Slexipag orally disintegrating tablet and preparation method thereof

Abstract

In the preparation process, mannitol and microcrystalline cellulose are used as filling agents, polyvinylpolypyrrolidone and low-substituted hydroxy propyl cellulose are used as disintegrating agents, and aspartame and menthol are used as taste masking agents, so that the problems of poor material fluidity, sticking, easiness in cracking during tabletting and the like are solved; by adopting a direct tabletting method, the adverse effect of high temperature and high humidity on the selexipag is reduced, and the selexipag tablet has the advantages of rapid disintegration within 30 seconds, rapid dissolution, better compressibility, better stability, good taste, simple preparation method and the like, is more suitable for patients with dysphagia, especially the old and children, has great clinical significance and is worthy of popularization and application. The method is suitable for large-scale industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a selipag oral disintegrating tablet and a preparation method thereof. BACKGROUND

[0002] Pulmonary arterial hypertension (PAH) is a progressive and malignant disease, and patients often need long-term medication for maintenance treatment. Selipag, as an orally effective prostacyclin receptor agonist, has become an important drug for the treatment of PAH, but the existing ordinary tablet of selipag has obvious limitations in administration: elderly patients and patients with advanced PAH combined with right heart failure often have dysphagia, and the ordinary tablet is easy to cause coughing and aspiration risk; the compliance of some patients is reduced due to difficulty in taking medicine, which affects the treatment effect.

[0003] The oral disintegrating tablet is a new oral dosage form, which can be quickly disintegrated in the oral cavity without water, and significantly improves the medication experience of patients with dysphagia. However, selipag has the physicochemical properties of being easily oxidized and sensitive to moisture, and a high proportion of disintegrating agent commonly used in the preparation of conventional oral disintegrating tablets may lead to a decrease in drug stability, and the poor flowability of the material in the direct tabletting process and the easy cracking of the tablet during tabletting have not been solved. Therefore, it is an urgent need in the field to develop a selipag oral disintegrating tablet that disintegrates rapidly, has good stability, has a suitable taste, and has a simple preparation method. SUMMARY

[0004] The purpose of the present application is to provide a selipag oral disintegrating tablet based on the prior art, which uses mannitol and microcrystalline cellulose as fillers, cross-linked polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose as disintegrating agents, and aspartame and menthol as taste masking agents, solves the problems of poor material flowability, sticking, and easy cracking of the tablet during tabletting, uses a direct tabletting method, reduces the adverse effects of high temperature and humidity on selipag, has the advantages of rapid disintegration within 30 seconds, rapid dissolution, good compressibility, good stability, good taste, simple preparation method, etc., is more suitable for patients with dysphagia, especially the elderly and children, has great clinical significance, is suitable for large-scale industrial production, and is more suitable for patients with dysphagia, especially the elderly and children.

[0005] Another purpose of the present application is to provide a preparation method of the above-mentioned selipag oral disintegrating tablet.

[0006] The technical solution of the present application is as follows:

[0007] A selipag oral disintegrating tablet, comprising active ingredient selipag and excipients, is made from the following components by weight: selipag 20-50 parts, filler 80-150 parts, disintegrating agent 30-60 parts, taste masking agent 5-20 parts, glidant 1-5 parts, lubricant 1-5 parts. The filler is mannitol and microcrystalline cellulose, the disintegrating agent is cross-linked polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose, the taste masking agent is aspartame and menthol, the glidant is colloidal silicon dioxide, and the lubricant is sodium stearyl fumarate.

[0008] For the present application, in the preparation of the oral disintegrating tablet, selipag and the filler are mixed uniformly, and then the disintegrating agent, the taste masking agent, colloidal silicon dioxide and sodium stearyl fumarate are added in sequence, and the stirring is continued until the dispersion is uniform, and then the tablet is pressed.

[0009] In the present application, the selipag is micronized and the particle size is controlled to be 5-10 μm.

[0010] In the present application, the filler is mannitol and microcrystalline cellulose, wherein the mannitol has high water solubility and can promote the rapid dissolution of the tablet in the oral cavity, and the microcrystalline cellulose can improve the flowability and compressibility of the material, and the mannitol and the microcrystalline cellulose as the filler can be compounded to form a synergistic effect, and the amount of the filler and the weight ratio of the mannitol and the microcrystalline cellulose can alleviate the problems of slow disintegration rate of the oral disintegrating tablet and poor flowability of the material in the direct tablet pressing process, and the problems of sticking, tablet cracking and the like in the tablet pressing process can be alleviated.

