orally disintegrating tablets using the conventional mixed compression preparation route, it was found that orally disintegrating phenelzine tablets prepared with most fillers and disintegrants had a long disintegration time, and even a decrease in efficacy after disintegration and entering the gastrointestinal tract.

[0016] While maintaining the simplest preparation process, we explored filling agents and disintegrants with proportions more suitable for fenelazol to address the issue of long disintegration time. Among numerous filling agents and disintegrants, we found that fenelazol orally disintegrating tablets prepared using lactose, mannitol, or erythritol as filling agents and croscarmellose sodium, carboxymethyl cellulose sodium, or croscarmellose as disintegrants under a mixed compression preparation route exhibited better disintegration. The best disintegration effect was observed in fenelazol orally disintegrating tablets prepared using a filling agent consisting of mannitol and erythritol in a 3:1 mass ratio and a disintegrant consisting of croscarmellose sodium (FMC) and croscarmellose (PVPP) in a 1:1.5–2.5 mass ratio. Furthermore, fenelazol showed the best efficacy after disintegration and entry into the gastrointestinal tract.

[0017] Furthermore, the orally disintegrating tablet contains, by weight, 15-50 parts feneline, 2500-6000 parts filler, 20-80 parts disintegrant, 5-30 parts binder, 3-20 parts flavoring agent, and 3-15 parts lubricant.

[0018] More preferably, the orally disintegrating tablet contains, by weight, 30-50 parts fenelitonee, 20-30 parts fenelitonee, 3400-5100 parts filler, 30-40 parts disintegrant, 10-15 parts binder, 5-10 parts flavoring agent, and 5-8 parts lubricant.

[0019] Most specifically, a method for preparing phenelzine orally disintegrating tablets is characterized by comprising the following steps:

[0020] Step (1) Raw material processing: The main non-nelitone ketone, fillers mannitol and erythritol, disintegrants croscarmellose sodium cellulose and croscarmellose are passed through a 100-mesh sieve for later use; the binder povidone K30 and lubricant stearate fumarate are passed through a 200-mesh sieve for later use.

[0021] Step (2) Preparation of mixed powder: According to the mass parts, 3400-5100 parts of the sieved filler, 20-30 parts of the active ingredient fenelitonee, 30-40 parts of the disintegrant, 10-15 parts of povidone K30, and 5-10 parts of sucralose are added to a three-dimensional motion mixer and mixed for 10 minutes. Then, 5-8 parts of sodium stearate fumarate are added and the mixture is stirred for another 15 minutes to obtain the total mixed powder for later use. The mass ratio of mannitol to erythritol in the filler is 3:1, and the mass ratio of croscarmellose sodium to croscarmellose in the disintegrant is 1:1.5-2.5.

[0022] Step (3) Add the total powder mixture into the rotary tablet press and control the tableting speed. The hardness is controlled at 3-8 kg. The tablets are then obtained.

[0023] The present invention has the following technical effects:

[0024] Compared with ordinary fenelazine tablets, the orally disintegrating tablets of this invention do not require water or chewing. They disintegrate rapidly upon contact with saliva on the tongue and are propelled into the stomach by swallowing, achieving their therapeutic effect. The disintegration rate is as fast as 9 seconds. After disintegration, fenelazine can effectively exert its efficacy in the gastrointestinal tract. The drug has low irritation to the digestive tract mucosa, reducing adverse reactions caused by drug irritation. In terms of bioavailability and safety, it has the characteristics of high bioavailability and accurate and safe dosage. In terms of process route, the granulation process is short, simple and easy to operate, and direct mixing can lead to tableting. This preparation method is conducive to promotion. Detailed Implementation

[0025] The present invention will be specifically described below through embodiments. It should be noted that the following embodiments are only used to further illustrate the present invention and should not be construed as limiting the scope of protection of the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention based on the above description.

[0026] Example 1

[0027] A method for preparing fenelazol orally disintegrating tablets, comprising the following steps:

[0028] Step (1) Raw material processing: The main non-nelitone ketone, fillers mannitol and erythritol, disintegrants croscarmellose sodium cellulose and croscarmellose are passed through a 100-mesh sieve for later use; the binder povidone K30 and lubricant stearate fumarate are passed through a 200-mesh sieve for later use.

