Sublingual tablet, preparation method therefor, and use thereof

Abstract

The present invention provides a sublingual tablet, a preparation method therefor, and use thereof. The sublingual tablet comprises a main drug and auxiliary materials, wherein the main drug is a compound represented by formula (I), and the auxiliary materials include a filler, a disintegrating agent, a flavoring agent, and a lubricant.

Description

A sublingual tablet, its preparation method and uses Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a sublingual tablet, its preparation method, and its use in the preparation of a drug for treating male erectile dysfunction. Background Technology

[0002] Erectile dysfunction (ED), commonly known as impotence, refers to a man's persistent inability to achieve or maintain a sufficient level of penile erection in response to sexual stimulation. A clinical diagnosis of ED is only made after a course of illness lasting more than three months. According to epidemiological data (J Androl, 2011, 32:496), the overall prevalence of ED among adult men in my country is 17.1%, increasing with age, reaching 29.1% in those over 50 years of age. Among drug treatments for ED, phosphodiesterase 5 (PDE5) inhibitors are convenient, safe, effective, and easily accepted by most patients, making them the first-line treatment in clinical practice. Currently approved oral PDE5 inhibitors for the treatment of erectile dysfunction include: sildenafil (Viagra), vardenafil (Levitra), tadalafil (Cialis), and avanafil (Stendra). Sildenafil, developed by Pfizer, was approved by the FDA in 1998, becoming the first oral medication approved by the FDA for the treatment of erectile dysfunction (ED). Subsequently, in 2003, Bayer and GlaxoSmithKline jointly launched vardenafil, and Eli Lilly launched tadalafil. In 2012, the FDA approved avanafil.

[0003] Because phosphodiesterases (PDE5s) have at least 11 enzyme systems and more subtypes, highly selective PDE5 inhibitors are crucial for developing treatments for erectile dysfunction. Of the four currently marketed PDE5 inhibitors, sildenafil and vardenafil have poor selectivity for PDE1 and PDE6, leading to side effects such as facial flushing and visual disturbances, and posing potential cardiovascular risks. Furthermore, both compounds have short half-lives, making them unsuitable for long-term use. Tadalafil has a longer half-life, allowing for once-daily dosing, but its poor selectivity for PDE11 and side effects such as back pain and muscle soreness affect patient compliance. Avanafil, while having lower clinical adverse reactions due to its high selectivity, also has a short half-life, making it unsuitable for long-term use. Unmet clinical needs remain for PDE5 inhibitors, and highly selective, long-half-life PDE5 inhibitors represent the future direction of PDE5 inhibitor development.

[0004] Epimedium (Epimedium brevicornum Maxim.) has a long history of medicinal use in China. Due to its effects of tonifying kidney yang, strengthening tendons and bones, and dispelling wind and dampness, it is mainly used to treat impotence and premature ejaculation. With the development of basic sciences and scientific research instruments, research on traditional natural medicines like Epimedium has become increasingly in-depth and comprehensive. Studies have shown that Epimedium contains a complex and numerous effective components, among which the main component is icariin (molecular formula: C...). 33 H 40 O 15 (Molecular weight 676.67) belongs to the flavonoid class of compounds. The structures of some flavonoid compounds in Epimedium are shown below:

[0005] Icariin has a specific physiological effect of producing sexual arousal. The CO-cGMP-PDE5 pathway plays a key role in the treatment of erectile dysfunction. It reduces apoptosis of the smooth muscle of the corpus cavernosum by inhibiting fibrosis, oxidation and protection, and regulates the secretion of sex hormones and gonadotropins, thus protecting the sex organs and gonads.

