Adenafil citrate orally disintegrating tablet as well as preparation method and application thereof

Abstract

The invention provides an aldenafil citrate orally disintegrating tablet as well as a preparation method and application thereof. The aldenafil citrate orally disintegrating tablet comprises the following components: a pharmaceutical active component, an auxiliary carrier, a disintegrating agent, a filling agent, a flavoring agent, an adhesive and a lubricant, the active pharmaceutical ingredient comprises aldenafil citrate and / or a pharmaceutically acceptable salt thereof; the auxiliary carrier comprises any one or a combination of at least two of a water-soluble vitamin E derivative, an organic acid or an organic acid salt. The adenafil citrate orally disintegrating tablet provided by the invention has better taste, is convenient to take, does not need water, can be quickly disintegrated in the oral cavity, the disintegration time limit does not exceed 60 seconds, the maximum plasma concentration time does not exceed 1 hour, and the requirement that the adenafil citrate needs to take effect quickly under specific conditions is met.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to an orally disintegrating tablet of edenafil citrate, its preparation method, and its application. Background Technology

[0002] Aldenafil citrate is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). It does not directly relax the corpora cavernosa, but it significantly promotes normal penile erection and erectile function in cases of hypoactive erectile dysfunction induced by sexual arousal. This increase in erectile function does not promote the release of nitric oxide (NO), although NO can promote its effect. When sexual stimulation induces local NO release, ardenafil citrate's inhibition of PDE5 increases cGMP levels within the corpora cavernosa, relaxes smooth muscle, and allows blood to flow into the corpora cavernosa; however, in the absence of sexual stimulation, the recommended dose of ardenafil citrate has no effect.

[0003] The formulation of edenafil citrate has undergone comprehensive innovation and improvement in terms of drug spatial structure, molecular docking model, target selection specificity, in vivo absorption and metabolism, and dosage. In men, it can more efficiently and rapidly cross the cell barrier, thereby quickly reaching the drug target site and exerting its efficacy. Simultaneously, edenafil citrate exhibits smooth transport within the body, preventing drug residue buildup. Compared to similar drugs from abroad, it boasts better absorption and metabolism, and improved safety. In terms of efficacy, clinical data also show that edenafil citrate tablets can significantly improve penile penetration success rate (from 45.08% to 89.62%) and sexual intercourse completion rate (from 10.76% to 78.21%), and significantly improve the erectile function index (an average increase of more than 10 points) compared to pre-treatment levels.

[0004] Furthermore, tablets containing edenafil citrate can also be used to treat Alzheimer's disease, serving to treat cognitive decline, mental symptoms and behavioral disorders, and the gradual decline in daily living abilities, among other degenerative diseases of the central nervous system.

[0005] Currently, the marketed dosage form of edenafil citrate is tablets, with a strength of 30 mg (calculated as edenafil) and a recommended dose of 60 mg (calculated as edenafil). Orally disintegrating tablets are not yet marketed. CN115990140A discloses a lyophilized tablet of a nalidix compound and its preparation method. This lyophilized tablet is a lyophilized oral preparation, requiring the active ingredient to be encapsulated with cyclodextrin, followed by freeze-drying for 10 hours, reducing the ambient humidity to below 20% using a dehumidifier, and then unmolding and packaging. This method suffers from problems such as complex preparation process, long processing time, high environmental requirements, high energy consumption, and low production efficiency.

[0006] Furthermore, due to the bitter and astringent chemical properties of the active ingredient, edenafil citrate, direct ingestion can cause unpleasant tastes such as bitterness, astringency, and numbness, which can persist for a long time, leading to a poor clinical experience. Human saliva has a pH of approximately 6.5-7.5, and the solubility of edenafil citrate raw material in a medium with a pH of 6.8 is only 0.04 mg / mL. Given the limited volume of saliva in the oral cavity, edenafil citrate may not be completely dissolved in saliva, resulting in poor oral absorption. Additionally, the insoluble substances can cause a gritty or other unpleasant taste.

[0007] Given the problems with existing technologies, there is an urgent need to provide an orally disintegrating tablet of edenafil citrate that can leverage the advantages of rapid disintegration, rapid onset of action and absorption, excellent taste masking effect, high solubility in saliva, good medication compliance, simple preparation process, high production capacity and low energy consumption. Summary of the Invention

[0008] To address the shortcomings of existing technologies, the present invention aims to provide an orally disintegrating tablet of edenafil citrate, its preparation method, and its application. The orally disintegrating tablet of edenafil citrate provided by the present invention has a good taste, is convenient to take, requires no water, disintegrates rapidly in the oral cavity, has a disintegration time of no more than 60 seconds, and a maximum blood concentration time of no more than 1 hour, thus meeting the requirement that edenafil citrate needs to take effect rapidly under specific circumstances.

[0009] To achieve this objective, the present invention adopts the following technical solution: In a first aspect, the present invention provides an orally disintegrating tablet of edenafil citrate, wherein the components of the orally disintegrating tablet of edenafil citrate include a pharmaceutical active ingredient, an auxiliary carrier, a disintegrant, a filler, a flavoring agent, a binder, and a lubricant. The active pharmaceutical ingredient includes edenafil citrate and / or its pharmaceutically acceptable salts; The auxiliary carrier includes any one or a combination of at least two of water-soluble vitamin E derivatives, organic acids, or organic acid salts.

