Solid oral formulations containing vardenafil citrate and methods of making and using the same

Abstract

The application discloses a preparation method of a solid oral preparation containing vardenafil citrate, which comprises the following steps: uniformly mixing vardenafil citrate, a diluent and a first part of a disintegrant; adding a binder to obtain soft material after mixing; screening the soft material to prepare wet granules; drying the wet granules to prepare dry granules; adding a second part of the disintegrant and a lubricant, and mixing again to obtain medicine granules, which are the solid oral preparation; the first part of the disintegrant accounts for 30%-70% of the total mass of the disintegrant, and the second part of the disintegrant accounts for 30%-70% of the total mass of the disintegrant. The solid oral preparation containing vardenafil citrate has the advantages that a preferred formula can achieve a dissolution rate of more than 75% within 2 minutes, a dissolution rate of more than 85% within 5 minutes, a dispersed tablet can be completely disintegrated and dispersed in water within 3 minutes, the requirement of rapid effect is met, the compatibility of the excipient and the main drug is good, and the preparation is stable in quality under the conditions of high temperature, high humidity and strong light.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a method for preparing a solid oral dosage form containing androdenafil citrate, the solid oral dosage form prepared by the method, and the application of the solid oral dosage form containing androdenafil citrate in the preparation of a treatment for conditions such as erectile dysfunction, pulmonary hypertension, benign prostatic hyperplasia, tumors, and neurodegenerative diseases such as Alzheimer's disease. Background Technology

[0002] Erectile dysfunction (ED) is the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse, and it is one of the most common sexual dysfunctions in men. Epidemiological surveys show that approximately 150 million men worldwide suffer from ED, and the incidence rate increases significantly with age. ED not only affects the quality of life of patients and their partners, but may also be closely related to chronic diseases such as cardiovascular disease, diabetes, and depression.

[0003] Treatment options for erectile dysfunction (ED) include psychotherapy, behavioral therapy, vacuum pressure devices, penile cavernous body injections, penile prosthesis implantation, and medication. Among these, oral medication is the first-line treatment due to its convenience, non-invasiveness, and high patient acceptance. Currently, the most commonly used oral ED medications in clinical practice are phosphodiesterase-5 (PDE5) inhibitors, including sildenafil (Viagra®), tadalafil (Cialis®), and vardenafil (Levitra®). Sildenafil, developed by Pfizer, was first marketed in the United States in 1998 and entered the Chinese market in 2000 under the brand name "Viagra". Sildenafil selectively inhibits PDE5, reducing cGMP degradation, relaxing the smooth muscle of the corpora cavernosa, increasing blood flow, and thus inducing erection.

[0004] Although sildenafil is effective, it still has some drawbacks: a relatively slow onset of action (peak concentration is reached approximately 30-60 minutes after oral administration), poor efficacy in some patients, and potential side effects such as transient visual disturbances, headaches, and facial flushing. Therefore, developing next-generation PDE5 inhibitors with faster onset of action, higher selectivity, and fewer side effects has been a hot topic in drug development.

[0005] Currently, androdenafil citrate raw material has poor flowability, making direct tableting difficult. Therefore, there is a need to develop a tablet formulation and preparation process suitable for industrial production. Existing technologies lack sufficient research on formulation screening and process optimization for androdenafil citrate tablets, particularly regarding the selection of excipients, optimization of dosage, and parameter control in the preparation process. Therefore, there is an urgent need to develop an androdenafil citrate tablet with a rational formulation, stable process, and controllable quality.

[0006] The above background information is provided only to aid in understanding the inventive concept and technical solution of this invention. It does not necessarily belong to the prior art of this invention. In the absence of clear evidence that the above information was disclosed before the filing date of this invention, the above background information should not be used to evaluate the novelty and inventiveness of this invention. Summary of the Invention

[0007] In view of this, in order to overcome the shortcomings of the prior art, the first aspect of the present invention is to provide a solid oral dosage form containing androdenafil citrate.