[0006] Based on long-term research and accumulation of knowledge on the natural drug Epimedium, the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, discovered a compound with high phosphodiesterase (PDE5) inhibitory activity in the extract of Epimedium. Using the natural product Epimedium flavonoids as the lead structure and referencing computational chemistry data, the team conducted a refined "structural fine-tuning" design and synthesis through structural modification and splicing synthesis techniques. Ultimately, they obtained a candidate compound with better overall drug-like properties than sildenafil, as shown in formula (I):

[0007] This compound is a selective PDE5 inhibitor, screened from numerous active compounds based on extensive structure-activity relationship studies. Preclinical toxicology, pharmacodynamics, and pharmacokinetic studies have revealed that its activity is an order of magnitude higher than sildenafil, and its selectivity relative to other isoenzymes (including PDE1 and PDE6) is significantly improved compared to sildenafil. Compared to sildenafil, it possesses numerous advantages, including high activity, high selectivity, low toxicity, well-defined efficacy, and a simple structure that is easy to synthesize. Furthermore, it has independent intellectual property rights (see WO2010066111A1).

[0008] This invention features a simple and reliable manufacturing process, convenient administration, rapid onset of action, improved bioavailability, and guaranteed therapeutic efficacy. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to overcome the problem of slow onset of action of ordinary oral tablets in the prior art, and to provide a sublingual tablet of compound (I) and its preparation method. The sublingual tablet can be easily taken and disintegrates after being placed under the tongue for a few seconds.

[0010] To solve the above technical problems, the present invention adopts the following technical approach:

[0011] In a first aspect, the present invention provides a sublingual tablet, characterized in that it comprises an active pharmaceutical ingredient and excipients, wherein the active pharmaceutical ingredient is a compound of formula (I):

[0012] The excipients include fillers, disintegrants, flavoring agents, and lubricants.

[0013] In some embodiments, the filler may be one or more selected from microcrystalline cellulose, mannitol, sorbitol, pregelatinized starch, maltitol, mannitol crosspolymer / copolymer / mannitol-sorbitol co-treated product, and mannitol microcrystalline crosspolymer / calcium co-treated product.

[0014] In a further embodiment, the filler may be one or more selected from microcrystalline cellulose, mannitol, and sorbitol;

[0015] In a further embodiment, the filler may be one or both selected from microcrystalline cellulose and mannitol.

[0016] In a further embodiment, the filler may be a mannitol microcrystalline cross-polymerized calcium co-treated material.

[0017] In some embodiments, the disintegrant may be one or more selected from crospovidone, crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch.

[0018] In a further embodiment, the disintegrant may be crospovidone.

[0019] In some embodiments, the flavoring agent may be one or more selected from aspartame, cyclamate, sucralose, and stevioside.

[0020] In a further embodiment, the flavoring agent may be sucralose.

[0021] In some embodiments, the lubricant may be one or more selected from magnesium stearate, sodium stearate fumarate, talc, and colloidal silica.

[0022] In a further embodiment, the lubricant may be magnesium stearate.

[0023] In some embodiments, the sublingual tablets of the present invention comprise, by weight percentage, the following components: 1-30% active ingredient, 46-90% filler, 2-20% disintegrant, 0.1-3% flavoring agent, and 0.1-2% lubricant.

[0024] In a further embodiment, the active pharmaceutical ingredient comprises 2-15% by mass;

[0025] In a further embodiment, the filler has a mass percentage of 60-90%;

[0026] In a further embodiment, the disintegrant has a mass percentage of 5-10%;

[0027] In a further embodiment, the flavoring agent has a mass percentage of 0.2% to 2%;

[0028] In a further embodiment, the lubricant has a mass percentage of 0.2% to 1%.

[0029] When the fillers are mannitol and microcrystalline cellulose, the composite excipient mannitol microcrystalline crosspolymer calcium co-treated material can be selected to replace mannitol and microcrystalline cellulose.