[0010] The orally disintegrating tablets of edenafil citrate provided by this invention have the following advantages: (1) They are convenient to take, require no water, and rapidly disintegrate or dissolve in the oral cavity. The disintegration time does not exceed 60 seconds, which can solve the swallowing difficulties of some patients, such as the elderly, stroke patients, bedridden patients, patients with esophageal problems, and patients with mental disorders, thereby improving patient medication compliance. They are also convenient to use when traveling or when water is inconvenient; (2) They fully mask the bitter and astringent taste of edenafil citrate; (3) They rapidly disintegrate in saliva, with a cumulative dissolution rate of not less than 50% at 5 minutes and a maximum blood concentration time of not more than 1 hour. They are absorbed through the oral mucosa and take effect rapidly, meeting the requirement that oral PDE5 inhibitors take effect rapidly under specific circumstances in the treatment of erectile dysfunction.

[0011] Preferably, the components of the edenafil citrate orally disintegrating tablets include, by weight percentage, 10-60 wt% of the active pharmaceutical ingredient, 1-10 wt% of the auxiliary carrier, 5-15 wt% of the disintegrant, 20-80 wt% of the filler, 1-5 wt% of the flavoring agent, 1-5 wt% of the binder and 0.5-2 wt% of the lubricant.

[0012] The mass percentage of the active pharmaceutical ingredient can be 10wt%, 15wt%, 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt%, 55wt%, or 60wt%, etc.

[0013] The mass percentage of the auxiliary carrier can be 1wt%, 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, or 10wt%, etc.

[0014] The mass percentage of the disintegrant can be 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, or 15wt%, etc.

[0015] The mass percentage of the filler can be 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt%, 55wt%, 60wt%, 65wt%, 70wt%, 75wt%, or 80wt%, etc.

[0016] The flavoring agent may have a mass percentage of 1wt%, 1.5wt%, 2wt%, 2.5wt%, 3wt%, 3.5wt%, 4wt%, 4.5wt%, or 5wt%, etc.

[0017] The adhesive may have a mass percentage of 1wt%, 1.5wt%, 2wt%, 2.5wt%, 3wt%, 3.5wt%, 4wt%, 4.5wt%, or 5wt%, etc.

[0018] The mass percentage of the lubricant can be 0.5wt%, 0.6wt%, 0.7wt%, 0.8wt%, 0.9wt%, 1wt%, 1.1wt%, 1.2wt%, 1.3wt%, 1.4wt%, 1.5wt%, 1.6wt%, 1.7wt%, 1.8wt%, 1.9wt%, or 2wt%, etc.

[0019] Preferably, the auxiliary carrier includes a water-soluble vitamin E derivative, and also includes organic acids or organic acid salts (acidic excipients).

[0020] The combination of water-soluble vitamin E derivatives and acidic excipients as auxiliary carriers has a synergistic effect, which can significantly improve the solubility of edenafil citrate and neutralize the unpleasant taste such as bitterness, astringency, and numbing sensation of edenafil citrate.

[0021] Preferably, the water-soluble vitamin E derivative is d-α-tocopherol polyethylene glycol succinate.

[0022] Preferably, the polyethylene glycol in the d-α-tocopherol polyethylene glycol succinate has a molecular weight of 500~3000 Da, for example, it can be 500 Da, 800 Da, 1000 Da, 1500 Da, 2000 Da, 2500 Da or 3000 Da.

[0023] Preferably, the organic acid includes any one or a combination of at least two of citric acid, fumaric acid, or tartaric acid.

[0024] Preferably, the organic acid salt is sodium citrate monosodium citric acid.

[0025] Preferably, the citric acid is anhydrous citric acid.

[0026] Preferably, the sodium citrate is anhydrous sodium citrate.

[0027] Preferably, the auxiliary carrier includes d-α-tocopherol polyethylene glycol succinate, and further includes any one or a combination of at least two of anhydrous sodium citrate, anhydrous citric acid, or fumaric acid.

[0028] Preferably, the mass ratio of the water-soluble vitamin E derivative to the organic acid or organic acid salt is (1~3):(1~3).

[0029] The specific point values ​​in the first (1~3) can be 1, 1.2, 1.5, 1.7, 2, 2.3, 2.5, 2.8 or 3, etc.

[0030] The specific point values ​​in the second (1~3) can be 1, 1.2, 1.5, 1.7, 2, 2.3, 2.5, 2.8 or 3, etc.

[0031] Preferably, the mass ratio of the water-soluble vitamin E derivative to the organic acid or organic acid salt is (1~2):(1~2).

[0032] The specific point value in the first (1~2) can be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2, etc.

[0033] The specific point values ​​in the second (1~2) can be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2, etc.

[0034] Preferably, the disintegrant comprises any one or a combination of at least two of carboxymethyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, or sodium carboxymethyl starch.

[0035] Preferably, the filler comprises any one or a combination of at least two of microcrystalline cellulose, mannitol, lactose, xylitol, maltitol, sorbitol, pregelatinized starch, corn starch, or gelatin.

[0036] Preferably, the filler comprises microcrystalline cellulose, and further comprises any one or a combination of at least two of mannitol, lactose or xylitol.

[0037] Preferably, the flavoring agent includes any one or a combination of at least two of aspartame, sucralose, acesulfame potassium, stevioside, or sodium saccharin.

[0038] Preferably, the adhesive comprises any one or a combination of at least two of the following: povidone, starch paste, dextrin, pregelatinized starch, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, gum arabic, tragacanth gum, ethyl cellulose, or hydroxypropyl methyl cellulose.