[0008] To achieve the above objectives, the present invention adopts the following technical solution: A solid oral dosage form containing androdenafil citrate, comprising androdenafil citrate, a diluent, and a disintegrant, wherein the diluent is a mixture of microcrystalline cellulose and lactose, and the disintegrant comprises an internal disintegrant and an external disintegrant. In the preparation of the solid oral dosage form, the disintegrant is added in two parts: the internal disintegrant is added during the raw material mixing stage before the preparation of the soft mass; the external disintegrant is added during the final mixing stage after granulation.

[0009] According to some preferred embodiments of the present invention, the mass ratio of microcrystalline cellulose to lactose in the diluent is 1:2 to 3:1, and can be 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, or 3:1. Preferably, the mass ratio of microcrystalline cellulose to lactose in the diluent is 1:1 to 3:1. More preferably, the mass ratio of microcrystalline cellulose to lactose in the diluent is 1.5:1 to 2.5:1.

[0010] According to some preferred embodiments of the present invention, the mass ratio of the internally added disintegrant to the externally added disintegrant is 1:2 to 2:1, and may be 1:2, 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1, or 2:1. Preferably, the mass ratio of the internally added disintegrant to the externally added disintegrant is 0.5:1 to 1.2:1. More preferably, the mass ratio of the internally added disintegrant to the externally added disintegrant is 0.8:1 to 1.2:1.

[0011] According to some preferred embodiments of the invention, the solid oral dosage form comprises, by weight percentage: 10%–25% androdenafil citrate; 60%–80% diluent; 3%–7% disintegrant; 2%–6% binder; and 0.5%–2% lubricant. Preferably, the dosage form comprises 15%–20% androdenafil citrate; 70%–75% diluent; 5%–7% disintegrant; 3%–5% binder; and 1%–1.5% lubricant. More preferably, the dosage form comprises 16%–17% androdenafil citrate; 71%–73% diluent; 6%–7% disintegrant; 3.5%–4.5% binder; and 1%–1.2% lubricant.

[0012] According to some preferred embodiments of the present invention, the diluent is selected from one or more of starch, lactose, and microcrystalline cellulose; the disintegrant is selected from one or more of sodium carboxymethyl starch and crospovidone; the binder is selected from one or more of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, povidone, gelatin, and ethyl cellulose; and the lubricant is selected from one or more of magnesium stearate, talc, and microcrystalline silica.

[0013] According to some preferred embodiments of the invention, the disintegrant is crospovidone and / or sodium carboxymethyl starch; the binder is povidone and / or hydroxypropyl methylcellulose; and the lubricant is magnesium stearate.

[0014] Preferably, the diluent contains microcrystalline cellulose PH101, lactose G200, and crospovidone XL and / or sodium carboxymethyl starch; the binder is povidone K30 and / or povidone S630 and / or hydroxypropyl methylcellulose E15. More preferably, the diluent contains microcrystalline cellulose PH101, lactose G200, crospovidone XL, and povidone K30.

[0015] According to some preferred embodiments of the present invention, the solid oral dosage form is a tablet, dispersible tablet, capsule or granule.

[0016] According to some preferred embodiments of the invention, when the solid oral dosage form is a tablet or a dispersible tablet, the solid oral dosage form includes a coating layer on the outer surface of the tablet or dispersible tablet. Preferably, the coating layer material is Opadry 200F220031 and / or Opadry 85G62549, with a coating weight gain of 2-4%.

[0017] A second aspect of the present invention is to provide a method for preparing the above-mentioned solid oral dosage form, comprising the following steps: Mix and homogenize the androdenafil citrate, diluent, and first-part disintegrant (with added disintegrant); Add adhesive and mix to obtain a soft material; The soft material is sieved to prepare wet granules; The wet granules are dried to prepare dry granules; A second disintegrant (external disintegrant) and a lubricant are added, and the mixture is stirred again to obtain drug particles, which are the solid oral dosage form.

