A highly stable composition of leflunomide and a method for preparing the same

Abstract

The application provides a high-stability leflunomide composition and a preparation method thereof, and belongs to the field of medicines.The composition comprises an active ingredient, a water-soluble film material, an anti-sticking agent, a plasticizer and a pore-forming agent, wherein the active ingredient is leflunomide, and the leflunomide is wrapped in a mixture of the water-soluble film material, the anti-sticking agent, the plasticizer and the pore-forming agent.The composition has good stability, can be not coated with a film coating, does not need to add a drying agent, has simple production operation, stable product quality and low cost.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a highly stable leflunomide composition and its preparation method. Background Technology

[0002] Leflunomide tablets are the original drug developed by Sanofi-Aventis as ARAVA, which was approved by the U.S. Food and Drug Administration in 1998 for the treatment of active moderate to severe rheumatoid arthritis and psoriasis. Leflunomide exerts its effect by inhibiting mitochondrial dihydroorotate dehydrogenase (DHODH), an enzyme that plays a crucial role in the synthesis of uridine monophosphate (rUMP), required for the synthesis of DNA and RNA. Therefore, leflunomide inhibits the proliferation of rapidly dividing cells, especially lymphocytes.

[0003] Leflunomide is a drug with low solubility and high permeability. Studies have shown that micronizing the leflunomide particles significantly improves its water solubility, thereby greatly enhancing its bioavailability. However, micronization of the raw material increases the specific surface area, making it more susceptible to degradation into teriflunomide due to external environmental factors. Teriflunomide is a strictly controlled impurity II listed in the Chinese Pharmacopoeia for leflunomide.

[0004] Leflunomide is a prodrug whose active metabolite, teriflunomide (i.e., impurity II in the Chinese Pharmacopoeia), is formed by the ring-opening of the isoxazole ring of leflunomide. Structural analysis and experiments have revealed that this ring-opening reaction is susceptible to pH, temperature, and humidity. Currently, commercially available leflunomide tablets are packaged in double aluminum foil blister packs or bottles with desiccants to prevent external humidity from affecting product quality. Patent WO2007118684A1 proposes a method for improving the stability of leflunomide tablets by adding an acidic substance internally. While this method can temporarily improve the stability of the composition, long-term stability issues may still arise during storage, especially in high-humidity areas. Patent CN201711457877 improves stability by adding different micronized organic acids internally and externally, but its production process is cumbersome, requiring micronized raw materials with controlled particle size, resulting in high production costs and hindering commercial production.

[0005] Therefore, there is still an urgent need for a leflunomide composition that is stable, easy to operate, and requires no special treatment of excipients. Summary of the Invention

[0006] To address the issues of decreased product quality and stability resulting from increased production utilization, and to facilitate commercial production, we have developed a unique water-soluble coating material—polyvinyl alcohol (PVA)—through continuous experimentation. The inventors discovered that PVA, when used in combination with certain excipients, can form a moisture-proof coating film, preventing moisture from penetrating the leflunomide composition and protecting the original leflunomide from external environmental factors. The coated leflunomide can then be directly mixed with other excipients and compressed into tablets. This process is simple, requires no special treatment of the excipients, and can be purchased and used directly. The formulation and operation not only solve the stability issues of leflunomide formulations but also significantly reduce commercial production costs.

[0007] To address the aforementioned technical problems, the present invention provides the following technical solutions.

[0008] In a first aspect, the present invention provides a composition.

[0009] A composition comprising: an active ingredient, a water-soluble film material, an anti-adhesion agent, a plasticizer, and a pore-forming agent, wherein the active ingredient is leflunomide, and the leflunomide is encapsulated within a mixture of the water-soluble film material, the anti-adhesion agent, the plasticizer, and the pore-forming agent.

[0010] In some embodiments, the water-soluble film material includes at least one selected from polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, and corn gluten. In some preferred embodiments, the water-soluble film material is polyvinyl alcohol.

[0011] In some embodiments, the polyvinyl alcohol is a partially hydrolyzed polyvinyl alcohol. In some preferred embodiments, the polyvinyl alcohol is polyvinyl alcohol 1788.

[0012] In some embodiments, the anti-adhesion agent includes at least one selected from glyceryl monostearate, glyceryl caprylate, talc, and magnesium stearate. In some preferred embodiments, the anti-adhesion agent is glyceryl monostearate.

[0013] In some embodiments, the plasticizer includes at least one selected from propylene glycol, glycerin, triethyl citrate, and polyethylene glycol 6000. In some preferred embodiments, the plasticizer is propylene glycol.

[0014] In some embodiments, the porogen includes at least one of lactose or sucrose. In some preferred embodiments, the porogen is lactose.

[0015] In some embodiments, the particle size D90 of the active ingredient is ≤50 μm.

[0016] In some preferred embodiments, the water-soluble film material is polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose.

[0017] In some preferred embodiments, the water-soluble film material is partially hydrolyzed polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose.

[0018] In some preferred embodiments, the water-soluble film material is polyvinyl alcohol 1788, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose.