[0030] In a second aspect, the present invention provides a method for preparing a sublingual tablet as described in the first aspect above, comprising the following steps:

[0031] (1) Pretreatment of active pharmaceutical ingredient and excipients: Pass the active pharmaceutical ingredient and excipients through a 60-mesh sieve and set aside;

[0032] (2) Weighing: Weigh the main drug and excipients according to the prescription;

[0033] (3) Mixing: Mix the prescribed amount of main drug, filler and disintegrant evenly to obtain premixed powder, add flavoring agent and lubricant and mix evenly to obtain total powder;

[0034] (4) Tableting: Tableting is performed using a tablet press.

[0035] Thirdly, the present invention provides another sublingual tablet, characterized in that it comprises an active ingredient and excipients, wherein the active ingredient is a compound of formula (I):

[0036] The excipients include water-soluble fillers and water-dispersible carriers.

[0037] In some embodiments, the sublingual tablets of the present invention contain, by weight percentage, the following contents of each component: active pharmaceutical ingredient 15.6%–40.0%, water-soluble filler 38.5%–79%, and water-dispersible carrier 5%–25%; more preferably, the following contents of each component: active pharmaceutical ingredient 15.6%–38.5%, water-soluble filler 38.5%–75.0%, and water-dispersible carrier 4.5%–23.1%. In some embodiments, the water-soluble filler may be one or more mixtures selected from hydrolyzed dextran, sorbitol, mannitol, alginate, and dextrin.

[0038] In some embodiments, the water-dispersible carrier may be one or a mixture selected from gelatin, polyvinyl alcohol, polyvinylpyrrolidone, and water-soluble cellulose derivatives.

[0039] In a further embodiment, the water-dispersible carrier may be gelatin and / or polyvinylpyrrolidone.

[0040] Fourthly, the present invention provides a method for preparing a sublingual tablet as described in the third aspect above, the method comprising:

[0041] 1) Dissolve the prescribed amount of water-dispersible carrier in purified water, and heat to 80℃~100℃ under stirring to obtain a water-dispersible carrier solution;

[0042] 2) Add the prescribed amount of the active pharmaceutical ingredient and water-soluble filler to the solution from step 1) after cooling (e.g., to room temperature);

[0043] 3) Add purified water to the solution from step 2) and stir until well mixed;

[0044] 4) Dispense the liquid medicine into a grooved polyamide / aluminum / polyvinyl chloride cold-stamped solid pharmaceutical composite hard sheet, for example, 0.4 ml / sheet, and freeze-dry it in a freeze dryer;

[0045] Preferably, the freeze dryer is pre-frozen at -40℃ to -180℃ for 1 to 120 minutes (preferably at -40℃ to -80℃ for 30 minutes) before placing the composite hard sheet containing the drug solution inside. The sheet is then freeze-dried at 0.01 mbar to 10 mbar pressure, preferably 0.01 mbar to 1 mbar, at -70℃ to 45℃ for 1 to 10 hours to obtain the sublingual tablet. Preferably, the cold trap temperature of the freeze dryer is -50℃ to -70℃. More preferably, the freeze-drying temperature is -20℃ to -45℃, maintained for 1 to 3 hours; then increased from -20℃ to -45℃ to -32℃ to -10℃; maintained at -32℃ to -10℃ for 2 to 5 hours; then increased from -32℃ to -10℃ to 0℃ to 40℃; maintained at 0℃ to 40℃ for 1 to 2 hours to obtain the sublingual tablet.

[0046] In the above method, the amount of purified water used in step 1) can be 70-90% of the total water volume, and the amount of purified water used in step 3) can be 10-30% of the total water volume.

[0047] Fifthly, the present invention provides the use of sublingual tablets as described in the first or third aspect above, or sublingual tablets prepared by the preparation methods described in the second or fourth aspect above, in the preparation of drugs for treating male erectile dysfunction.

[0048] Due to the adoption of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0049] 1. The sublingual tablets of this invention can be easily taken. They disintegrate when placed under the tongue in the absence of water. They disintegrate rapidly and release the drug quickly. At the same time, the drug enters the digestive tract with swallowing. They have the advantages of convenient administration, fast absorption, rapid onset of action, low irritation to the digestive tract mucosa, and high bioavailability, which greatly improves the clinical compliance of patients and has obvious advantages in clinical use.