[0011] In a preferred embodiment, the weight ratio of the mannitol and the microcrystalline cellulose in the filler is 1.2-2.3:1, which can be but is not limited to 1.2:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.2:1, 2.3:1 or 2.5:1, and further preferably, the weight ratio of the mannitol and the microcrystalline cellulose in the filler is 1.5-2.0:1.

[0012] In the present application, the disintegrating agent is cross-linked polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose, wherein the cross-linked polyvinylpyrrolidone has high swelling property, and the low-substituted hydroxypropyl cellulose has both hydrophilicity and capillary effect, and the two can be compounded to form a synergistic effect, and the amount of the disintegrating agent and the weight ratio of the cross-linked polyvinylpyrrolidone and the low-substituted hydroxypropyl cellulose can promote the rapid disintegration of the oral disintegrating tablet in a short time.

[0013] In a preferred embodiment, the weight ratio of crospovidone and low-substituted hydroxypropyl cellulose in the disintegrant is 1.2-2.8:1, which can be but is not limited to 1.2:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.2:1, 2.3:1, 2.5:1, 2.6:1 or 2.8:1, and further preferably, the weight ratio of crospovidone and low-substituted hydroxypropyl cellulose in the filler is 1.5-2.5:1.

[0014] In the present application, the taste-masking agent is aspartame and menthol, aspartame has a sweet taste to mask the bitter taste, menthol has a cooling taste and further neutralizes the peculiar smell of the drug, and aspartame and menthol can be compounded to form a synergistic effect, the amount of the taste-masking agent and the weight ratio of aspartame and menthol can be controlled to greatly improve the taste and have a good taste-masking effect.

[0015] In a preferred embodiment, the weight ratio of aspartame and menthol in the taste-masking agent is 1.2-2.8:1, which can be but is not limited to 1.2:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.2:1, 2.3:1, 2.5:1, 2.6:1 or 2.8:1, and further preferably, the weight ratio of aspartame and menthol in the filler is 1.5-2.5:1.

[0016] In the present application, the glidant is colloidal silicon dioxide, which can effectively reduce the friction between materials and improve the flowability to ensure the stability of tablet weight difference during tabletting; the lubricant is sodium stearyl fumarate, which can reduce the adhesion of materials to the die of the tablet machine to avoid problems such as cracking and sticking, and ensure that the tablet appearance and hardness are qualified.

[0017] In a preferred embodiment, the selitogepag orally disintegrating tablet mentioned in the present application is prepared from the following components in parts by weight: selitogepag 25-35 parts, filler 100-140 parts, disintegrant 40-50 parts, taste-masking agent 9-12 parts, colloidal silicon dioxide 2.5-3.5 parts, and sodium stearyl fumarate 1.5-2.5 parts; the weight ratio of mannitol and microcrystalline cellulose in the filler is 1.5-2.0:1; the weight ratio of crospovidone and low-substituted hydroxypropyl cellulose in the disintegrant is 1.5-2.5:1; and the weight ratio of aspartame and menthol in the taste-masking agent is 1.5-2.5:1.

[0018] In a more preferred aspect, the selitrexed orally disintegrating tablet mentioned in the present application is prepared from the following components by weight: selitrexed 30 parts, filler 100-140 parts, disintegrant 42-48 parts, taste masking agent 9-12 parts, colloidal silicon dioxide 3.0 parts, sodium stearyl fumarate 2.0 parts; the weight ratio of mannitol and microcrystalline cellulose in the filler is 1.5-2.0:1; the weight ratio of crospovidone and low-substituted hydroxypropyl cellulose in the disintegrant is 1.5-2.5:1; the weight ratio of aspartame and menthol in the taste masking agent is 1.5-2.5:1.