[0019] In some embodiments, the percentage of the mass of the plasticizer to the total mass of the water-soluble film material, anti-adhesive, plasticizer, and porogen is <30.0%. In some embodiments, the percentage of the mass of the plasticizer to the total mass of the water-soluble film material, anti-adhesive, plasticizer, and porogen is 10.6%-28.8%. In some embodiments, the percentage of the mass of the plasticizer to the total mass of the water-soluble film material, anti-adhesive, plasticizer, and porogen is 10.6%, 22.1%, 26.3%, 26.8%, 28.3%, or 28.8%.

[0020] In some embodiments, the percentage of the mass of the anti-adhesive agent relative to the total mass of the water-soluble film material, anti-adhesive agent, plasticizer, and porogen is >3.8%. In some embodiments, the percentage of the mass of the anti-adhesive agent relative to the total mass of the water-soluble film material, anti-adhesive agent, plasticizer, and porogen is 4.4%-12.8%. In some embodiments, the percentage of the mass of the anti-adhesive agent relative to the total mass of the water-soluble film material, anti-adhesive agent, plasticizer, and porogen is 4.4%, 7.0%, 10.0%, 10.5%, 10.7%, 11.5%, or 12.8%.

[0021] In some embodiments, the percentage of the mass of the porogen to the total mass of the water-soluble film material, anti-adhesive, plasticizer, and porogen is ≥8.9%. In some embodiments, the percentage of the mass of the porogen to the total mass of the water-soluble film material, anti-adhesive, plasticizer, and porogen is 8.9%-29.4%. In some embodiments, the percentage of the mass of the porogen to the total mass of the water-soluble film material, anti-adhesive, plasticizer, and porogen is 8.9%, 10.0%, 10.5%, 11.3%, 12.8%, 23.3%, or 29.4%.

[0022] In some embodiments, the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:(1.0-2.0):(1.7-7.0):(0.3-7.0). In some preferred embodiments, the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:(1.0-2.0):(1.7-5.0):(0.3-6.7). In some preferred embodiments, the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(0.3-2.0). In some preferred embodiments, the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10:(1-2):(1.7-5):(1.7-6.7). In some preferred embodiments, the mass ratio of the water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.0-2.0). In some more preferred embodiments, the mass ratio of the water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.5-2.0). In some more preferred embodiments, the mass ratio of the water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0).

[0023] In some embodiments, the water-soluble film material is polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(0.3-2.0). In some embodiments, the water-soluble film material is partially hydrolyzed polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(0.3-2.0). In some embodiments, the water-soluble film material is polyvinyl alcohol 1788, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(0.3-2.0).

[0024] In some embodiments, the water-soluble film material is polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.0-2.0). In some embodiments, the water-soluble film material is partially hydrolyzed polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.0-2.0). In some embodiments, the water-soluble film material is polyvinyl alcohol 1788, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.0-2.0).

[0025] In some embodiments, the water-soluble film material is polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.5-2.0). In some embodiments, the water-soluble film material is partially hydrolyzed polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.5-2.0). In some embodiments, the water-soluble film material is polyvinyl alcohol 1788, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.5-2.0).

[0026] In some embodiments, the water-soluble film material is polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0). In some embodiments, the water-soluble film material is partially hydrolyzed polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0). In some embodiments, the water-soluble film material is polyvinyl alcohol 1788, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0).

[0027] In some embodiments, the water-soluble film material is polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:2.0. In some embodiments, the water-soluble film material is partially hydrolyzed polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:2.0. In some embodiments, the water-soluble film material is polyvinyl alcohol 1788, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:2.0.

[0028] In some embodiments, the mass ratio of the total mass of the water-soluble film material, anti-adhesive, plasticizer, and porogen to the mass of leflunomide is 1.0:100.0-10.0:100.0. In some embodiments, the mass ratio of the total mass of the water-soluble film material, anti-adhesive, plasticizer, and porogen to the mass of leflunomide is 3.0:100.0-6.0:100.0, 5.0:100.0-6.0:100.0, 5.5:100.0-6.0:100.0, or 5.7:100.0.

[0029] In some embodiments, the water-soluble film material is polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(0.3-2.0), 10.0:2.0:5.0:(1.0-2.0), 10.0:2.0:5.0:(1.5-2.0), or 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.0:100.0-6.0:100.0, 5.5:100.0-6.0:100.0, or 5.7:100.0.

[0030] In some embodiments, the water-soluble film material is partially hydrolyzed polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(0.3-2.0), 10.0:2.0:5.0:(1.0-2.0), 10.0:2.0:5.0:(1.5-2.0), or 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.0:100.0-6.0:100.0, 5.5:100.0-6.0:100.0, or 5.7:100.0.

[0031] In some embodiments, the water-soluble film material is polyvinyl alcohol 1788, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(0.3-2.0), 10.0:2.0:5.0:(1.0-2.0), 10.0:2.0:5.0:(1.5-2.0), or 10.0:2.0:5.0:(1.7-2.0); the total mass of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.0:100.0-6.0:100.0, 5.5:100.0-6.0:100.0, or 5.7:100.0.