[0050] 2. The sublingual tablets of this invention have a simple formulation process, require no special production conditions or equipment, have no special requirements for drug packaging, are low in cost, and are easy to industrialize.

[0051] 3. The present invention uses mannitol microcrystalline cross-polymerized calcium co-treatment material to produce sublingual tablets that not only have no gritty feel, but also have better compressibility and flowability of particles, faster disintegration, and lower brittleness. The use of the novel excipient mannitol microcrystalline cross-polymerized calcium co-treatment material results in sublingual tablets with a smooth and clean appearance, good taste, short disintegration time, high hardness, and low brittleness compared with the prior art. Attached Figure Description

[0052] Figure 1 shows the dissolution curves of the sublingual tablets of prescriptions 1, 2, 3, 4, 5, and 8 of this invention.

[0053] Figure 2 shows the dissolution curves of the sublingual tablets of Examples 5-11 of the present invention. Detailed Implementation

[0054] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Any product identical or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0055] Unless otherwise specified, the techniques or conditions described in the following embodiments are generally performed in accordance with conventional techniques or conditions described in the literature in this field, or in accordance with the product manual and the manufacturer's recommendations.

[0056] Unless otherwise specified, all starting materials and reagents are either commercially available or synthesized according to known methods.

[0057] The detection methods for evaluation indicators such as disintegration time, friability, texture, unflappable appearance, and powder flowability in the embodiments or specific examples of the present invention are as follows:

[0058] Disintegration time limit: The disintegration time limit test method 0921 of the 2020 edition of the Chinese Pharmacopoeia is adopted. A basket is suspended from a support via a stainless steel shaft at the top and immersed in a 1000ml beaker. The position of the basket is adjusted so that the lowest point is when the sieve is 25mm from the bottom of the beaker. The beaker contains water at 37℃±1℃. The water level is adjusted so that when the basket is raised to its highest point, the sieve is 15mm below the water surface. The top of the basket must not be submerged in the solution. All tablets should completely disintegrate and dissolve within 5 minutes. If one tablet fails to completely disintegrate or dissolve, six more tablets should be tested again, and all should meet the requirements.

[0059] Friability: The 2020 edition of the Chinese Pharmacopoeia, 0923, Tablet Friability Test Method, was adopted. Using a tablet friability tester, several tablets were taken, ensuring a total weight of approximately 6.5g. The powder detached from the tablets was blown away with a blower, and the tablets were accurately weighed. The tablets were placed in a cylinder and rotated 100 times. The tablets were then removed, and the powder was removed again using the same method. The tablets were accurately weighed. The weight loss should not exceed 1%, and no broken, cracked, or pulverized tablets should be detected. This test is generally performed only once. If the weight loss exceeds 1%, it should be repeated twice. The average weight loss from the three tests should not exceed 1%, and no broken, cracked, or pulverized tablets should be detected.

[0060] Taste: The bitterness, astringency, numbing sensation, and gritty sensation were evaluated by administering the medication orally to six healthy volunteers. Bitterness was categorized as: "+++" strong bitterness; "++" noticeable bitterness, tolerable; "+" slight bitterness; "-" no noticeable bitterness. Astringency was categorized as: "+++" strong astringency; "++" noticeable astringency, tolerable; "+" slight astringency; "-" no noticeable astringency. Numbness was categorized as: "+++" strong numbness; "++" noticeable numbness, tolerable; "+" slight numbness; "-" no noticeable numbness. Gridliness was categorized as: "+++" strong gridliness; "++" noticeable gridliness, tolerable; "+" slight gridliness; "-" no noticeable gridliness. Overall taste evaluation: (×) Unacceptable, (√) Acceptable, (√√) Good.