[0019] In a more preferred aspect, the selitrexed orally disintegrating tablet mentioned in the present application is prepared from the following components by weight: selitrexed 30 parts, filler 100-140 parts, disintegrant 42-48 parts, taste masking agent 9-12 parts, colloidal silicon dioxide 3.0 parts, sodium stearyl fumarate 2.0 parts; the weight ratio of mannitol and microcrystalline cellulose in the filler is 1.5-2.0:1; the weight ratio of crospovidone and low-substituted hydroxypropyl cellulose in the disintegrant is 2.0:1; the weight ratio of aspartame and menthol in the taste masking agent is 2.0:1.

[0020] For example, the selitrexed orally disintegrating tablet mentioned in the present application is prepared from the following components by weight: selitrexed 30 parts, filler 100 parts (mannitol 63 parts, microcrystalline cellulose 37 parts, weight ratio 1.7:1), disintegrant 45 parts (crospovidone 30 parts, low-substituted hydroxypropyl cellulose 15 parts, weight ratio 2.0:1), taste masking agent 9 parts (aspartame 6.0 parts, menthol 3.0 parts, weight ratio 2.0:1), colloidal silicon dioxide 3.0 parts, sodium stearyl fumarate 2.0 parts. The selitrexed is micronized to control the particle size at 5-10 μm.

[0021] For example, the selitrexed orally disintegrating tablet mentioned in the present application is prepared from the following components by weight: selitrexed 30 parts, filler 100 parts (mannitol 63 parts, microcrystalline cellulose 37 parts, weight ratio 1.7:1), disintegrant 45 parts (crospovidone 30 parts, low-substituted hydroxypropyl cellulose 15 parts, weight ratio 2.0:1), taste masking agent 9 parts (aspartame 6.0 parts, menthol 3.0 parts, weight ratio 2.0:1), colloidal silicon dioxide 3.0 parts, sodium stearyl fumarate 2.0 parts. The selitrexed is micronized to control the particle size at 5-10 μm.

[0022] For example, the selipag oral disintegrating tablet mentioned in the present application is made of the following components by weight: selipag 30 parts, filler 120 parts (mannitol 72 parts, microcrystalline cellulose 48 parts, weight ratio 1.5:1), disintegrating agent 45 parts (crospovidone 30 parts, low-substituted hydroxypropyl cellulose 15 parts, weight ratio 2.0:1), taste masking agent 9 parts (aspartame 6.0 parts, menthol 3.0 parts, weight ratio 2.0:1), colloidal silicon dioxide 3.0 parts, sodium stearyl fumarate 2.0 parts. Selipag is micronized to control the particle size at 5-10 μm.

[0023] For example, the selipag oral disintegrating tablet mentioned in the present application is made of the following components by weight: selipag 30 parts, filler 120 parts (mannitol 72 parts, microcrystalline cellulose 48 parts, weight ratio 1.5:1), disintegrating agent 45 parts (crospovidone 30 parts, low-substituted hydroxypropyl cellulose 15 parts, weight ratio 2.0:1), taste masking agent 9 parts (aspartame 6.0 parts, menthol 3.0 parts, weight ratio 2.0:1), colloidal silicon dioxide 3.0 parts, sodium stearyl fumarate 2.0 parts. Selipag is micronized to control the particle size at 5-10 μm.

[0024] For example, the selipag oral disintegrating tablet mentioned in the present application is made of the following components by weight: selipag 30 parts, filler 120 parts (mannitol 72 parts, microcrystalline cellulose 48 parts, weight ratio 1.5:1), disintegrating agent 45 parts (crospovidone 30 parts, low-substituted hydroxypropyl cellulose 15 parts, weight ratio 2.0:1), taste masking agent 9 parts (aspartame 6.0 parts, menthol 3.0 parts, weight ratio 2.0:1), colloidal silicon dioxide 3.0 parts, sodium stearyl fumarate 2.0 parts. Selipag is micronized to control the particle size at 5-10 μm.

[0025] For example, the selipag oral disintegrating tablet mentioned in the present application is made of the following components by weight: selipag 30 parts, filler 120 parts (mannitol 72 parts, microcrystalline cellulose 48 parts, weight ratio 1.5:1), disintegrating agent 45 parts (crospovidone 30 parts, low-substituted hydroxypropyl cellulose 15 parts, weight ratio 2.0:1), taste masking agent 9 parts (aspartame 6.0 parts, menthol 3.0 parts, weight ratio 2.0:1), colloidal silicon dioxide 3.0 parts, sodium stearyl fumarate 2.0 parts. Selipag is micronized to control the particle size at 5-10 μm.