[0032] In some embodiments, the water-soluble film material is polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.0:100.0-6.0:100.0, 5.5:100.0-6.0:100.0, or 5.7:100.0. In some embodiments, the water-soluble film material is partially hydrolyzed polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.0:100.0-6.0:100.0, 5.5:100.0-6.0:100.0, or 5.7:100.0. In some embodiments, the water-soluble film material is polyvinyl alcohol 1788, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.0:100.0-6.0:100.0, 5.5:100.0-6.0:100.0, or 5.7:100.0.

[0033] In some embodiments, the water-soluble film material is polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.0:100.0-6.0:100.0, 5.5:100.0-6.0:100.0, or 5.7:100.0.

[0034] In some embodiments, the water-soluble film material is partially hydrolyzed polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.0:100.0-6.0:100.0, 5.5:100.0-6.0:100.0, or 5.7:100.0.

[0035] In some embodiments, the water-soluble film material is polyvinyl alcohol 1788, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.0:100.0-6.0:100.0, 5.5:100.0-6.0:100.0, or 5.7:100.0.

[0036] In some embodiments, the composition further includes other excipients, including at least one of fillers, disintegrants, flow aids, or lubricants.

[0037] In some embodiments, the filler includes at least one of lactose, microcrystalline cellulose, and starch.

[0038] In some embodiments, the disintegrant includes at least one of pregelatinized starch, crospovidone, sodium carboxymethyl starch, hydroxypropyl cellulose, and sodium crospovidone carboxymethyl cellulose.

[0039] In some embodiments, the flow aid includes at least one of talc and silica.

[0040] In some embodiments, the lubricant includes at least one of stearic acid, magnesium stearate, and sodium stearate fumarate.

[0041] In some embodiments, the filler content is 50.0 wt%-90.0 wt% based on the total mass of the composition. In some embodiments, the filler content is 80.0 wt%-90.0 wt% based on the total mass of the composition. In some embodiments, the filler content is 81.0 wt%, 82.0 wt%, 83.0 wt%, 84.0 wt%, 85.0 wt%, 86.0 wt%, 87.0 wt%, 88.0 wt%, 89.0 wt%, or 90.0 wt% based on the total mass of the composition. In some embodiments, the filler content is 86.0 wt% based on the total mass of the composition.

[0042] In some embodiments, the content of the disintegrant is 1.0 wt% to 10.0 wt% based on the total mass of the composition. In some embodiments, the content of the disintegrant is 1.0 wt% to 5.0 wt% based on the total mass of the composition. In some embodiments, the content of the disintegrant is 1.0 wt%, 2.0 wt%, 3.0 wt%, 4.0 wt%, 5.0 wt%, 6.0 wt%, 7.0 wt%, 8.0 wt%, 9.0 wt%, or 10.0 wt% based on the total mass of the composition. In some embodiments, the content of the disintegrant is 2.0 wt% based on the total mass of the composition.

[0043] In some embodiments, the content of the flow aid is 0.5 wt% to 5.0 wt% based on the total mass of the composition. In some embodiments, the content of the flow aid is 0.5 wt% to 2.0 wt% based on the total mass of the composition. In some embodiments, the content of the flow aid is 0.5 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, or 5.0 wt% based on the total mass of the composition. In some embodiments, the content of the flow aid is 1.0 wt% based on the total mass of the composition.

[0044] In some embodiments, the lubricant content is 0.5 wt% to 3.0 wt% based on the total mass of the composition. In some embodiments, the lubricant content is 0.5 wt% to 2.0 wt% based on the total mass of the composition. In some embodiments, the lubricant content is 0.5 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, or 3.0 wt% based on the total mass of the composition. In some embodiments, the lubricant content is 0.5 wt% based on the total mass of the composition.

[0045] In some embodiments, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and porogen, calculated by the total mass of the composition, is 1.0 wt% to 99.0 wt%. In some embodiments, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and porogen, calculated by the total mass of the composition, is 2.0 wt% to 50.0 wt%. In some embodiments, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and porogen, calculated by the total mass of the composition, is 2.0 wt% to 20.0 wt%. In some embodiments, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and porogen, calculated by the total mass of the composition, is 5.0 wt% to 15.0 wt%. In some embodiments, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and porogen, calculated by the total mass of the composition, is 10.0 wt% to 11.0 wt%. In some embodiments, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent, calculated based on the total mass of the composition, is 10.5 wt%. In some embodiments, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent, calculated based on the total mass of the composition, is 1.0 wt%, 5.0 wt%, 8.0 wt%, 10.0 wt%, 11.0 wt%, 12.0 wt%, 15.0 wt%, 20.0 wt%, 30.0 wt%, 40.0 wt%, 50.0 wt%, 60.0 wt%, 70.0 wt%, 80.0 wt%, 90.0 wt%, or 99.9 wt%, calculated based on the total mass of the composition.

[0046] In some embodiments, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent, calculated by the total mass of the composition, is 10.0 wt%-11.0 wt%; the content of the filler is 80.0 wt%-90.0 wt%; the content of the disintegrant is 1.0 wt%-5.0 wt%; the content of the flow aid is 0.5 wt%-2.0 wt%; and the content of the lubricant is 0.5 wt%-2.0 wt%.