[0018] According to some preferred embodiments of the present invention, the first partial disintegrant accounts for 30% to 70% of the total mass of the disintegrant, and the second partial disintegrant accounts for 30% to 70% of the total mass of the disintegrant. The mass ratio between the first partial disintegrant and the second partial disintegrant is 1:2 to 2:1.

[0019] According to some preferred embodiments of the present invention, the solid oral dosage form is a granule; or the drug granules are compressed into tablets or dispersible tablets, or the drug granules are filled into empty capsules to form a capsule.

[0020] According to some preferred embodiments of the present invention, when the solid oral dosage form is a tablet or a dispersible tablet, the step further includes coating the tablet or dispersible tablet to obtain a coating layer.

[0021] A third aspect of the present invention is to provide the use of the solid oral dosage form as described above in the preparation of a medicament for treating at least one of male erectile dysfunction, pulmonary hypertension, benign prostatic hyperplasia, prevention / treatment of tumors, and neurodegenerative diseases such as Alzheimer's disease.

[0022] Due to the adoption of the above technical solutions, compared with the prior art, the advantages of the present invention are as follows: the solid oral dosage form containing androdenafil citrate of the present invention, with a preferred formulation, can achieve a dissolution rate of more than 75% within 2 minutes and more than 85% within 5 minutes. The dispersible tablets can completely disintegrate and disperse in water within 3 minutes, meeting the requirements for rapid onset of action. The excipients and the active pharmaceutical ingredient have good compatibility, and the formulation is stable in quality under high temperature, high humidity, and strong light conditions. Attached Figure Description

[0023] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0024] Figure 1 A comparison of dissolution curves of androdenafil citrate tablets with different mass ratios of microcrystalline cellulose to lactose; Figure 2A comparison of dissolution curves of androdenafil citrate tablets with different amounts of cross-linked povidone. Figure 3 This is a comparison of the dissolution curves of androdenafil citrate tablets with different internal and external ratios of cross-linked povidone. Detailed Implementation

[0025] To enable those skilled in the art to better understand the technical solutions of the present invention, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0026] The main test materials and manufacturer information used in the following examples are as follows: Androdenafil citrate: synthesized according to a known method (CN101891747A, Compounds that inhibit type 5 phosphodiesterase and their preparation method); Microcrystalline cellulose PH101: Asahi Kasei Corporation, Japan; Lactose G200: Metformin (Germany); Cross-linked polyvinylpyrrolidone XL: ISP Corporation, USA; Povidone K30: BASF, Germany; Magnesium stearate: Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Obadai 200F220031 (Moisture-proof, stomach-soluble film-coating powder): Shanghai Carrefour Coating Technology Co., Ltd.; Obadai 85G62549 (Ordinary gastrointestinal-soluble film-coated powder): Shanghai Carrefour Coating Technology Co., Ltd.

[0027] The testing methods used are as follows: 1) Dissolution test method: Instrument: ZRS-8 Intelligent Dissolution Tester; Tianjin Tianda Tianfa Company 752 Single Beam UV Spectrophotometer: Shanghai Jinghua Technology Co., Ltd. Dissolution conditions: basket method, dissolution medium is 900 mL of hydrochloric acid solution (simulated gastric juice) with pH 1.2, rotation speed 100 rpm. Sampling time points: 1, 2, 3, 5, 10, 15 min Assay method: At the sampling time point, take 2 ml of the filtrate and place it in a 5 ml centrifuge tube, dilute it 1.5 times, and use it as the test solution. Simultaneously, take 5 mg of androdenafil citrate reference standard, place it in a 100 ml volumetric flask, add pH 1.2 HCl to dissolve and dilute to volume, obtaining a 50 μg / ml androdenafil citrate solution. Dilute this solution to 10 μg / ml, 15 μg / ml, 20 μg / ml, 30 μg / ml, and 40 μg / ml and detect at 295 nm to prepare a standard curve. Then, take the test solution and measure the absorbance at 295 nm using ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2010 Edition, Part II, Appendix IVA). Substitute the absorbance values ​​into the working curve to calculate the dissolution rate and plot the cumulative dissolution curve.