[0039] Preferably, the lubricant comprises any one or a combination of at least two of magnesium stearate, calcium stearate, or talc.

[0040] Preferably, the components of the orally disintegrating citrate tablets also include a gliding agent.

[0041] Preferably, the flow aid comprises colloidal silica.

[0042] Preferably, the components of the orally disintegrating citrate tablets include, by weight percentage, 10-60 wt% of the active pharmaceutical ingredient, 1-10 wt% of the auxiliary carrier, 5-15 wt% of the disintegrant, 20-80 wt% of the filler, 1-5 wt% of the flavoring agent, 1-5 wt% of the binder, 0.5-2 wt% of the lubricant and 0.5-2 wt% of the flow aid.

[0043] The mass percentage of the active pharmaceutical ingredient can be 10wt%, 15wt%, 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt%, 55wt%, or 60wt%, etc.

[0044] The mass percentage of the auxiliary carrier can be 1wt%, 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, or 10wt%, etc.

[0045] The mass percentage of the disintegrant can be 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, or 15wt%, etc.

[0046] The mass percentage of the filler can be 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt%, 55wt%, 60wt%, 65wt%, 70wt%, 75wt%, or 80wt%, etc.

[0047] The flavoring agent may have a mass percentage of 1wt%, 1.5wt%, 2wt%, 2.5wt%, 3wt%, 3.5wt%, 4wt%, 4.5wt%, or 5wt%, etc.

[0048] The adhesive may have a mass percentage of 1wt%, 1.5wt%, 2wt%, 2.5wt%, 3wt%, 3.5wt%, 4wt%, 4.5wt%, or 5wt%, etc.

[0049] The mass percentage of the lubricant can be 0.5wt%, 0.6wt%, 0.7wt%, 0.8wt%, 0.9wt%, 1wt%, 1.1wt%, 1.2wt%, 1.3wt%, 1.4wt%, 1.5wt%, 1.6wt%, 1.7wt%, 1.8wt%, 1.9wt%, or 2wt%, etc.

[0050] The mass percentage of the glial agent can be 0.5wt%, 0.6wt%, 0.7wt%, 0.8wt%, 0.9wt%, 1wt%, 1.1wt%, 1.2wt%, 1.3wt%, 1.4wt%, 1.5wt%, 1.6wt%, 1.7wt%, 1.8wt%, 1.9wt%, or 2wt%, etc.

[0051] Preferably, the disintegration time of the orally disintegrating tablets of citrate in artificial saliva does not exceed 60 s, for example, it can be 60 s, 55 s, 50 s, 45 s, 40 s, 35 s, 30 s, 25 s, 20 s or 15 s, etc.

[0052] Preferably, the complete dissolution time of the orally disintegrating citrate tablets does not exceed 30 min, for example, it can be 30 min, 25 min, 20 min, 15 min, 10 min, 8 min, 5 min, 2 min or 1 min, etc.

[0053] Preferably, the cumulative dissolution rate of the orally disintegrating citrate tablets at 5 min is not less than 50%, for example, it can be 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%, etc.

[0054] Preferably, the time to maximum plasma concentration of the orally disintegrating citrate tablets does not exceed 1 hour, for example, it can be 1 hour, 0.9 hours, 0.8 hours, 0.7 hours, 0.6 hours, 0.5 hours, 0.4 hours, 0.3 hours, 0.2 hours or 0.1 hours.

[0055] In a second aspect, the present invention provides a method for preparing orally disintegrating citrate tablets as described in the first aspect, the method comprising: A mixture is prepared by mixing a filler and a partial disintegrant; the active pharmaceutical ingredient and an auxiliary carrier are dissolved in an aqueous solution containing a binder, and then sprayed onto the mixture for wet granulation and drying to obtain intermediate particles; the intermediate particles, flavoring agent, lubricant and remaining disintegrant are mixed and compressed into tablets to obtain the orally disintegrating tablets of edenafil citrate.

[0056] Preferably, the mass ratio of the partial disintegrant to the remaining disintegrant is (1~2):(1~2).

[0057] The specific point value in the first (1~2) can be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2, etc.

[0058] The specific point values ​​in the second (1~2) can be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2, etc.

[0059] Preferably, the average particle size of the active pharmaceutical ingredient does not exceed 20 μm, and may be, for example, 20 μm, 19 μm, 18 μm, 17 μm, 16 μm, 15 μm, 14 μm, 13 μm, 12 μm, 11 μm, 10 μm or 5 μm.

[0060] Preferably, the water content of the intermediate particles does not exceed 2wt%, for example, it can be 2wt%, 1.9wt%, 1.8wt%, 1.7wt%, 1.6wt%, 1.5wt%, 1.4wt%, 1.3wt%, 1.2wt%, 1.1wt%, 1wt%, or 0.5wt%, etc.

[0061] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0062] Preferably, the intermediate particles are further sieved before being mixed and compressed into tablets.

[0063] Preferably, the mixing and tableting process also includes the addition of a flow aid.

[0064] Thirdly, the present invention provides the use of edenafil citrate orally disintegrating tablets as described in the first aspect in the preparation of a medicament for the treatment of Alzheimer's disease.

[0065] Fourthly, the present invention provides the use of edenafil citrate orally disintegrating tablets as described in the first aspect in the preparation of a medicament for the treatment of erectile dysfunction.