[0047] In some embodiments, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent is 10.5 wt% based on the total mass of the composition; the content of the filler is 86.0 wt%; the content of the disintegrant is 2.0 wt%; the content of the flow aid is 1.0 wt%; and the content of the lubricant is 0.5 wt%.

[0048] In some embodiments, the filler is lactose and microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, the flow aid is silica, and the lubricant is magnesium stearate. Based on the total mass of the composition, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent is 10.5 wt%; the content of the filler is 86.0 wt%; the content of the disintegrant is 2.0 wt%; the content of the flow aid is 1.0 wt%; and the content of the lubricant is 0.5 wt%.

[0049] In some embodiments, the filler is lactose and microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, the flow aid is silica, and the lubricant is magnesium stearate. The total content of the active ingredient, water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent, calculated by the total mass of the composition, is 10.5 wt%; the content of lactose as a filler is 32.8 wt%; the content of microcrystalline cellulose is 53.2 wt%; the content of the disintegrant is 2.0 wt%; the content of the flow aid is 1.0 wt%; and the content of the lubricant is 0.5 wt%.

[0050] In some embodiments, the filler is lactose and microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, the flow aid is silica, and the lubricant is magnesium stearate. Based on the total mass of the composition, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent is 10.5 wt%; the content of the filler is 86.0 wt%; the content of the disintegrant is 2.0 wt%; the content of the flow aid is 1.0 wt%; and the content of the lubricant is 0.5 wt%.

[0051] In some embodiments, the filler is lactose and microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, the flow aid is silica, and the lubricant is magnesium stearate. The total content of the active ingredient, water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent, calculated by the total mass of the composition, is 10.5 wt%; the content of lactose as a filler is 32.8 wt%; the content of microcrystalline cellulose is 53.2 wt%; the content of the disintegrant is 2.0 wt%; the content of the flow aid is 1.0 wt%; and the content of the lubricant is 0.5 wt%.

[0052] In some embodiments, the water-soluble film material is polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); the mass ratio of the total mass of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.7:100.0; calculated based on the total mass of the composition, the total content of the active ingredient, water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0wt%-11.0wt%; the content of the filler is 80.0wt%-90.0wt%; the content of the disintegrant is 1.0wt%-5.0wt%; the content of the flow aid is 0.5wt%-2.0wt%; and the content of the lubricant is 0.5wt%-2.0wt%.

[0053] In some embodiments, the water-soluble film material is partially hydrolyzed polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); and the ratio of the total mass of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.7:100.0. The total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent, calculated by the total mass of the composition, is 10.0 wt%-11.0 wt%; the content of the filler is 80.0 wt%-90.0 wt%; the content of the disintegrant is 1.0 wt%-5.0 wt%; the content of the flow aid is 0.5 wt%-2.0 wt%; and the content of the lubricant is 0.5 wt%-2.0 wt%.

[0054] In some embodiments, the water-soluble film material is polyvinyl alcohol 1788, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.7:100.0. The total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent, calculated by the total mass of the composition, is 10.0 wt%-11.0 wt%; the content of the filler is 80.0 wt%-90.0 wt%; the content of the disintegrant is 1.0 wt%-5.0 wt%; the content of the flow aid is 0.5 wt%-2.0 wt%; and the content of the lubricant is 0.5 wt%-2.0 wt%.

[0055] In some embodiments, the water-soluble film material is polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.7:100.0; and the filler is emulsion... The composition comprises sugar and microcrystalline cellulose, wherein the disintegrant is sodium carboxymethyl starch, the flow aid is silica, and the lubricant is magnesium stearate. Based on the total mass of the composition, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent is 10.5 wt%; the content of the filler is 86.0 wt%; the content of the disintegrant is 2.0 wt%; the content of the flow aid is 1.0 wt%; and the content of the lubricant is 0.5 wt%.

[0056] In some embodiments, the water-soluble film material is partially hydrolyzed polyvinyl alcohol, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.7:100.0; the filler... The composition comprises lactose and microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, the flow aid is silicon dioxide, and the lubricant is magnesium stearate. Based on the total mass of the composition, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent is 10.5 wt%; the content of the filler is 86.0 wt%; the content of the disintegrant is 2.0 wt%; the content of the flow aid is 1.0 wt%; and the content of the lubricant is 0.5 wt%.

[0057] In some embodiments, the water-soluble film material is polyvinyl alcohol 1788, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.7:100.0; the filler... The composition comprises lactose and microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, the flow aid is silicon dioxide, and the lubricant is magnesium stearate. Based on the total mass of the composition, the total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent is 10.5 wt%; the content of the filler is 86.0 wt%; the content of the disintegrant is 2.0 wt%; the content of the flow aid is 1.0 wt%; and the content of the lubricant is 0.5 wt%.

[0058] In some embodiments, the water-soluble film material is polyvinyl alcohol 1788, the anti-adhesion agent is glyceryl monostearate, the plasticizer is propylene glycol, and the pore-forming agent is lactose; the mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:(1.7-2.0); the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent to the mass of leflunomide is 5.7:100.0; the filler is lactose and microcrystalline cellulose. The disintegrant is sodium carboxymethyl starch, the flow aid is silicon dioxide, and the lubricant is magnesium stearate. Based on the total mass of the composition, the total content of the active ingredient, water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.5 wt%; the content of lactose as a filler is 32.8 wt%; the content of microcrystalline cellulose is 53.2 wt%; the content of the disintegrant is 2.0 wt%; the content of the flow aid is 1.0 wt%; and the content of the lubricant is 0.5 wt%.