[0028] 2) Test methods for related substances and their content in pharmaceuticals: High performance liquid chromatography (HPLC) with a C18 column, gradient elution, and a detection wavelength of 220 nm is used. Related substances generally refer to organic impurities that are generated during the production or storage of pharmaceuticals and have a structure similar to the main component of the drug, including starting materials, intermediates, by-products, degradation products, and residual solvents.

[0029] 3) Disintegration test method: The disintegration time of androdenafil citrate tablets was tested using the SOTAX DT2 disintegrator (SOTAX, Switzerland) according to Appendix XA of the 2010 edition of the Chinese Pharmacopoeia, Part II, with water as the medium and a temperature of 37°C.

[0030] 4) Dispersion uniformity test method: Performed according to the requirements of Appendix IA Dispersible Tablets in Part II of the 2010 edition of the Chinese Pharmacopoeia.

[0031] 5) Particle flowability test method: The fixed conical bottom method is used. The base is a 7cm diameter petri dish. Two glass funnels are stacked alternately and fixed on an iron stand, with the outlet of the lower funnel 5cm from the base. Several samples are taken and slowly added from the upper funnel, allowing the sample to accumulate on the base through the buffer of the two funnels, forming a cone, until the highest cone is obtained. The height H of the cone is measured. Each sample is measured three times, and the average value is taken. The angle of repose is calculated using the following formula: α = arctg(H / R), where α is the angle of repose and R is the radius of the base.

[0032] 6) Tablet hardness test method: The tablet hardness was measured using a YPD-200C tablet hardness tester (Shanghai Huanghai Pharmaceutical Testing Instruments Co., Ltd.).

[0033] The inventors in this case previously prepared a novel PDE5 inhibitor, Xiongdinafil citrate. Pharmacological studies have shown that this compound exhibits stronger PDE5 inhibitory activity than sildenafil, with better selectivity and faster onset of action. However, the active pharmaceutical ingredient of this compound has poor flowability, making direct tableting difficult, and it is sensitive to light and humidity. Therefore, developing an oral solid dosage form that can rapidly disintegrate, rapidly dissolve, and has good stability, suitable for large-scale production, is crucial to realizing the clinical advantages of this compound. Based on this, this invention provides an oral solid dosage form of Xiongdinafil citrate with rapid disintegration, rapid dissolution, good stability, and suitability for industrial production, and also provides a method for preparing this dosage form and its application in the preparation of drugs for treating erectile dysfunction, pulmonary hypertension, benign prostatic hyperplasia, etc. Details are as follows: First aspect: Solid oral dosage forms The solid oral dosage form containing androdenafil citrate of the present invention comprises, by weight percentage: androdenafil citrate 10%~25%; diluent 60%~80%; disintegrant 3%~7%; binder 2%~6%; lubricant 0.5%~2%. Preferably, it comprises androdenafil citrate 15%~20%; diluent 70%~75%; disintegrant 5%~7%; binder 3%~5%; lubricant 1%~1.5%. More preferably, it comprises androdenafil citrate 16%~17%; diluent 71%~73%; disintegrant 6%~7%; binder 3.5%~4.5%; lubricant 1%~1.2%.

[0034] The diluent is selected from one or more of starch, lactose, and microcrystalline cellulose; the disintegrant is selected from one or more of sodium carboxymethyl starch and crospovidone; the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, gelatin, and ethyl cellulose; and the lubricant is selected from one or more of magnesium stearate, talc, and micronized silica gel. Preferably, the disintegrant is crospovidone and / or sodium carboxymethyl starch; the binder is povidone and / or hydroxypropyl methylcellulose; and the lubricant is magnesium stearate. More preferably, the microcrystalline cellulose in the diluent is microcrystalline cellulose PH101, the lactose in the diluent is lactose G200, the disintegrant is crospovidone XL and / or sodium carboxymethyl starch; and the binder is povidone K30 and / or povidone S630 and / or hydroxypropyl methylcellulose E15. Most preferably, the disintegrant is crospovidone XL; and the binder is povidone K30.