[0066] Compared with the prior art, the present invention has the following beneficial effects: The orally disintegrating tablets of edenafil citrate provided by this invention have the following advantages: (1) They are convenient to take, require no water, and rapidly disintegrate or dissolve in the oral cavity. The disintegration time does not exceed 60 seconds, which can solve the swallowing difficulties of some patients, such as the elderly, stroke patients, bedridden patients, patients with esophageal problems, and patients with mental disorders, thereby improving patient medication compliance. They are also convenient to use when traveling or when water is inconvenient; (2) They fully mask the bitter and astringent taste of edenafil citrate; (3) They rapidly disintegrate in saliva, with a cumulative dissolution rate of not less than 50% at 5 minutes and a maximum blood concentration time of not more than 1 hour. They are absorbed through the oral mucosa and take effect rapidly, meeting the requirement that oral PDE5 inhibitors take effect rapidly under specific circumstances in the treatment of erectile dysfunction. Detailed Implementation

[0067] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0068] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0069] The sources of materials used in the following specific embodiments are as follows: Example 1 This embodiment provides an orally disintegrating tablet of edenafil citrate, which comprises the following components by weight percentage: The preparation method includes: adding the active pharmaceutical ingredient and auxiliary carrier to an aqueous solution containing 5 wt% binder and stirring to dissolve; adding the filler and half a dose of disintegrant to a fluidized bed, spraying the above liquid, and setting the inlet air temperature to 60℃, the spraying speed to 18 rpm, and the air volume to 40 m³ / h. 3 Granulation is carried out at 10 rpm for 10 min, and the moisture content is controlled to not exceed 2 wt% to obtain intermediate granules. The intermediate granules are granulated by sieving through a 20-mesh sieve, and then mixed evenly with flavoring agent, lubricant, glidant and remaining disintegrant. The mixture is mixed at 10 rpm for 10 min and then compressed into tablets using a high-speed rotary tablet press to obtain orally disintegrating tablets of edenafil citrate with a tablet weight of 140 mg / tablet and a hardness of 30~80 N.

[0070] Example 2: Auxiliary Carrier This embodiment provides three types of orally disintegrating citrate tablets, which differ from Example 1 only in that: (2.1) No anhydrous sodium citrate was added to the auxiliary carrier, and the reduction was made up by d-α-tocopherol polyethylene glycol succinate; (2.2) The auxiliary carrier did not contain "d-α-tocopherol polyethylene glycol succinate", and the reduction was made up by "anhydrous sodium citrate"; (2.3) No auxiliary carrier was added, and the reduction was made up by the filler (the mass ratio of mannitol and microcrystalline cellulose remained unchanged at 2:1).

[0071] Example 3: Auxiliary Carrier This embodiment provides five types of orally disintegrating citrate tablets, which differ from Example 1 only in that: (3.1) Replace “anhydrous sodium citrate” with an equal amount of “anhydrous citric acid” in the auxiliary carrier; (3.2) Replace “anhydrous sodium citrate” with an equal amount of “fumaric acid” in the auxiliary carrier; (3.3) Replace “anhydrous sodium citrate” with an equal amount of “tartaric acid” in the auxiliary carrier; (3.4) Replace “anhydrous sodium citrate” with an equal amount of “acetic acid” in the auxiliary carrier; (3.5) Replace “anhydrous sodium citrate” with an equal amount of “lactic acid” in the auxiliary carrier.

[0072] Example 4: Auxiliary Carrier This embodiment provides four types of orally disintegrating citrate tablets, which differ from Example 1 only in that: (4.1) Adjust the total content of the auxiliary carrier to 0.3%, and keep the mass ratio of anhydrous sodium citrate and d-α-tocopherol polyethylene glycol succinate unchanged at 2:1; adjust the amount of auxiliary carrier accordingly with filler (keeping the mass ratio of mannitol and microcrystalline cellulose unchanged at 2:1) so that the total mass percentage is 100%; (4.2) Adjust the total content of the auxiliary carrier to 1%, and keep the mass ratio of anhydrous sodium citrate and d-α-tocopherol polyethylene glycol succinate unchanged at 2:1; adjust the amount of auxiliary carrier accordingly with filler (keeping the mass ratio of mannitol and microcrystalline cellulose unchanged at 2:1) so that the total mass percentage is 100%; (4.3) Adjust the total content of the auxiliary carrier to 5%, and keep the mass ratio of anhydrous sodium citrate and d-α-tocopherol polyethylene glycol succinate unchanged at 2:1; adjust the amount of auxiliary carrier accordingly with filler (keeping the mass ratio of mannitol and microcrystalline cellulose unchanged at 2:1) so that the total mass percentage is 100%; (4.4) Adjust the total content of auxiliary carrier to 10%, and keep the mass ratio of anhydrous sodium citrate and d-α-tocopherol polyethylene glycol succinate unchanged at 2:1; adjust the amount of auxiliary carrier accordingly with filler (keeping the mass ratio of mannitol and microcrystalline cellulose unchanged at 2:1) so that the total mass percentage is 100%.

[0073] Example 5: Auxiliary Carrier This embodiment provides four types of orally disintegrating citrate tablets, which differ from Example 1 only in that: (5.1) Keep the total content of the auxiliary carrier at 3%, and adjust the mass ratio of anhydrous sodium citrate and d-α-tocopherol polyethylene glycol succinate to 3:1; (5.2) Keep the total content of the auxiliary carrier at 3%, and adjust the mass ratio of anhydrous sodium citrate and d-α-tocopherol polyethylene glycol succinate to 1:1; (5.3) Keep the total content of the auxiliary carrier at 3% and adjust the mass ratio of anhydrous sodium citrate and d-α-tocopherol polyethylene glycol succinate to 1:2; (5.4) Keep the total content of the auxiliary carrier at 3% and adjust the mass ratio of anhydrous sodium citrate and d-α-tocopherol polyethylene glycol succinate to 1:3.