[0061] Unopened tablets: In accordance with the contents of the 2020 edition of the Chinese Pharmacopoeia, under the General Rules for Tablet Preparations 0101, the unopened tablets should have a complete and smooth appearance, uniform color, no sticking or cracking, and appropriate hardness and abrasion resistance to prevent wear and breakage during packaging and transportation.

[0062] Powder flowability: Commonly expressed by the angle of repose. The angle of repose is the maximum angle formed by the free inclined plane of the powder accumulation layer and the horizontal plane. The smaller the angle of repose, the smaller the friction and the better the flowability. It is generally believed that the flowability is better when the angle of repose is <30°, and can meet the flowability requirements in the production process when it is <40°. When it is >40°, it is generally considered that the flowability requirements in the production process are not met.

[0063] In vitro dissolution: The dissolution was determined according to Method 2 of Section IV of the 2020 Chinese Pharmacopoeia. The dissolution medium was pH 6.8 phosphate buffer, with a volume of 900 ml and a rotation speed of 50 rpm. Samples were taken at 1, 3, 5, 7 and 10 minutes to test the dissolution.

[0064] Unless otherwise specified in the following examples, all raw materials were commercially available or prepared using conventional methods in the art. The raw materials were purchased from, but are not limited to, the following companies: Shandong Tefaman Pharmaceutical Co., Ltd., Zhuhai Dongchen Pharmaceutical Co., Ltd., Rydenmer GmbH (Germany), BASF (China) Co., Ltd., Yancheng Jiekang Sucralose Manufacturing Co., Ltd., Anhui Shanhe Pharmaceutical Excipients Co., Ltd., SPI Pharma, Inc., Roquette (France), and the Shanghai Representative Office of the German company, M. Löwsberg Milk House.

[0065] The compound of formula (I) used as the main drug is prepared into a basic compound according to WO2010066111A1 and then reacted with hydrochloric acid to form a salt.

[0066] The preferred preparation method of the sublingual tablets of the present invention is as follows:

[0067] 1) Pass the active pharmaceutical ingredient and excipients through a 60-mesh sieve separately and set aside;

[0068] 2) Weigh the raw and auxiliary materials obtained in step 1) according to the prescription amount;

[0069] 3) Mix the weighed active ingredient, filler, and disintegrant from step 2) evenly to obtain a premixed powder. Add flavoring agent and lubricant and mix evenly to obtain a total powder.

[0070] 4) The total powder obtained in step 3) is compressed into tablets using a tablet press with a 6mm circular die and a hardness range of 30-50N.

[0071] Example 1: Filler Screening Test

[0072] Preparation method: The active pharmaceutical ingredient and excipients are passed through a 60-mesh sieve and weighed according to the prescription amount; the active pharmaceutical ingredient (the compound shown in Formula I), filler, and disintegrant are mixed evenly, and flavoring agent and lubricant are added and mixed evenly to obtain a total powder; the total powder is compressed into tablets to obtain the final product.

[0073] Table 1. Filler Screening Test Formulation Information and Evaluation

[0074] The results showed that the disintegration time was within 1 minute, the particle flowability (angle of repose) and compressibility of the prepared particles were good, and the surface of the compressed tablets was smooth and beautiful.

[0075] Example 2: Disintegrant Screening Test

[0076] Table 2. Formulation information and evaluation of disintegrant screening tests.

[0077] The results showed that the disintegration time was within 1 minute, and the resulting granules exhibited good flowability (angle of repose) and compressibility, with the compressed tablets having a smooth and aesthetically pleasing surface. Therefore, a disintegrant concentration of 5%–10% is sufficient to achieve the desired disintegration effect.

[0078] Example 3: Screening Test of Filler Composite Excipients

[0079] Table 3. Formulation information and evaluation of filler composite excipients in screening tests.