[0059] In some embodiments, the composition is in the form of a tablet.

[0060] In a second aspect, the present invention provides a method for preparing the composition described in the first aspect.

[0061] In some embodiments, a method for preparing the composition of the first aspect includes: mixing a water-soluble film material, an anti-adhesion agent, a plasticizer, and a pore-forming agent with water to obtain a mixture A; fluidizing an active ingredient to obtain a fluidized active ingredient; spraying the mixture A onto the fluidized active ingredient; encapsulating the active ingredient within the mixture of the water-soluble film material, the anti-adhesion agent, the plasticizer, and the pore-forming agent; and drying to obtain the composition.

[0062] In some embodiments, a method for preparing the composition of the first aspect includes: mixing a water-soluble film material, an anti-adhesion agent, a plasticizer, and a pore-forming agent with water to obtain a mixture B; then mixing an active ingredient with the mixture B to obtain a suspension; fluidizing the suspension; and drying it to obtain the composition.

[0063] In some embodiments, a method for preparing the composition of the first aspect includes: mixing a water-soluble film material, an anti-adhesion agent, a plasticizer, and a pore-forming agent with water to obtain a mixture A; fluidizing an active ingredient to obtain a fluidized active ingredient; spraying the mixture A onto the fluidized active ingredient to encapsulate the active ingredient within the mixture of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent; and drying to obtain a mixture C; then mixing the mixture B with other excipients and compressing it into tablets to obtain the composition; or

[0064] In some embodiments, a method for preparing the composition of the first aspect includes: mixing a water-soluble film material, an anti-adhesion agent, a plasticizer, and a pore-forming agent with water to obtain a mixture B; mixing an active ingredient with the mixture B to obtain a suspension; fluidizing and drying the suspension to obtain a mixture D; and mixing the mixture D with other excipients and compressing it into tablets to obtain the composition.

[0065] In some embodiments, the total mass of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent in the mixture A accounts for 10wt%-20wt% of the mass of the mixture A; and / or

[0066] In some embodiments, the total mass of water-soluble film material, anti-adhesion agent, plasticizer and pore-forming agent in the mixture B accounts for 10wt%-20wt% of the mass of the mixture B.

[0067] Beneficial effects

[0068] Compared with the prior art, a certain embodiment provided by the present invention has at least one of the following beneficial effects:

[0069] (1) In the composition provided by the present invention, when the percentage of the mass of the plasticizer to the total mass of the water-soluble film material, anti-adhesion agent, plasticizer and pore-forming agent is <30.0%, for example 10.6%-28.8%, and the percentage of the mass of the anti-adhesion agent to the total mass of the water-soluble film material, anti-adhesion agent, plasticizer and pore-forming agent is >3.8%, for example 4.4%-12.8%, the resulting encapsulated particles are uniform in size and the fine powder is evenly distributed.

[0070] (2) In the composition provided by the present invention, when the mass ratio of water-soluble film material: anti-adhesive: plasticizer: pore-forming agent is in the range of 10.0:(1.0-2.0):(1.7-5.0):(0.3-6.7), the resulting encapsulated particles are uniform in size and the fine powder particles are evenly distributed.

[0071] (3) Compared with other film materials, polyvinyl alcohol is more conducive to the stability of leflunomide sheets.

[0072] (4) Compared with other ratios, in the composition provided by the present invention, the weight ratio of water-soluble film material: anti-adhesive: plasticizer: pore-forming agent of 10.0:2.0:5.0:(0.3-2.0) is more conducive to improving the stability of related substances of leflunomide tablets.

[0073] (5) The composition provided by this invention has excellent stability. It achieves high stability of the substances in conventional polyethylene bottles without coating or adding a desiccant, which helps reduce production costs. The method provided by this invention is simple to operate, produces stable product quality, and has low cost.

[0074] (6) Compared with other types of encapsulation materials, water-soluble film materials are more conducive to the dissolution of leflunomide tablets.

[0075] (7) When the percentage of the mass of the porogen to the total mass of the water-soluble film material, anti-adhesive, plasticizer and porogen is ≥8.9%, for example 8.9%-29.4%, or the mass ratio of the water-soluble film material, anti-adhesive, plasticizer and porogen is 10.0:(1.0-2.0):(1.7-5.0):(1.7-6.7) or 10.0:2.0:5.0:(1.7-6.7), it is beneficial to improve the dissolution rate of the obtained leflunomide tablets.

[0076] (8) In the composition of the present invention, the total mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer and pore-forming agent to the mass of leflunomide is 1.0:100.0-10.0:100.0, preferably 5.0:100.0-6.0:100.0; more preferably 5.7:100.0; the most preferred weight ratio of water-soluble film material: anti-adhesion agent: plasticizer: pore-forming agent is 10.0:2.0:5.0:(1.7-2.0). The leflunomide tablets obtained by this formulation have uniform particle size of the coating, uniform distribution of fine powder, high dissolution and good stability of related substances.