[0026] For example, the selipag oral disintegrating tablet mentioned in the present application is made of the following components by weight: selipag 30 parts, filler 120 parts (mannitol 75.6 parts, microcrystalline cellulose 44.4 parts, weight ratio 1.7:1), disintegrating agent 48 parts (crospovidone 32 parts, low-substituted hydroxypropyl cellulose 16 parts, weight ratio 2.0:1), taste masking agent 9 parts (aspartame 6.0 parts, menthol 3.0 parts, weight ratio 2.0:1), colloidal silicon dioxide 3.0 parts, sodium stearyl fumarate 2.0 parts. The selipag is micronized, and the particle size is controlled to be 5-10 μm.

[0027] For example, the selipag oral disintegrating tablet mentioned in the present application is made of the following components by weight: selipag 30 parts, filler 120 parts (mannitol 75.6 parts, microcrystalline cellulose 44.4 parts, weight ratio 1.7:1), disintegrating agent 45 parts (crospovidone 27 parts, low-substituted hydroxypropyl cellulose 18 parts, weight ratio 1.5:1), taste masking agent 9 parts (aspartame 6.0 parts, menthol 3.0 parts, weight ratio 2.0:1), colloidal silicon dioxide 3.0 parts, sodium stearyl fumarate 2.0 parts. The selipag is micronized, and the particle size is controlled to be 5-10 μm.

[0028] For example, the selipag oral disintegrating tablet mentioned in the present application is made of the following components by weight: selipag 30 parts, filler 120 parts (mannitol 75.6 parts, microcrystalline cellulose 44.4 parts, weight ratio 1.7:1), disintegrating agent 45 parts (crospovidone 32.2 parts, low-substituted hydroxypropyl cellulose 12.8 parts, weight ratio 2.5:1), taste masking agent 9 parts (aspartame 6.0 parts, menthol 3.0 parts, weight ratio 2.0:1), colloidal silicon dioxide 3.0 parts, sodium stearyl fumarate 2.0 parts. The selipag is micronized, and the particle size is controlled to be 5-10 μm.

[0029] For example, the selipag oral disintegrating tablet mentioned in the present application is made of the following components by weight: selipag 30 parts, filler 120 parts (mannitol 75.6 parts, microcrystalline cellulose 44.4 parts, weight ratio 1.7:1), disintegrating agent 45 parts (crospovidone 30 parts, low-substituted hydroxypropyl cellulose 15 parts, weight ratio 2.0:1), taste masking agent 12 parts (aspartame 8.0 parts, menthol 4.0 parts, weight ratio 2.0:1), colloidal silicon dioxide 3.0 parts, sodium stearyl fumarate 2.0 parts. The selipag is micronized, and the particle size is controlled to be 5-10 μm.

[0030] The present application also provides a preparation method of the above-mentioned selipag oral disintegrating tablet, which comprises the following steps:

[0031] (1) Pretreatment: micronize the selipag, and sieve the auxiliary fillers, disintegrating agents and taste masking agents for standby use;

[0032] (2) Mixing: mix selitogepa and fillers evenly, then add disintegrants, taste masking agents, glidants and lubricants in sequence, continuously stir until evenly dispersed, and then compress into tablets.

[0033] For the present application, in step (1), selitogepa is micronized to control the particle size to be 5-10 μm.

[0034] In step (1), the excipients fillers and disintegrants are sieved through a 100-150 mesh sieve, preferably a 120 mesh sieve. The excipients taste masking agents are sieved through a 60-100 mesh sieve, preferably an 80 mesh sieve.

[0035] In step (2), the weight ratio of mannitol and microcrystalline cellulose in the fillers is 1.2-2.3:1, which can be but is not limited to 1.2:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.2:1, 2.3:1 or 2.5:1, and further preferably, the weight ratio of mannitol and microcrystalline cellulose in the fillers is 1.5-2.0:1.

[0036] In step (2), the weight ratio of crospovidone and low-substituted hydroxypropyl cellulose in the disintegrants is 1.2-2.8:1, which can be but is not limited to 1.2:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.2:1, 2.3:1, 2.5:1, 2.6:1 or 2.8:1, and preferably, the weight ratio of crospovidone and low-substituted hydroxypropyl cellulose in the fillers is 1.5-2.5:1.