[0080] The results showed that when mannitol microcrystalline crosspolymer was used, the resulting sublingual tablets not only lacked a gritty texture, but also exhibited better compressibility and flowability, faster disintegration, and lower brittleness. Compared with existing technologies, the sublingual tablets produced using the novel excipient mannitol microcrystalline crosspolymer had a smooth and clean appearance, better taste, shorter disintegration time, higher hardness, and lower brittleness.

[0081] Example 4: Flavoring Agent Screening Test

[0082] Table 4. Prescription information for screening different flavoring agents

[0083] Table 5. Effects of different flavoring agent formulations on the taste of sublingual tablets.

[0084] The results showed that aspartame had a persistent sweet taste and lingered on the tongue, stevioside had a certain bitterness and numbing sensation, and sucralose had a good taste effect. There were no significant differences in disintegration time and crumbability among the three.

[0085] This invention relates to a sublingual tablet and its preparation method, characterized in that it comprises an active pharmaceutical ingredient (API) and excipients; the API is a compound represented by formula (I), and the excipients include a filler, a disintegrant, and a flavoring agent. The sublingual tablet is easy to take and disintegrates within seconds of being placed under the tongue.

[0086] The beneficial effects of the present invention have been confirmed by the following comparative experiments.

[0087] Comparative Example 1:

[0088] The results showed that the disintegration time of Comparative Formulas 1 to 3 all exceeded 1 minute, and a hard core remained after 2 minutes. Therefore, lactose is not suitable as a filler for this formula.

[0089] In vitro dissolution test

[0090] Six tablets each of formulations 1, 2, 3, 4, 5, and 8 from the examples were taken and dissolved according to the dissolution test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). 900 ml of pH 6.8 phosphate buffer was used as the solvent, and the rotation speed was 50 rpm. The dissolution was measured by high-performance liquid chromatography (HPLC) at 1, 3, 5, 7, and 10 minutes. The dissolution amount at different times was calculated, and the dissolution curves are shown in Figure 1. The results in Figure 1 show that the sublingual tablets of the present invention dissolve rapidly, with a dissolution rate of over 85% within 3 minutes.

[0091] Example 5

[0092] Prepare sublingual tablets according to the formulation in the table and the following preparation steps:

[0093] 1) Dissolve the prescribed amount of gelatin in 80% of the total amount of water in purified water, heat to 80°C while stirring to dissolve, and cool to room temperature to obtain a gelatin solution;

[0094] 2) Add the prescribed amount of the active ingredient and mannitol to the solution from step 1) and stir until dissolved;

[0095] 3) Add 20% purified water (the total amount of water used in the prescription) to the solution in step 2) and stir well;

[0096] 4) Dispense the drug solution at 0.4 ml / unit into a grooved polyamide / aluminum / polyvinyl chloride cold-stamped solid pharmaceutical composite hard sheet, and pre-freeze it in a freeze dryer at -40℃ for 30 min;

[0097] Solid pharmaceutical composite hard sheets containing drug solution were cold-pressed and molded into shape. They were placed in a freeze dryer at -20℃ and maintained for 30 min; then the temperature was lowered from -20℃ to -45℃ and maintained for 120 min; then the temperature was raised from -45℃ to -15℃ and maintained for 240 min; then the temperature was raised from -15℃ to 0℃ and maintained for 100 min; and then the temperature was raised from 0℃ to 40℃ and maintained for 60 min.

[0098] After drying, the samples are sealed in aluminum foil blister packs, with each groove containing one sublingual tablet.

[0099] Example 6:

[0100] This embodiment is basically the same as embodiment 5, except that the proportion of the main drug is changed to 32.3%, mannitol is changed to 48.4%, and gelatin is changed to 19.4%.

[0101] Example 7

[0102] This embodiment is basically the same as embodiment 5, except that the proportion of the main drug is changed to 22.7%, mannitol is changed to 68.2%, and gelatin is changed to 9.1%.