[0029] Step (2) Preparation of mixed powder: According to the mass parts, 3400-5100 parts of the sieved filler, 30 parts of the active ingredient fenelitonee, 35 parts of the disintegrant, 12 parts of povidone K30, and 8 parts of sucralose are added to a three-dimensional motion mixer and mixed for 10 minutes. Then, 6 parts of sodium stearate fumarate are added and the mixture is stirred and mixed for another 15 minutes to obtain the total mixed powder for later use. The mass ratio of mannitol to erythritol in the filler is 3:1, and the mass ratio of croscarmellose sodium to croscarmellose in the disintegrant is 1:2.

[0030] Step (3) Add the total powder mixture into the rotary tablet press and control the tableting speed. The hardness is controlled at 3-8 kg. The tablets are then obtained.

[0031] Three batches of fenelone orally disintegrating tablets (batch numbers BK-X2308001, BK-X2308002 and BK-X2308003, respectively) were prepared using the method in Example 1. The disintegration time of the fenelone orally disintegrating tablets was tested. Six parallel tests were repeated for each batch. The results are shown in Table 1.

[0032] Table 1: Disintegration time of each batch of fenelazol orally disintegrating tablets in Example 1

[0033]

[0034] The disintegration time of the orally disintegrating tablets is basically stable at 9–13 seconds, demonstrating excellent disintegration performance stability.

[0035] During the preparation process, the type, ratio, and amount of filler and disintegrant have different effects on the disintegration efficiency of fenelazol. By keeping the other components constant, we changed the selection and ratio of the filler and the type and ratio of the disintegrant, and statistically analyzed the disintegration rate of the prepared fenelazol orally disintegrating tablets. The results are shown in Table 2.

[0036] Table 2: Effect of fillers or disintegrants on disintegration time

[0037]

[0038] It can be seen that when other components remain constant, changes in the filler have a significant impact on the disintegration time of orally disintegrating tablets. When using a single filler, mannitol produces the shortest disintegration time. However, when using a combination of mannitol and erythritol as fillers in a 3:1 ratio, the disintegration time of the prepared tablets is significantly shortened. Considering the choice of disintegrant while keeping other components constant, PVPP produces the shortest disintegration time when using a single disintegrant. When using a combination of disintegrants, FMC and PVPP show the best effect, with the shortest disintegration time achieved when their ratio is controlled between 1:1.5 and 2.5.

[0039] The fenelitonee orally disintegrating tablets prepared in this invention were subjected to an in vitro simulation experiment to verify their effect after entering the gastrointestinal tract.

[0040] Test method: Prepare 900 mL of pH 1.2 hydrochloric acid buffer solution according to the dissolution test method. Use this solution as the dissolution medium. Set the rotation speed to 75 rpm for the slurry method. Take samples at 1 minute, 2 minutes, 4 minutes, 6 minutes, and 8 minutes to determine the solubility. The test results are shown in Table 3.

[0041] Table 3:

[0042]

[0043] The orally disintegrating fenelazol tablets prepared according to this invention do not affect the efficacy of the main component, fenelazol, upon entering the gastrointestinal tract. This effectively improves drug utilization while reducing drug irritation to the digestive tract mucosa and minimizing adverse reactions caused by drug irritation.

[0044] Example 2

[0045] A method for preparing fenelazol orally disintegrating tablets, comprising the following steps:

[0046] Step (1) Raw material processing: The main non-nelitone, filler lactose, disintegrant croscarmellose sodium and croscarmellose are passed through a 100-mesh sieve for later use; the binder povidone K30 and lubricant stearate fumarate sodium are passed through a 200-mesh sieve for later use;

[0047] Step (2) Preparation of mixed powder: According to the mass fraction, 2500 parts of the sieved filler, 15 parts of the active ingredient fenelitonee, 20 parts of the disintegrant, 5 parts of povidone K30, and 10 parts of sucrose are added to a three-dimensional motion mixer and mixed for 10 minutes. Then, 3 parts of sodium stearate fumarate are added and the mixture is stirred for another 15 minutes to obtain the total mixed powder for later use. The mass ratio of mannitol to erythritol in the filler is 3:1, and the mass ratio of croscarmellose sodium to croscarmellose in the disintegrant is 1:1.5.