[0037] In step (2), the weight ratio of aspartame and menthol in the taste masking agents is 1.2-2.8:1, which can be but is not limited to 1.2:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.2:1, 2.3:1, 2.5:1, 2.6:1 or 2.8:1, and preferably, the weight ratio of aspartame and menthol in the fillers is 1.5-2.5:1.

[0038] In the present application, the glidant is colloidal silicon dioxide, which can effectively reduce the friction between materials, improve the flowability and ensure the stability of tablet weight difference during compression; the lubricant is sodium stearyl fumarate, which can reduce the adhesion of materials to the die of the tablet press, avoid problems such as cracking and sticking, and ensure the qualification of tablet appearance and hardness.

[0039] The technical solution of the present application has the following advantages:

[0040] The present application provides a preparation method of the slpargepage orally disintegrating tablet, which uses mannitol and microcrystalline cellulose as fillers, uses cross-linked polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose as disintegrants, and uses aspartame and menthol as taste masking agents, so as to solve the problems of poor material flowability, sticking, and tablet cracking during tabletting, and to reduce the adverse effects of high temperature and humidity on slpargepage by using a direct tabletting method, so that the slpargepage orally disintegrating tablet has the advantages of rapid disintegration within 30 seconds, rapid dissolution, good compressibility, good stability, good taste, simple preparation method, etc., and is more suitable for patients with difficulty in swallowing, especially the elderly and children, has great clinical significance, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0041] The present application can be better understood according to the following examples. However, those skilled in the art will readily understand that the content described in the examples is only for illustration of the present application and should not and will not limit the present application described in detail in the claims.

[0042] Examples 1-10

[0043] A slpargepage orally disintegrating tablet is prepared from the following components by weight, and the components and weights of examples 1-10 are shown in Table 1.

[0044] Table 1: Components and amounts

[0045]

[0046] The preparation method of the slpargepage orally disintegrating tablet in example 1 includes the following steps:

[0047] (1) Pretreatment: The slpargepage is micronized to control the particle size to be 5-10 μm; the fillers (mannitol and microcrystalline cellulose) and the disintegrants (cross-linked polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose) are sieved through a 120-mesh sieve, and the taste masking agents (aspartame and menthol) are sieved through an 80-mesh sieve, and are ready for use;

[0048] (2) Mixing: The slpargepage, mannitol, and microcrystalline cellulose are mixed uniformly, cross-linked polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose are added, and stirred and dispersed uniformly, and then aspartame, menthol, colloidal silicon dioxide, and sodium fumarate are added, and stirred and dispersed again;

[0049] (3) Tabletting: The mixture obtained in step (2) is tabletted by using a rotary tabletting machine, the tabletting speed is controlled to be 30-50 tablets per minute, the tablet hardness is controlled to be 3-5 kgf, and the tablet weight difference is controlled to be within ±4%, and the orally disintegrating tablet is obtained.

[0050] In the preparation method, compared with example 1, the difference between examples 2-10 lies in the total amount and the ratio between the components of the fillers, the disintegrants, and the taste masking agents.

[0051] Comparative Examples 1-10

[0052] A selipag oral disintegration tablet was made from the following components by weight, the components and weights of Comparative Example 1-5 are shown in Table 2.

[0053] Table 2 Components and amounts

[0054] Component Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Selipag (5-10 μm) 30 parts 30 parts 30 parts 30 parts 30 parts Mannitol 60 parts 85.7 parts 75.6 parts 75.6 parts 75.6 parts Microcrystalline cellulose 60 parts 34.3 parts 44.4 parts 44.4 parts 44.4 parts Crospovidone 30 parts 30 parts 22.5 parts 33.75 parts 30 parts Low-substituted hydroxypropyl cellulose 15 parts 15 parts 22.5 parts 11.25 parts 15 parts Aspartame 6.0 parts 6.0 parts 6.0 parts 6.0 parts 6.75 parts Menthol 3.0 parts 3.0 parts 3.0 parts 3.0 parts 2.25 parts Colloidal silicon dioxide 3.0 parts 3.0 parts 3.0 parts 3.0 parts 3.0 parts Sodium stearyl fumarate 2.0 parts 2.0 parts 2.0 parts 2.0 parts 2.0 parts

[0055] The preparation methods of Comparative Examples 1-2, Comparative Examples 3-4 and Comparative Example 5 were basically the same as Example 1, except that the proportions of mannitol and microcrystalline cellulose in the filler were different, the proportions of crospovidone and low-substituted hydroxypropyl cellulose in the disintegrant were different, and the proportions of aspartame and menthol in the taste masking agent were different.