[0035] Preferably, the diluent is a mixture of microcrystalline cellulose and lactose, wherein the mass ratio of microcrystalline cellulose to lactose is 1:2 to 3:1, and can be 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, or 3:1. More preferably, the mass ratio of microcrystalline cellulose to lactose in the diluent is 1:1 to 3:1. More preferably, the mass ratio of microcrystalline cellulose to lactose in the diluent is 1.5:1 to 2.5:1, and most preferably 2:1.

[0036] Preferably, in the preparation of solid oral dosage forms, the disintegrant is added in two parts: an internal disintegrant, which is added during the raw material mixing stage before the preparation of the soft mass; and an external disintegrant, which is added during the final mixing stage after granulation. The mass ratio of the internal to external disintegrant is 1:2 to 2:1, and can be 1:2, 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1, or 2:1. Preferably, the mass ratio of the internal to external disintegrant is 0.5:1 to 1.2:1. More preferably, the mass ratio of the internal to external disintegrant is 0.8:1 to 1.2:1, and most preferably, it is 1:1.

[0037] Solid oral dosage forms are tablets, dispersible tablets, capsules, or granules. The preferred formulation of this solid oral dosage form has the following dissolution rate in simulated gastric juice (0.1 mol / L hydrochloric acid): not less than 70% after 2 minutes and not less than 85% after 5 minutes (basket method, 100 rpm, 900 mL). When the solid oral dosage form is a tablet or dispersible tablet, it includes a gastrointestinal film coating layer (formed from gastrointestinal film coating powders such as Opadry 200F220031 and / or Opadry 85G62549) on the outer surface of the tablet or dispersible tablet, with a coating weight gain of 2% to 5%. The dispersible tablet completely disintegrates in water within 3 minutes and passes through a No. 2 sieve specified in the Chinese Pharmacopoeia, with dispersion uniformity meeting the pharmacopoeia requirements.

[0038] The second aspect: the preparation method of solid oral dosage forms, including the following steps: (1) Mix the androdenafil citrate, diluent, and internal disintegrant evenly, with a stirring speed of 150-250 rpm, a shearing speed of 400-500 rpm, and a mixing time of 10-20 minutes; (2) Add the adhesive solution (an aqueous solution of polyvinyl ketone K30), mix and obtain a soft material; then sieve the soft material (e.g., 20 mesh) to prepare wet granules; the stirring speed is 200~400 rpm and the shearing speed is 600~1000 rpm; (3) Dry the wet granules to a moisture content of ≤3% to prepare dry granules; the drying temperature is 50~70℃; (4) Add external disintegrant and lubricant, mix thoroughly, stirring at 160-200 rpm and shearing at 400-500 rpm for 10-20 minutes; obtain drug granules, which are solid oral preparations. At this time, the solid oral preparation is granules.

[0039] If tablets or dispersible tablets are required, the mixed drug particles are compressed into tablets or dispersible tablets. If capsules are required, the mixed drug particles are filled into empty capsules to form capsules. If the solid oral dosage form is a tablet or dispersible tablet, the preparation steps also include coating the tablet or dispersible tablet with a gastric-soluble film coating powder to obtain a film coating layer, with a coating weight gain of 2% to 5%. The hardness of the obtained tablet or dispersible tablet is 60 to 90 N. Strong light can cause a slight increase in related substances in androdenafil citrate tablets, while high humidity may cause the povidone K30 in the unprocessed tablets to absorb moisture, leading to tablet swelling. Therefore, the unprocessed tablets should be coated to improve their stability. Furthermore, solid oral dosage forms containing androdenafil citrate need to disintegrate rapidly after oral administration for rapid onset of action. Therefore, the coating material should mainly be a gastric-soluble material that can dissolve rapidly in the stomach, preferably Opadry 200F220031 (moisture-proof gastric-soluble type).

[0040] The coating process parameters are: inlet air temperature 75~85℃, tablet bed temperature 37~40℃, atomization pressure 2.0~3.0 bar, coating pan speed 8~12 rpm, and material flow rate 2.0~3.0 g / min.