[0074] Example 6 Disintegrant This embodiment provides four types of orally disintegrating citrate tablets, which differ from Example 1 only in that: (6.1) Adjust the content of the disintegrant "carboxymethyl cellulose" to 8%; adjust the amount of disintegrant accordingly with fillers (keeping the mass ratio of mannitol and microcrystalline cellulose unchanged at 2:1) so that the total mass percentage is 100%; (6.2) Adjust the content of the disintegrant "carboxymethyl cellulose" to 15%; adjust the amount of disintegrant accordingly with fillers (keeping the mass ratio of mannitol and microcrystalline cellulose unchanged at 2:1) so that the total mass percentage is 100%; (6.3) Adjust the content of the disintegrant "carboxymethyl cellulose" to 5%; adjust the amount of disintegrant accordingly with fillers (keeping the mass ratio of mannitol and microcrystalline cellulose constant at 2:1) so that the total mass percentage is 100%; (6.4) Adjust the content of the disintegrant "carboxymethyl cellulose" to 3%; adjust the amount of disintegrant accordingly with filler (keep the mass ratio of mannitol and microcrystalline cellulose at 2:1) so that the total mass percentage is 100%.

[0075] Example 7 Disintegrant This embodiment provides five types of orally disintegrating citrate tablets, which differ from Example 1 only in that: (7.1) The disintegrant “carboxymethyl cellulose” was replaced with an equal amount of “low-substituted hydroxypropyl cellulose”; (7.2) The disintegrant “carboxymethyl cellulose” was replaced with an equal amount of “sodium carboxymethyl starch”; (7.3) The disintegrant "carboxymethyl cellulose" was replaced with an equal amount of "crospovidone"; (7.4) The disintegrant “carboxymethyl cellulose” is replaced with an equal amount of “crosslinked carboxymethyl cellulose sodium”; (7.5) The disintegrant “carboxymethyl cellulose” was replaced with an equal amount of “carboxymethyl cellulose calcium”.

[0076] Example 8 Filler This embodiment provides four types of orally disintegrating citrate tablets, which differ from Example 1 only in that: (8.1) Maintain the total content of fillers at 51% and adjust the mass ratio of mannitol to microcrystalline cellulose to 3:1; (8.1) Maintain the total content of fillers at 51% and adjust the mass ratio of mannitol and microcrystalline cellulose to 1:1; (8.1) Maintain the total content of fillers at 51% and adjust the mass ratio of mannitol and microcrystalline cellulose to 1:2; (8.1) Keep the total content of filler at 51% and adjust the mass ratio of mannitol and microcrystalline cellulose to 1:3.

[0077] Example 9 Filler This embodiment provides six types of orally disintegrating citrate tablets, which differ from Example 1 only in that: (9.1) No “microcrystalline cellulose” was added to the filler, and the reduction was made up by “mannitol”; (9.2) No mannitol was added to the filler, and the reduction was made up by microcrystalline cellulose; (9.3) The filler is 51% "lactose"; (9.4) Replace “mannitol” in the filler with an equal amount of “lactose”; (9.5) The filler is 51% xylitol; (9.6) Replace “mannitol” in the filler with an equal amount of “xylitol”.

[0078] Example 10 Flavoring Agent This embodiment provides four types of orally disintegrating citrate tablets, which differ from Example 1 only in that: (10.1) Adjust the content of the flavoring agent "aspartan" to 0.5%; adjust the amount of flavoring agent accordingly with fillers (keeping the mass ratio of mannitol and microcrystalline cellulose unchanged at 2:1) so that the total mass percentage is 100%; (10.2) Adjust the content of the flavoring agent "aspartan" to 1%; adjust the amount of flavoring agent accordingly with fillers (keeping the mass ratio of mannitol and microcrystalline cellulose unchanged at 2:1) so that the total mass percentage is 100%; (10.3) Adjust the content of the flavoring agent "aspartan" to 3%; adjust the amount of flavoring agent accordingly with fillers (keep the mass ratio of mannitol and microcrystalline cellulose at 2:1) so that the total mass percentage is 100%; (10.4) Adjust the content of the flavoring agent "aspartan" to 5%; adjust the amount of flavoring agent accordingly with filler (keeping the mass ratio of mannitol and microcrystalline cellulose unchanged at 2:1) so that the total mass percentage is 100%.

[0079] Example 11 Flavoring Agent This embodiment provides four types of orally disintegrating citrate tablets, which differ from Example 1 only in that: (11.1) Replace "aspartan" in the flavoring agent with an equal amount of "sucralose"; (11.2) Replace "aspartan" in the flavoring agent with an equal amount of "acesulfame K"; (11.3) Replace "aspartan" in the flavoring agent with an equal amount of "stevioside"; (11.4) Replace “aspartan” in the flavoring agent with an equal amount of “saccharin sodium”.

[0080] Comparative Example 1 This comparative example provides a commercially available edenafil citrate tablet, marketed under the brand name Aleix, in a 30 mg strength.