[0056] Effect verification

[0057] Disintegration time: According to the disintegration time limit inspection method introduced in the 0921 Tablets General Introduction of the Chinese Pharmacopoeia 2025 Edition (Volume 4), one tablet of the product should be completely disintegrated and pass through the sieve within 60 seconds. If there is a small amount of light floating or adhering to the inner wall of the stainless steel tube or the sieve, but no hard core, it can be considered to meet the requirements.

[0058] Dissolution: According to the dissolution and release determination method introduced in the 0931 Tablets General Introduction of the Chinese Pharmacopoeia 2025 Edition (Volume 4), the dissolution results of the sample in pH 6.8 phosphate buffer were investigated, and the dissolution was determined at 30 min.

[0059] Taste evaluation experiment:

[0060] Volunteer requirements: 10, half male and half female, no oral diseases, fasting and drinking prohibited 1 hour before the experiment.

[0061] Evaluation process: The volunteers took the sample orally without drinking water, and recorded the disintegration time (subjective feeling).

[0062] Score according to the following dimensions (1-5 points, 5 points for the best):

[0063] Disintegration speed: 5 points = rapid disintegration, 3 points = moderate disintegration speed, 1 point = slow disintegration.

[0064] Taste: 5 points = no bitterness, 3 points = slight bitterness, 1 point = obvious bitterness.

[0065] Gravel feeling: 5 points = no gravel feeling, 3 points = slight grainy feeling, 1 point = obvious gravel feeling.

[0066] The disintegration time, dissolution, taste and stability of the oral disintegration tablets obtained in the examples and comparative examples were investigated, and the results are shown in Table 3.

[0067] Table 3 Disintegration time, dissolution, taste and stability results

[0068]

[0069] The above examples 1-10 all use the preparation method described in the present application, and the results show that the disintegration time of the sample is ≤30 seconds, and the 15 min dissolution is >90%, which meets the requirements. In Comparative Example 1 and Comparative Example 2, the ratio of mannitol and microcrystalline cellulose in the filler is 1:1 and 2.5:1, the disintegration time is 38 seconds and 45 seconds, and the dissolution is 86.0% and 89.9%, which shows that too low or too high ratio of mannitol and microcrystalline cellulose in the filler leads to slow disintegration time, reduced dissolution, high content of related substances, and low stability; in Comparative Example 3 and Comparative Example 4, the ratio of crospovidone and low-substituted hydroxypropyl cellulose in the disintegrant is 1:1 and 3:1, the disintegration time is 61 seconds and 49 seconds, and the dissolution is 90.7% and 91.4%, which shows that too low or too high ratio of crospovidone and low-substituted hydroxypropyl cellulose in the disintegrant leads to slow disintegration time, reduced dissolution, high content of related substances, and low stability.

[0070] The taste score of each of examples 1-10 is ≥4.0, which meets the design target. In Comparative Example 5, the ratio of aspartame and menthol is 3.0:1 (too high), and the taste score is slightly low, which shows that too high ratio of taste masking agent may affect the taste.

[0071] The results in examples 1-10 show that, by using appropriate prescription ratio, the prepared sample has rapid disintegration within 30 seconds, rapid dissolution, good compressibility, good stability, and good taste.

[0072] Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

[0073] The above examples are only used to illustrate the technical solutions of the present application, and not to limit it; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that they can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacements for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A selepag orally disintegrating tablet, characterized in that, It is made from the following components in parts by weight: 20-50 parts of selepag, 80-150 parts of filler, 30-60 parts of disintegrant, 5-20 parts of flavor masker, 1-5 parts of flow aid, and 1-5 parts of lubricant. The filler is mannitol and microcrystalline cellulose, the disintegrant is crospovidone and low-substituted hydroxypropyl cellulose, the flavor masker is aspartame and menthol, the flow aid is colloidal silica, and the lubricant is sodium fumarate stearate.