[0103] Example 8

[0104] This embodiment is basically the same as embodiment 5, except that the proportion of the main drug is changed to 15.6%, mannitol is changed to 78.1%, and gelatin is changed to 6.3%.

[0105] Example 9

[0106] This embodiment is basically the same as embodiment 5, except that the proportion of the main drug is changed to 21.7%, mannitol is changed to 65.2%, and gelatin is changed to 13.0%.

[0107] Example 10

[0108] This embodiment is basically the same as embodiment 5, except that the proportion of the main drug is changed to 23.8%, mannitol is changed to 71.4%, and gelatin is changed to 4.8%.

[0109] Example 11

[0110] This embodiment is basically the same as embodiment 5, except that the proportion of the main drug is changed to 20.8%, mannitol is changed to 62.5%, and gelatin is changed to 16.7%.

[0111] Comparative Examples 2 and 3:

[0112] The preparation process is the same as in Example 5. After freeze-drying, the slices of Comparative Examples 2 and 3 are not smooth and flat, cannot be completely removed from the mold, are easily broken when touched, and have poor formability.

[0113] Disintegration time limit test

[0114] Disintegration time limit: The disintegration time limit test method 0921 of the 2020 edition of the Chinese Pharmacopoeia is adopted. A basket is suspended from a support via a stainless steel shaft at the top and immersed in a 1000ml beaker. The position of the basket is adjusted so that the lowest point is when the sieve is 25mm from the bottom of the beaker. The beaker contains water at 37℃±1℃. The water level is adjusted so that when the basket is raised to its highest point, the sieve is 15mm below the water surface. The top of the basket must not be submerged in the solution. All tablets should completely disintegrate and dissolve within 5 minutes. If one tablet fails to completely disintegrate or dissolve, six more tablets should be tested again, and all should meet the requirements.

[0115] In vitro dissolution test

[0116] Six tablets from each of Examples 5 to 11 were taken and dissolved according to the dissolution test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), using 900 ml of pH 6.8 phosphate buffer as solvent and a rotation speed of 50 rpm. The dissolution was measured by high-performance liquid chromatography (HPLC) at 1, 3, 5, 7, and 10 minutes. The dissolution amount at different times was calculated, and the dissolution curves are shown in Figure 2. The results in Figure 2 show that the sublingual tablets of the present invention dissolve rapidly, with a dissolution rate of over 85% within 3 minutes.

[0117] The above embodiments are merely illustrative examples of key processes in this invention and do not exhaustively list all parameters. Specific embodiments of the process of this invention include, but are not limited to, the above embodiments. Obvious variations based on the above embodiments are still within the protection scope of this invention.

Claims

1. A sublingual tablet, characterized in that: It comprises an active pharmaceutical ingredient and excipients, wherein the active pharmaceutical ingredient is a compound of formula (I): The excipients include fillers, disintegrants, flavoring agents, and lubricants.

2. The sublingual tablet according to claim 1, wherein, The filler is selected from one or more of microcrystalline cellulose, mannitol, sorbitol, pregelatinized starch, maltitol, mannitol crosspolymer / copolymer / mannitol-calcium copolymer, and mannitol microcrystalline crosspolymer / calcium copolymer. Preferably, the filler is selected from one or more of microcrystalline cellulose, mannitol, and sorbitol. Or preferably, the filler is selected from one or two of microcrystalline cellulose and mannitol. Or preferably, the filler is mannitol microcrystalline crosspolymer / calcium copolymer.

3. The sublingual tablet according to claim 1, wherein, The disintegrant is selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch. Preferably, the disintegrant is crospovidone.

4. The sublingual tablet according to claim 1, wherein, The flavoring agent is selected from one or more of aspartame, cyclamate, sucralose, and stevioside, preferably sucralose.

5. The sublingual tablet according to claim 1, wherein, The lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, talc, and colloidal silica. Preferably, the lubricant is magnesium stearate.