[0041] Third aspect: The application of solid oral dosage forms in drug preparation The solid oral dosage form prepared above is used in the preparation of a drug for treating at least one of the following diseases: (1) Male erectile dysfunction; (2) Pulmonary hypertension; (3) Benign prostatic hyperplasia (with lower urinary tract symptoms); (4) Combined with chemotherapy drugs, targeted drugs, and PD-1 monoclonal antibodies for the prevention / treatment of tumors; (5) Neurodegenerative diseases such as Alzheimer's disease.

[0042] Example 1: Preparation of androdenafil citrate tablets In this embodiment, the androdenafil citrate tablets comprise the following raw materials (based on 1000 tablets, each tablet weighing 0.25g): Table 1 Formulation Table for Example 1 The denominator for the percentage calculations of each component in the table above is the total mass of the tablet core (androgenetic acid citrate, microcrystalline cellulose PH101, lactose G200, crospovidone XL (internal), crospovidone XL (external), povidone K30, magnesium stearate). This product is a tablet and does not include a special solvent; the packaging material used is aluminum foil and polyvinylidene chloride solid pharmaceutical composite hard sheet (PVDC).

[0043] The preparation method of androdenafil citrate tablets in this embodiment includes the following steps: Step 1: Pass the denafil citrate, microcrystalline cellulose, lactose, and internally added cross-linked polyvinylpyrrolidone (internal disintegrant) through an 80-mesh sieve, and then mix them evenly by hand in a mortar using the equal-volume doubling method.

[0044] In other embodiments, an HLSH2-6A wet mixing granulator can be used, with a stirring speed of 200 rpm, a shearing speed of 450 rpm, and a mixing time of 10 min.

[0045] Step 2: Add 10% (w / w) of polyvinyl chloride K30 aqueous solution as a binder and stir to form a soft material.

[0046] Step 3: Pass through a 20-mesh sieve to prepare wet granules.

[0047] Step 4: Spread the wet granules evenly in a stainless steel tray and dry them in a 60℃ forced-air drying oven for 2 hours. The moisture content is measured to be ≤2.5%, and the dry granules are obtained.

[0048] Step 5: Pass the dry granules through a 20-mesh sieve for granulation.

[0049] Step 6: Add crospovidone (external disintegrant) and magnesium stearate, mix thoroughly, and obtain drug particles.

[0050] Step 7: Use a TDP-751 single-punch tablet press (Shanghai Zhimin Packaging Equipment Co., Ltd. Pharmaceutical Machinery Branch) to compress tablets. Adjust the pressure to make the tablet hardness 70~80N, the tablet weight 250mg, and control the tablet weight difference within ±5%.

[0051] In some other embodiments, the TDP-751 single-punch tablet press can be replaced with a ZPS-8 rotary tablet press for tableting.

[0052] Step 8: Prepare a 20% (w / w) aqueous dispersion of Opadry 200F220031, and coat it in a sugar coating pan to obtain androdenafil citrate tablets.

[0053] During coating, the inlet air temperature is 80℃, the tablet bed temperature is 37~40℃, the atomization pressure is 2.5 bar, the pot speed is 8~12 rpm, the material flow rate is 2.5 g / min, and the coating weight gain is 3%.

[0054] The detection results of the tablets in this embodiment are as follows: The drug particles have a repose angle of 34.1° and good flowability.

[0055] The tablets have a smooth, pale yellow appearance. After coating, they turn light blue, have a hardness of 72 N, and a disintegration time of <1 minute.

[0056] Dissolution test results: 75.2% dissolution rate at 2 minutes, 88.6% dissolution rate at 5 minutes, and 96.1% dissolution rate at 10 minutes.

[0057] Related substances in pharmaceuticals: 0.091% at 0 days, 0.109% at 60°C for 10 days, 0.095% under strong light (4500Lx) for 10 days, and 0.098% at 75% RH for 10 days.

[0058] Drug content: 99.9% in 0 days, and all indicators meet the quality standards.