[0048] Step (3) Add the total powder mixture into the rotary tablet press and control the tableting speed. The hardness is controlled at 3-8 kg. The tablets are then obtained.

[0049] The fenelazol orally disintegrating tablets prepared in this embodiment have a disintegration time of 11–14 seconds. Orally disintegrating tablets can effectively improve drug utilization while reducing drug irritation to the gastrointestinal mucosa and minimizing adverse reactions caused by drug irritation.

[0050] Example 3

[0051] A method for preparing fenelazol orally disintegrating tablets, comprising the following steps:

[0052] Step (1) Raw material processing: The main non-nelitone ketone, fillers mannitol and erythritol, and disintegrant crosslinked polyvinyl ketone are passed through a 100-mesh sieve for later use; the binder polyvinyl ketone K30 and lubricant sodium stearate fumarate are passed through a 200-mesh sieve for later use.

[0053] Step (2) Preparation of mixed powder: According to the mass parts, 6000 parts of the sieved filler, 50 parts of the active ingredient fenelitonee, 80 parts of the disintegrant, 30 parts of povidone K30 and 20 parts of aspartame are added to a three-dimensional motion mixer and mixed for 10 minutes. Then, 15 parts of sodium stearate fumarate are added and the mixture is stirred and mixed for another 15 minutes to obtain the total mixed powder for later use. The mass ratio of mannitol to erythritol in the filler is 3:1, and the mass ratio of croscarmellose sodium to croscarmellose in the disintegrant is 1:2.5.

[0054] Step (3) Add the total powder mixture into the rotary tablet press and control the tableting speed. The hardness is controlled at 3-8 kg. The tablets are then obtained.

[0055] The fenelazol orally disintegrating tablets prepared in this embodiment have a disintegration time of 11–15 seconds. Orally disintegrating tablets can effectively improve drug utilization while reducing drug irritation to the gastrointestinal mucosa and minimizing adverse reactions caused by drug irritation.

Claims

1. A process for the preparation of a non-friable tablet of finerenone, characterized by: The tablet is prepared by mixing and compressing phenelzine as the main drug with fillers, disintegrants, binders, flavoring agents and lubricants as excipients. The fillers are composed of mannitol and erythritol in a mass ratio of 3:

1. The disintegrants are composed of croscarmellose sodium and croscarmellose in a mass ratio of 1:1.5 to 2.

5. The binders are at least one of hydroxypropyl methylcellulose, croscarmellose sodium, and povidone K30. The lubricants are at least one of silica, magnesium stearate and sodium stearate fumarate.

2. A process for the preparation of a non-fenretinide orally disintegrating tablet as claimed in claim 1, wherein: In the phenelzine orally disintegrating tablets, the binder in the excipients is povidone K30 and the lubricant is sodium stearate fumarate.

3. A process for preparing a non-friable finasteride orally disintegrating tablet according to claim 1 or 2, characterized in that: The orally disintegrating tablets contain, by weight, 15-50 parts feneline, 2500-6000 parts filler, 20-80 parts disintegrant, 5-30 parts binder, 3-20 parts flavoring agent, and 3-15 parts lubricant.

4. A process for the preparation of a non-friable film tablet of finerenone, characterized in that, Follow these steps: Step (1) Raw material processing: The active pharmaceutical ingredient phenelzine, the fillers mannitol and erythritol, the disintegrants croscarmellose sodium and croscarmellose sodium are passed through a 100-mesh sieve for later use; the binder povidone K30 and the lubricant stearate fumarate sodium are passed through a 200-mesh sieve for later use. Step (2) Preparation of mixed powder: According to the mass parts, 3400~5100 parts of the sieved filler, 20~30 parts of the active ingredient fenelitonee, 30~40 parts of the disintegrant, 10~15 parts of povidone K30 and 5~10 parts of sucralose are added to a three-dimensional motion mixer and mixed for 10 minutes. Then add 5~8 parts of sodium stearate fumarate and continue to stir and mix for 15 minutes to obtain the total mixed powder for later use. The mass ratio of mannitol to erythritol in the filler is 3:1, and the mass ratio of croscarmellose sodium cellulose to croscarmellose in the disintegrant is 1:1.5~2.

5. Step (3) Add the total powder mixture into the rotary tablet press and control the tableting speed. The hardness is controlled at 3~8kg. The tablets are then obtained.

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