[0077] Terminology Definition

[0078] In the foregoing description of this invention, all figures disclosed herein, whether or not the words “approximately” or “about” are used, are approximate values. Based on the disclosed figures, the value of each figure may vary by less than ±10% or by a difference that is considered reasonable by those skilled in the art, such as ±1%, ±2%, ±3%, ±4%, or ±5%.

[0079] The terms "above", "below", and "within" are understood to include the number itself. For example, "two or more" means ≥ two.

[0080] The term “and / or” should be understood to mean any one of the options or any combination of two or more of the options.

[0081] The term "wt%" indicates a percentage by mass.

[0082] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples. Detailed Implementation

[0083] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0084] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0085] The polyvinyl alcohol used in the following examples is polyvinyl alcohol 1788.

[0086] In the following examples, the particle size of leflunomide was controlled to be D90≤50μm.

[0087] Example 1: Leflunomide Composition

[0088] The formulation of the leflunomide composition is shown in Table 1.

[0089] Table 1: Leflunomide Composition Formulations

[0090]

[0091] Preparation process: The above-mentioned amounts of polyvinyl alcohol, glyceryl monostearate, lactose, and propylene glycol are mixed and dissolved, and then water is added to obtain a mixture. The total mass of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent in the mixture accounts for 10 wt% of the mixture mass. Leflunomide is added and fluidized in a fluidizing device at an inlet air temperature of 35℃~45℃. The mixture is sprayed onto the fluidized leflunomide to coat it. The moisture is then removed by the temperature and airflow movement within the fluidizing device to obtain a leflunomide composition in which leflunomide is coated with polyvinyl alcohol, glyceryl monostearate, lactose, and propylene glycol.

[0092] Example 2: Leflunomide Composition

[0093] The formulation of the leflunomide composition is shown in Table 2.

[0094] Table 2: Leflunomide Composition Formulations

[0095]

[0096] Preparation process: The above-mentioned amounts of polyvinyl alcohol, glyceryl monostearate, lactose, and propylene glycol are mixed and dissolved, and then water is added to obtain a mixture. The total mass of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent in the mixture accounts for 20 wt% of the mixture mass. Leflunomide is added to the mixture to obtain a suspension. The suspension is fluidized in a fluidizing device at an inlet air temperature of 50℃~60℃, and the water is removed by the temperature and airflow movement within the fluidizing device to obtain a leflunomide composition in which leflunomide is encapsulated by polyvinyl alcohol, glyceryl monostearate, lactose, and propylene glycol.

[0097] Example 3: Leflunomide Tablets

[0098] Leflunomide tablets prescription: see Table 3.

[0099] Table 3: Leflunomide Tablet Prescription

[0100]

[0101] Preparation process: The leflunomide composition obtained in Example 1 above is mixed with lactose, microcrystalline cellulose, sodium carboxymethyl starch, silicon dioxide, and magnesium stearate to obtain leflunomide total powder. The leflunomide total powder is then compressed into tablets to obtain leflunomide tablet A.

[0102] Example 4: Investigation of Encapsulation Materials

[0103] Example 4-1 (Polyvinyl alcohol replaced with hydroxypropyl methylcellulose): Following the composition ratio of the leflunomide composition in Example 1, polyvinyl alcohol was replaced with the water-soluble film material hydroxypropyl methylcellulose. A leflunomide composition B, consisting of hydroxypropyl methylcellulose, glyceryl monostearate, lactose, and propylene glycol encapsulating leflunomide, was prepared according to the preparation process of Example 1. The leflunomide composition obtained in Example 1 of Example 3 was replaced with leflunomide composition B, and prepared according to the composition ratio and process of Example 3 to obtain leflunomide tablets B.

[0104] Example 4-2 (Polyvinyl alcohol replaced with octadecyl alcohol): Following the composition ratio of the leflunomide composition in Example 1, polyvinyl alcohol was replaced with octadecyl alcohol. A leflunomide composition C, containing octadecyl alcohol, glyceryl monostearate, lactose, and propylene glycol encapsulating leflunomide, was prepared according to the preparation process of Example 1. The leflunomide composition obtained in Example 1 as described in Example 3 was replaced with leflunomide composition C, and prepared according to the composition ratio and process of Example 3 to obtain leflunomide tablets C.

[0105] Example 5: Investigation of the component ratio of encapsulating material

[0106] The leflunomide composition encapsulating leflunomide in Example 1 is as shown in Formula 1. The leflunomide composition encapsulating leflunomide (hereinafter referred to as the encapsulation) was prepared according to Formulas 1 to 8 in Table 4 and the preparation process of Example 1. The encapsulation prepared according to the formula ratio and preparation process of the leflunomide tablets in Example 3 was used to prepare leflunomide tablets.

[0107] Table 4: Analysis of the proportions of encapsulating materials (parts by weight)

[0108]

[0109] Conclusion: As shown in Table 4, the different proportions of each formulation have a certain impact on the properties of the coating. The amount of anti-adhesive and plasticizer has a significant impact on the properties of the coating. The agglomeration of the coating affects the subsequent tablet production and also affects the uniformity of the content in the tablets.