2. The selepag orally disintegrating tablet according to claim 1, characterized in that, In its preparation process, selepag and filler are mixed evenly, and then disintegrant, flavor masker, colloidal silica and sodium fumarate stearate are added in sequence. The mixture is stirred continuously until it is evenly dispersed, and then compressed into tablets to obtain the final product.

3. The selepag orally disintegrating tablet according to claim 2, characterized in that, The filler has a mannitol to microcrystalline cellulose weight ratio of 1.2-2.3:1, preferably 1.5-2.0:1; the disintegrant has a cross-linked povidone to low-substituted hydroxypropyl cellulose weight ratio of 1.2-2.8:1, preferably 1.5-2.5:1; and the flavor masker has an aspartame to menthol weight ratio of 1.2-2.8:1, preferably 1.5-2.5:

1.

4. The selepag orally disintegrating tablet according to claim 3, characterized in that, It is made from the following components in parts by weight: 25-35 parts of selepag, 100-140 parts of filler, 40-50 parts of disintegrant, 9-12 parts of flavor masker, 2.5-3.5 parts of colloidal silica, and 1.5-2.5 parts of sodium fumarate stearate; the weight ratio of mannitol to microcrystalline cellulose in the filler is 1.5-2.0:1; the weight ratio of crospovidone to low-substituted hydroxypropyl cellulose in the disintegrant is 1.5-2.5:1; and the weight ratio of aspartame to menthol in the flavor masker is 1.5-2.5:

1.

5. The selepag orally disintegrating tablet according to claim 4, characterized in that, It is made from the following components in parts by weight: 30 parts selepag, 100-140 parts filler, 42-48 parts disintegrant, 9-12 parts flavor masker, 3.0 parts colloidal silica, and 2.0 parts sodium fumarate stearate; the weight ratio of mannitol to microcrystalline cellulose in the filler is 1.5-2.0:1; the weight ratio of crospovidone to low-substituted hydroxypropyl cellulose in the disintegrant is 1.5-2.5:1; and the weight ratio of aspartame to menthol in the flavor masker is 1.5-2.5:

1.

6. The selepag orally disintegrating tablet according to claim 5, characterized in that, It is made from the following components in parts by weight: 30 parts selepag, 100-140 parts filler, 42-48 parts disintegrant, 9-12 parts flavor masker, 3.0 parts colloidal silica, and 2.0 parts sodium fumarate stearate; the weight ratio of mannitol to microcrystalline cellulose in the filler is 1.5-2.0:1; the weight ratio of crospovidone to low-substituted hydroxypropyl cellulose in the disintegrant is 2.0:1; and the weight ratio of aspartame to menthol in the flavor masker is 2.0:

1.

7. The selepag orally disintegrating tablet according to any one of claims 1-6, characterized in that, The particle size of the sleipag is 5-10 μm.

8. The method for preparing selexipag orally disintegrating tablets according to claim 1, characterized in that, Includes the following steps: (1) Pretreatment: Sleipag is micronized, and excipients, fillers, disintegrants and flavor maskers are sieved and set aside. (2) Mixing: Mix sleipag and filler evenly, then add disintegrant, flavor masker, flow aid and lubricant in sequence, and continue stirring until evenly dispersed, then compress into tablets to obtain the product.

9. The method for preparing selepag orally disintegrating tablets according to claim 8, characterized in that, In step (1), Sleipag is micronized to control the particle size to 5-10 μm; excipients, fillers and disintegrants are passed through a 100-150 mesh sieve, preferably 120 mesh; excipients, flavor masking agents are passed through a 60-100 mesh sieve, preferably 80 mesh.

10. The method for preparing selepag orally disintegrating tablets according to claim 8, characterized in that, In step (2), the weight ratio of mannitol to microcrystalline cellulose in the filler is 1.2-2.3:1, preferably 1.5-2.0:1; the weight ratio of crospovidone to low-substituted hydroxypropyl cellulose in the disintegrant is 1.2-2.8:1, preferably 1.5-2.5:1; and the weight ratio of aspartame to menthol in the flavor masker is 1.2-2.8:1, preferably 1.5-2.5:1.

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