[0081] Test Example 1: Disintegration Time Limit Orally disintegrating tablets need to disintegrate rapidly in the oral cavity to release the drug. The test adopted the bilateral disintegration method. Using a vibrating water bath device (25±0.5℃), the test samples (Aldenafil Citrate Orally Disintegrating Tablets of Examples 1-11 and Aldenafil Citrate Tablets of Comparative Example 1) were placed in 20mL of artificial saliva with pH=6.8, and the shaking speed was 70 r / min. The time for the test sample to completely dissolve was recorded, i.e., the disintegration time limit.

[0082] The test results are shown in Table 1: (1) As can be seen from Example 1 and Comparative Example 1, the orally disintegrating tablets of citrate provided by the present invention have a shorter disintegration time than the commercially available product, Aleix, and can exert their effects more quickly. (2) As can be seen from Examples 2-5 and Examples 10-11, the auxiliary carrier and flavoring agent have little effect on the disintegration time, and all meet the requirement that the disintegration time does not exceed 60s. (3) As can be seen from Example 6, the disintegration time decreases with the increase of the amount of disintegrant. As can be seen from Example 7, the type of disintegrant affects the disintegration time. When low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch are used as disintegrants, the disintegration time exceeds 60s. (4) As can be seen from Example 9, the type of filler affects the disintegration time. When mannitol, lactose, or xylitol are used as fillers, the disintegration time exceeds 60s. When mannitol, lactose, or xylitol are used in combination with microcrystalline cellulose, they all meet the requirement that the disintegration time should not exceed 60 seconds. Among them, the combination of mannitol and microcrystalline cellulose has the best effect, and the two have a synergistic effect.

[0083] Table 1 Test Example 2 Dissolution Dissolution rate is crucial for evaluating drug release behavior and formulation performance. Common dissolution methods for evaluating the in vitro release of oral films include: basket method, slurry method, perforation and filtration method, and flow-through method. The basket method is the simplest but has the lowest precision, and it's difficult to maintain proper slurry conditions for poorly soluble drugs. The slurry method offers high precision and reproducibility, but involves multiple dissolution media, which doesn't match the physiological conditions of the oral cavity (pH 5.5–7.0). The perforation and filtration method considers saliva flow and allows for automated sampling, but requires complex instruments and control of the dissolution medium flow rate, resulting in a high error rate. The flow-through method better simulates the oral environment, offering high flexibility and reproducibility. Therefore, for evaluating the in vitro release of orally disintegrating tablets, the flow-through method better simulates the actual release in the oral environment and has in vivo-in vitro correlation.

[0084] The CE7smart flow cell dissolution analyzer (Switzerland SOTAX) was used. The dissolution conditions were as follows: a closed system using the flow cell method was employed. The test samples (Adelineate citrate orally disintegrating tablets from Examples 1-9 and Adelineate citrate tablets from Comparative Example 1) were placed in a flow cell with a conical section filled with 1 mm glass beads. 100 mL of phosphate buffer (pH 6.8) was used as the dissolution medium. The temperature was 37°C and the flow rate was 4 mL / min. 1 mL samples were taken at fixed time points. After the sampled dissolution solution was filtered through a 0.7 μm glass fiber membrane, the content of the active pharmaceutical ingredient Adelineate citrate in the dissolution solution was detected by liquid chromatography, and the cumulative dissolution rate at different time points was calculated.

[0085] The test results are shown in Table 2: (1) As can be seen from Example 1 and Comparative Example 1, the citrate edenafil orally disintegrating tablets provided by the present invention have a higher cumulative dissolution rate in a short time compared with the commercially available product, Aleix, and are basically completely dissolved in 5 minutes, thus exerting the drug effect more quickly. (2) As can be seen from Example 2, the water-soluble vitamin E derivative and acidic excipients in the auxiliary carrier have a synergistic effect, which can significantly accelerate the dissolution of citrate edenafil orally disintegrating tablets. As can be seen from Example 3, the type of acidic excipient affects the dissolution rate. When anhydrous citrate, fumaric acid, or tartaric acid is used as an acidic excipient and combined with d-α-tocopherol polyethylene glycol succinate, the dissolution rate is faster. Among them, the combination of anhydrous citrate and d-α-tocopherol polyethylene glycol succinate has the best effect. As can be seen from Example 4, the dissolution rate increases with the increase of the amount of auxiliary carrier. As shown in Example 5, when the mass ratio of anhydrous citric acid to d-α-tocopherol polyethylene glycol succinate is 1:(1~3), the dissolution rate is faster, and it is basically completely dissolved in 5 minutes. (3) As shown in Example 6, the dissolution rate increases with the increase of the amount of disintegrant. As shown in Example 7, the type of disintegrant affects the dissolution rate. When low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch are used as disintegrants, the dissolution effect is poor. (4) As shown in Example 9, the type of filler affects the disintegration time. When mannitol, lactose, or xylitol are used as fillers alone, the dissolution effect is poor. However, when mannitol, lactose, or xylitol are used in combination with microcrystalline cellulose, the dissolution rate can be improved. Among them, the combination of mannitol and microcrystalline cellulose has the best effect, and the two have a synergistic effect.

[0086] Table 2 Test Example 3: Friability and Appearance The brittleness of the test samples (Aldenafil Citrate Orally Disintegrating Tablets of Examples 1 and 8-9, and Aldenafil Citrate Tablets of Comparative Example 1) was tested according to General Chapter 0923 of the 2025 edition of the Chinese Pharmacopoeia, and their appearance was also examined.