[0110] The results from Formulas 2 and 6 show that when the percentage of the mass of plasticizer to the total mass of water-soluble film material, anti-adhesive, plasticizer and pore-forming agent is ≥30.0%, the resulting encapsulated material forms fewer granules and more fine powder.

[0111] The results of Formula 4 show that when the percentage of the mass of the anti-adhesive to the total mass of the water-soluble film material, anti-adhesive, plasticizer and pore-forming agent is ≤3.8%, the encapsulation material agglomerates and the fine powder particles are unevenly distributed, affecting the subsequent tableting process.

[0112] When the percentage of the mass of the plasticizer to the total mass of the water-soluble film material, anti-adhesive, plasticizer and porogen is <30.0%, for example 10.8%-28.9%, and the percentage of the mass of the anti-adhesive to the total mass of the water-soluble film material, anti-adhesive, plasticizer and porogen is >3.8%, for example 4.4%-12.7%, the resulting encapsulated material has uniform particle size and uniformly distributed fine powder.

[0113] The results from prescriptions 1, 3, 5, and 7 show that when the mass ratio of water-soluble film material: anti-adhesive: plasticizer: pore-forming agent is in the range of 10.0:(1.0-2.0):(1.7-5.0):(0.3-6.7), the resulting encapsulated material has uniform particle size and uniform distribution of fine powder.

[0114] Experimental Example 1: Investigation of Related Substances

[0115] The method for detecting related substances is as follows: Refer to the method for detecting related substances in Leflunomide Tablets in the Chinese Pharmacopoeia (2020 edition): Determine by high performance liquid chromatography (General Rule 0512). The peak area of ​​impurity II shall not be greater than 1.5 times (1.5%) the peak area of ​​the main peak in the control solution.

[0116] The leflunomide tablets from the above embodiments and commercially available leflunomide tablets (trade name Arava) were subjected to accelerated stability testing according to the Guidelines for Stability Testing of Raw Materials and Preparations in the Chinese Pharmacopoeia (2020 Edition) (General Chapter 9001) (the test conditions were a test temperature of 40℃±2℃ and a relative humidity of 75±5%). The commercially available product was removed from its original packaging and packaged in the same ordinary polyethylene bottle as the embodiments provided in this invention for accelerated stability testing. The results showed that the product of this invention met the standards of the Chinese Pharmacopoeia and its stability was significantly improved compared to the commercially available leflunomide product. Detailed data are shown in Table 5.

[0117] Table 5: Results of Accelerated Tests on Leflunomide Tablets (Percentage of Impurity II)

[0118]

[0119] in conclusion:

[0120] 1. As can be seen from the results of leflunomide tablets A and B in Table 5, compared with other encapsulation materials, the use of polyvinyl alcohol is more beneficial to the stability of related substances in leflunomide tablets.

[0121] 2. The low impurity II content of leflunomide tablets A and G after 6 months of accelerated testing indicates that the weight ratio of water-soluble film material: anti-adhesive: plasticizer: pore-forming agent in leflunomide tablets of 10.0:2.0:5.0:(0.3-2.0) is more conducive to improving the stability of related substances in leflunomide tablets.

[0122] 3. The leflunomide tablets provided by this invention exhibit excellent stability. High stability of the substances can be achieved in conventional polyethylene bottles without coating or the addition of desiccants, which helps reduce production costs. The method provided by this invention is simple to operate, produces stable product quality, and is low in cost.

[0123] Experimental Example 2: Dissolution Study

[0124] Dissolution testing method: Take this product and perform dissolution testing according to Method 2 (paddle method) of the Chinese Pharmacopoeia (2020 edition). Use 1000 ml of purified water as the dissolution medium, rotate at 100 rpm, and after 30 min, take a sample, filter, and detect the absorbance at a wavelength of 260 nm using ultraviolet-visible spectrophotometry. Separately, accurately weigh an appropriate amount of leflunomide reference standard, dissolve it in acetonitrile by shaking, add purified water, let it stand at room temperature, and then dilute to the final volume with purified water to prepare a reference solution containing approximately 10 μg / ml of leflunomide. Determine the dissolution rate using the same method and calculate the dissolution rate. The dissolution rate result should not be less than 75% of the labeled amount.

[0125] The leflunomide tablets obtained in the above examples were tested according to the dissolution test method, and the results are shown in Table 6.

[0126] Table 6: Dissolution rate of Leflunomide tablets

[0127]

[0128] in conclusion:

[0129] 1. The method of encapsulating leflunomide with water-soluble coating material provided by the present invention has no significant impact on the dissolution of leflunomide tablets and can meet the Chinese Pharmacopoeia standard. Wax coating material is not conducive to the release of leflunomide and affects the dissolution of leflunomide tablets.

[0130] 2. The leflunomide encapsulation composition provided by the present invention, with the proportions of each component within a reasonable range, can encapsulate leflunomide, facilitate tableting, and does not affect the dissolution of leflunomide tablets, while improving the stability of related substances in leflunomide tablets.

[0131] 3. In this invention, the percentage of the mass ratio of the pore-forming agent to the total mass of the water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent.