6. The sublingual tablet according to any one of claims 1-5, wherein, By weight percentage, it includes the following components: The active ingredient comprises 1-30%, preferably 2-15%; The filler content is 46-90%, preferably 60-90%; Disintegrant 2-20%, preferably 5-10%; Flavoring agent: 0.1-3%, preferably 0.2-2%; Lubricant: 0.1-2%, preferably 0.2-1%.

7. A method for preparing a sublingual tablet as described in any one of claims 1-6, comprising the following steps: (1) Pretreatment of active pharmaceutical ingredient and excipients: Pass the active pharmaceutical ingredient and excipients through a 60-mesh sieve and set aside; (2) Weighing: Weigh the main drug and excipients according to the prescription; (3) Mixing: Mix the prescribed amount of main drug, filler and disintegrant evenly to obtain premixed powder, add flavoring agent and lubricant and mix evenly to obtain total powder; (4) Tableting: Tableting is performed using a tablet press.

8. A sublingual tablet, characterized in that: It comprises an active pharmaceutical ingredient and excipients, wherein the active pharmaceutical ingredient is a compound of formula (I): The excipients include water-soluble fillers and water-dispersible carriers. Preferably, the content of each component, by weight percentage, is: active pharmaceutical ingredient 15.6%–40.0%, water-soluble filler 38.5%–79%, and water-dispersible carrier 5%–25%; Preferably, the content of each component is as follows: active pharmaceutical ingredient 15.6%–38.5%, water-soluble filler 38.5%–75.0%, and water-dispersible carrier 4.5%–23.1%. Preferably, the water-soluble filler is one or more selected from hydrolyzed dextran, sorbitol, mannitol, alginate, and dextrin. Preferably, the water-dispersible carrier is a mixture of one or more selected from gelatin, polyvinyl alcohol, polyvinylpyrrolidone, and water-soluble cellulose derivatives; more preferably, the water-dispersible carrier is gelatin and / or polyvinylpyrrolidone.

9. A method for preparing a sublingual tablet as described in claim 8, comprising the following steps: 1) Dissolve the prescribed amount of water-dispersible carrier in purified water, and heat to 80℃~100℃ under stirring to obtain a water-dispersible carrier solution; 2) Add the prescribed amount of the active pharmaceutical ingredient and water-soluble filler to the solution from step 1) after cooling (e.g., to room temperature); 3) Add purified water to the solution from step 2) and stir until well mixed; 4) Dispense the liquid medicine into a grooved polyamide / aluminum / polyvinyl chloride cold-stamped solid pharmaceutical composite hard sheet, for example, 0.4 ml / sheet, and freeze-dry it in a freeze dryer; Preferably, the freeze dryer is pre-frozen at -40℃ to -180℃ for 1 to 120 minutes (preferably at -40℃ to -80℃ for 30 minutes) before placing the composite hard sheet containing the drug solution inside. The sheet is then freeze-dried at 0.01 mbar to 10 mbar pressure, preferably 0.01 mbar to 1 mbar, at -70℃ to 45℃ for 1 to 10 hours to obtain the sublingual tablet. Preferably, the cold trap temperature of the freeze dryer is -50℃ to -70℃. More preferably, the freeze-drying temperature is -20℃ to -45℃, maintained for 1 to 3 hours; then increased from -20℃ to -45℃ to -32℃ to -10℃; maintained at -32℃ to -10℃ for 2 to 5 hours; then increased from -32℃ to -10℃ to 0℃ to 40℃; maintained at 0℃ to 40℃ for 1 to 2 hours to obtain the sublingual tablet.

10. The use of a sublingual tablet as described in any one of claims 1-6, or a sublingual tablet prepared by the preparation method described in claim 7, or a sublingual tablet prepared by the preparation method described in claim 8, or a sublingual tablet prepared by the preparation method described in claim 9, in the preparation of a drug for treating male erectile dysfunction.

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