[0087] The test results are shown in Table 3: (1) As can be seen from Example 9, the type of filler affects the friability and appearance. When mannitol, lactose, or xylitol are used as fillers alone, the friability is too high. However, when mannitol, lactose, or xylitol are used in combination with microcrystalline cellulose, the friability can be reduced. Among them, the combination of mannitol and microcrystalline cellulose has the best effect, and the two have a synergistic effect. (2) As can be seen from Example 8, when the mass ratio of mannitol to microcrystalline cellulose is in the range of (1~3):1, the surface of the product is smooth and the friability is lower.

[0088] Table 3 Test Example 4 Ten volunteers (5 men and 5 women) refrained from eating, drinking, or chewing gum for at least one hour before the test and rinsed their mouths with deionized water at least three times. Volunteers held the test sample (orally disintegrating citrate tablets from Examples 1-5 and Examples 10-11) in their mouths for 10 seconds, then spat it out and rinsed their mouths with deionized water at least 10 times until no unpleasant taste remained before tasting the next sample. The test samples were evaluated using the criteria of "extremely bitter, bitter, slightly bitter, not bitter, and sweet," with the evaluation result indicated by "Y" under the corresponding taste evaluation item. Each sample was tasted three times, and the highest-voted sample was selected as the final choice.

[0089] The test results are shown in Table 4: (1) As shown in Example 1, the orally disintegrating tablets of edenafil citrate provided by the present invention have a better taste and can fully mask the bitterness of edenafil citrate. (2) As shown in Example 2, the addition of the auxiliary carrier can mask the bitterness of edenafil citrate. Among them, the water-soluble vitamin E derivative and the acidic excipient have a synergistic effect. As shown in Example 3, the type of acidic excipient affects the taste. When anhydrous citric acid, fumaric acid or tartaric acid are used as acidic excipients and combined with d-α-tocopherol polyethylene glycol succinate, the taste is better. Among them, the combination of anhydrous citric acid and d-α-tocopherol polyethylene glycol succinate has the best effect. As shown in Example 4, the taste is better with the increase of the amount of auxiliary carrier. Example 5 shows that anhydrous citric acid to d-α-tocopherol polyethylene glycol succinate has a better taste when the mass ratio is (1~3):(1~2). (3) Example 10 shows that the taste is better with increasing amount of flavoring agent. Example 11 shows that the type of flavoring agent affects the taste; aspartame, sucralose, and acesulfame potassium have better taste when used as flavoring agents.

[0090] Table 4 Test Example 5 The α-ASTREE electronic tongue detection device, developed by AlphaMOS (France), was used. Test samples (orally disintegrating citrate tablets from Examples 1-5 and 10-11) were poured into dedicated beakers for the electronic tongue, with each beaker containing approximately 80 mL of sample. Once the electronic tongue entered the sample solution, it began acquiring the sample signal. The acquisition time for each sample was 120 s, and the data obtained at the 120th s mark was used as the output value. After measuring one sample, the electronic tongue was cleaned in a corresponding cleaning beaker. Initially, the signal intensity fluctuated, but stabilized after 2-3 measurements. Each sample was measured seven times, and the data from the last three measurements were used as the raw data for principal component analysis and distance analysis. Principal component analysis (PCA) was used in multivariate statistical analysis to analyze the data acquired by the electronic tongue. Using the built-in software of the electronic tongue, the difference between each orally disintegrating tablet solution sample and purified water can be visually observed. Furthermore, the spatial distance between them, known as the distance of bitterness in the e-tongue (D), can be calculated using chemometric methods. This indirectly indicates the effectiveness of the taste masking agent; a smaller D value indicates a better masking effect for unpleasant tastes. Here, D0 represents the distance of bitterness between edenafil citrate and purified water, and D... s To test the bitterness of the sample and purified water, ΔD is D0-D s Inhibition rate IR (%) = (D0 - D) s ) / D0×100.

[0091] The test results are shown in Table 5: (1) As shown in Example 1, the orally disintegrating tablets of edenafil citrate provided by the present invention have a better taste and can fully mask the bitterness of edenafil citrate. (2) As shown in Example 2, the addition of the auxiliary carrier can mask the bitterness of edenafil citrate. Among them, the water-soluble vitamin E derivative and the acidic excipient have a synergistic effect. As shown in Example 3, the type of acidic excipient affects the taste. When anhydrous citric acid, fumaric acid or tartaric acid are used as acidic excipients and combined with d-α-tocopherol polyethylene glycol succinate, the taste is better. Among them, the combination of anhydrous citric acid and d-α-tocopherol polyethylene glycol succinate has the best effect. As shown in Example 4, the taste is better with the increase of the amount of auxiliary carrier. Example 5 shows that anhydrous citric acid to d-α-tocopherol polyethylene glycol succinate has a better taste when the mass ratio is (1~3):(1~2). (3) Example 10 shows that the taste is better with increasing amount of flavoring agent. Example 11 shows that the type of flavoring agent affects the taste; aspartame, sucralose, and acesulfame potassium have better taste when used as flavoring agents.

[0092] Table 5 Test Example 6 Beagles were randomly divided into two groups of four dogs each (half male and half female). After fasting for 16 hours, one group received oral administration of edenafil citrate orally disintegrating tablets (Example 1), while the other group received oral administration of edenafil citrate tablets (Comparative Example 1). The dosage for both groups was 3 mg / kg. Blood samples (2 mL) were collected from each beagle before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, and 72 hours after administration. After coagulation at room temperature, serum was separated by centrifugation at 10,000 rpm and stored at -20°C. Once all dog samples were collected, they were processed and analyzed uniformly to minimize measurement errors. Various pharmacokinetic parameters, including the time to peak plasma concentration (T0), were calculated. max Maximum blood drug concentration C max Plasma concentration - Area under the curve (AUC) from 0 hours after a single dose to the last time point last Plasma concentration - Area under the curve (AUC) from 0 hours to infinity after a single dose INF_obs .