[0132] When ≥8.9%, for example, 8.9%-29.4%, or the mass ratio of water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent is 10.0:

[0133] (1.0-2.0):(1.7-5.0):(1.7-6.7) or 10.0:2.0:5.0:(1.7-6.7) is beneficial to improve the dissolution rate of the obtained leflunomide tablets.

[0134] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A composition, characterized in that, The dosage form of the composition is a tablet. The composition includes: an active ingredient, a water-soluble film material, an anti-adhesion agent, a plasticizer, and a pore-forming agent. The active ingredient is leflunomide, which is encapsulated within a mixture of the water-soluble film material, the anti-adhesion agent, the plasticizer, and the pore-forming agent. The encapsulated leflunomide is directly mixed with other excipients and then directly compressed into tablets. The water-soluble film material is polyvinyl alcohol 1788; The anti-adhesion agent is glyceryl monostearate; The plasticizer is propylene glycol; The pore-forming agent is lactose; The mass ratio of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent is 10.0:2.0:5.0:2.0; The other excipients include at least one of fillers, disintegrants, flow aids, or lubricants.

2. The composition according to claim 1, characterized in that, The particle size D90 of the active ingredient is ≤50 μm.

3. The composition according to claim 1, wherein the total mass ratio of the water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent to the mass ratio of leflunomide is 5.5:100.0-6.0:100.

0.

4. The composition according to claim 1, wherein the total mass ratio of the water-soluble film material, anti-adhesive, plasticizer, and pore-forming agent to the mass ratio of leflunomide is 5.7:100.

0.

5. The composition according to claim 1, wherein the filler comprises at least one selected from lactose, microcrystalline cellulose, and starch; and / or The disintegrant includes at least one of pregelatinized starch, crospovidone, sodium carboxymethyl starch, hydroxypropyl cellulose, and sodium crospovidone carboxymethyl cellulose; and / or The flow aid includes at least one of talc and silica; and / or The lubricant includes at least one of stearic acid, magnesium stearate, and sodium stearate fumarate.

6. The composition according to claim 1, wherein the filler content is 80.0 wt%-88.0 wt% based on the total mass of the composition; and / or The content of the disintegrant, calculated based on the total mass of the composition, is 1.0 wt%-5.0 wt%; and / or The content of the gliding agent, calculated based on the total mass of the composition, is 0.5 wt%-2.0 wt%; and / or The lubricant content, calculated based on the total mass of the composition, is 0.5 wt% to 2.0 wt%; and / or The total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer and pore-forming agent is 10.0wt%-11.0wt% based on the total mass of the composition.

7. The composition according to claim 1, wherein the filler content is 86.0 wt% based on the total mass of the composition; and / or The content of the disintegrant, calculated based on the total mass of the composition, is 2.0 wt%; and / or The content of the gliding agent is 1.0 wt% based on the total mass of the composition; and / or The lubricant content is 0.5 wt% based on the total mass of the composition; and / or The total content of the active ingredient, water-soluble film material, anti-adhesive, plasticizer and pore-forming agent is 10.5 wt% based on the total mass of the composition.

8. The composition according to claim 1, wherein the filler is lactose and microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, the flow aid is silica, the lubricant is magnesium stearate, and the total content of the active ingredient, water-soluble film material, anti-adhesion agent, plasticizer and pore-forming agent, calculated by the total mass of the composition, is 10.5 wt%; the content of the filler is 86.0 wt%; the content of the disintegrant is 2.0 wt%; the content of the flow aid is 1.0 wt%; and the content of the lubricant is 0.5 wt%.

9. The composition according to claim 1, wherein the filler is lactose and microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, the flow aid is silica, and the lubricant is magnesium stearate; and the total content of the active ingredient, water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent, calculated by the total mass of the composition, is 10.5 wt%; the content of lactose as a filler is 32.8 wt%; the content of microcrystalline cellulose is 53.2 wt%; the content of the disintegrant is 2.0 wt%; the content of the flow aid is 1.0 wt%; and the content of the lubricant is 0.5 wt%.

10. A method for preparing the composition according to any one of claims 1 to 9, comprising: A water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent are mixed with water to obtain mixture A, wherein the total mass of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent in mixture A accounts for 10wt%-20wt% of the mass of mixture A. The active ingredient is then fluidized to obtain a fluidized active ingredient, and mixture A is sprayed onto the fluidized active ingredient to encapsulate the active ingredient within the mixture of water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent. After drying, mixture C is obtained. Mixture C is then mixed with other excipients and compressed into tablets to obtain the composition.

11. A method for preparing the composition according to any one of claims 1 to 9, comprising: A water-soluble film material, an anti-adhesion agent, a plasticizer, and a pore-forming agent are mixed with water to obtain a mixture B, wherein the total mass of the water-soluble film material, anti-adhesion agent, plasticizer, and pore-forming agent in the mixture B accounts for 10wt%-20wt% of the mass of the mixture B; then the active ingredient is mixed with the mixture B to obtain a suspension, the suspension is fluidized and dried to obtain a mixture D, and then mixture D is mixed with other excipients and compressed into tablets to obtain the composition.

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