[0093] The test results are shown in Table 6: Compared with the commercially available product Aleix, the area under the blood concentration-time curve of the orally disintegrating citrate tablets provided by this invention is not significantly different, but the onset of action is more rapid.

[0094] Table 6 This invention illustrates an orally disintegrating tablet of citrate, its preparation method, and its application through the above embodiments. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily rely on the above embodiments for implementation. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials, additions of auxiliary components, and selection of specific methods, etc., all fall within the protection and disclosure scope of this invention.

[0095] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0096] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. An orally disintegrating tablet containing edenafil citrate, characterized in that, The components of the orally disintegrating citrate tablets include the active pharmaceutical ingredient, co-carrier, disintegrant, filler, flavoring agent, binder, and lubricant. The active pharmaceutical ingredient includes edenafil citrate and / or its pharmaceutically acceptable salts; The auxiliary carrier includes any one or a combination of at least two of water-soluble vitamin E derivatives, organic acids, or organic acid salts.

2. The orally disintegrating tablets of edenafil citrate according to claim 1, characterized in that, The components of the orally disintegrating citrate tablets, by weight percentage, include 10-60 wt% of the active pharmaceutical ingredient, 1-10 wt% of the auxiliary carrier, 5-15 wt% of the disintegrant, 20-80 wt% of the filler, 1-5 wt% of the flavoring agent, 1-5 wt% of the binder, and 0.5-2 wt% of the lubricant.

3. The orally disintegrating tablets of edenafil citrate according to claim 1 or 2, characterized in that, The auxiliary carrier includes a water-soluble vitamin E derivative, and also includes organic acids or organic acid salts; Preferably, the water-soluble vitamin E derivative is d-α-tocopherol polyethylene glycol succinate; Preferably, the organic acid includes any one or a combination of at least two of citric acid, fumaric acid, or tartaric acid; Preferably, the organic acid salt is sodium citrate monosodium citric acid.

4. The orally disintegrating tablets of edenafil citrate according to claim 3, characterized in that, The mass ratio of the water-soluble vitamin E derivative to the organic acid or organic acid salt is (1~3):(1~3); Preferably, the mass ratio of the water-soluble vitamin E derivative to the organic acid or organic acid salt is (1~2):(1~2).

5. The orally disintegrating tablets of edenafil citrate according to any one of claims 1 to 4, characterized in that, The disintegrant includes any one or a combination of at least two of carboxymethyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, or sodium carboxymethyl starch; Preferably, the filler comprises any one or a combination of at least two of the following: microcrystalline cellulose, mannitol, lactose, xylitol, maltitol, sorbitol, pregelatinized starch, corn starch, or gelatin; Preferably, the filler comprises microcrystalline cellulose, and further comprises any one or a combination of at least two of mannitol, lactose or xylitol; Preferably, the flavoring agent includes any one or a combination of at least two of aspartame, sucralose, acesulfame potassium, stevioside, or sodium saccharin; Preferably, the adhesive comprises any one or a combination of at least two of the following: povidone, starch paste, dextrin, pregelatinized starch, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, gum arabic, tragacanth gum, ethyl cellulose, or hydroxypropyl methyl cellulose; Preferably, the lubricant comprises any one or a combination of at least two of magnesium stearate, calcium stearate, or talc.

6. The orally disintegrating tablets of edenafil citrate according to any one of claims 1 to 5, characterized in that, The components of the orally disintegrating citrate tablets also include a gliding agent; Preferably, the flow aid comprises colloidal silica; Preferably, the components of the edenafil citrate orally disintegrating tablets, by weight percentage, include 10-60 wt% of the active pharmaceutical ingredient, 1-10 wt% of the auxiliary carrier, 5-15 wt% of the disintegrant, 20-80 wt% of the filler, 1-5 wt% of the flavoring agent, 1-5 wt% of the binder, 0.5-2 wt% of the lubricant and 0.5-2 wt% of the flow aid.

7. The method for preparing edenafil citrate orally disintegrating tablets according to any one of claims 1 to 6, characterized in that, The preparation method includes: A mixture is prepared by mixing a filler and a partial disintegrant; the active pharmaceutical ingredient and an auxiliary carrier are dissolved in an aqueous solution containing a binder, and then sprayed onto the mixture for wet granulation and drying to obtain intermediate particles; the intermediate particles, flavoring agent, lubricant and remaining disintegrant are mixed and compressed into tablets to obtain the orally disintegrating tablets of edenafil citrate.

8. The preparation method according to claim 7, characterized in that, The mass ratio of the partial disintegrant to the remaining disintegrant is (1~2):(1~2); Preferably, the average particle size of the active pharmaceutical ingredient does not exceed 20 μm; Preferably, the moisture content of the intermediate particles does not exceed 2 wt%; Preferably, the intermediate particles are further subjected to a sieving step before being mixed and compressed into tablets; Preferably, the mixing and tableting process also includes the addition of a flow aid.

9. The use of edenafil citrate orally disintegrating tablets according to any one of claims 1 to 6 in the preparation of a drug for treating Alzheimer's disease.

10. The use of edenafil citrate orally disintegrating tablets according to any one of claims 1 to 6 in the preparation of a drug for treating erectile dysfunction.

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