[0059] Example 2: Preparation of Androdenafil Citrate Dispersible Tablets The formulation of androdenafil citrate dispersible tablets in this embodiment is the same as in Example 1, and will not be repeated here.

[0060] The preparation method of androdenafil citrate dispersible tablets in this embodiment includes the following steps: Steps 1 to 6 are the same as in Example 1, and will not be repeated here. Step 7: Compress the mixed drug particles directly into dispersible tablets, controlling the hardness at 65~75N; Step 8 is the same as in Example 1, and will not be repeated here.

[0061] The detection results of the dispersible tablets in this embodiment are as follows: Disintegration time of dispersible tablets: 2 minutes and 15 seconds, which meets the pharmacopoeia requirements; Dispersion uniformity: All particles pass through sieve No. 2, resulting in rapid and uniform dispersion; Dissolution rate: 74.8% at 2 minutes and 87.9% at 5 minutes; It has a smooth appearance, with no cracks or sticking, and is suitable for dispersing in water before consumption.

[0062] Example 3: Preparation of Capsules The formulation of androdenafil citrate capsules in this embodiment is the same as in Example 1 (excluding coating), and will not be repeated here.

[0063] The preparation method of androdenafil citrate capsules in this embodiment includes the following steps: Steps 1 to 6 are the same as in Example 1, and will not be repeated here. Step 7: Take the drug particles after total mixing in Example 1, and measure the angle of repose of the particles. The result is 34.2° and the bulk density is 0.31 g / mL.

[0064] Using a fully automated capsule filling machine, the granules are filled into #0 gastric-soluble gelatin empty capsules, with each capsule containing 250mg.

[0065] Disintegration time determined according to the Chinese Pharmacopoeia method: all 6 capsules completely disintegrated within 3 minutes, and the particles dispersed. In vitro dissolution test results: dissolution rate was 72.8% at 2 minutes and 86.5% at 5 minutes.

[0066] Example 4: Preparation of Granules The formulation of androdenafil citrate granules in this embodiment is the same as in Example 1 (excluding coating), and will not be repeated here.

[0067] The preparation method of androdenafil citrate granules in this embodiment includes the following steps: Steps 1 to 6 are the same as in Example 1, and will not be repeated here. Step 7: Take the drug granules from the total mixture of Example 1 and directly use a granule filling machine to fill the drug granules into aluminum-plastic composite film bags, with each bag containing 250mg.

[0068] Pour the granules into a cup, add about 50 ml of water, and stir gently until they quickly disperse into a uniform suspension. The granules were measured to have a dispersion time of less than 30 seconds in water. The dissolution rate was 74.1% at 2 minutes and 88.2% at 5 minutes, comparable to the dissolution rates of the tablets and dispersible tablets in the previous examples.

[0069] Example 5 The difference between this embodiment and Example 1 is that the total amount of the disintegrant crospovidone XL added to the androdenafil citrate tablets in this embodiment is 3%. The remaining components, contents, and preparation methods are basically the same as in Example 1.

[0070] Example 6 The difference between this embodiment and Example 1 is that the total amount of the disintegrant crospovidone XL added to the androdenafil citrate tablets in this embodiment is 5%. The remaining components, contents, and preparation methods are basically the same as in Example 1.

[0071] Example 7 The difference between this embodiment and Example 1 is that the androdenafil citrate tablets in this embodiment use 10% povidone S630 instead of 10% povidone K30. The remaining ingredients, contents, and preparation methods are basically the same as in Example 1.

[0072] Example 8 The difference between this embodiment and Example 1 is that in this embodiment, the androdenafil citrate tablets use 3% hydroxypropyl methylcellulose E15 instead of 10% povidone K30 and sodium carboxymethyl starch instead of crospovidone XL. The remaining components, contents, and preparation methods are basically the same as in Example 1.

[0073] Example 9 The difference between this embodiment and Example 1 is that in the androdenafil citrate tablets of this embodiment, the diluent is microcrystalline cellulose: lactose in a mass ratio of 1:2. The remaining components, contents, and preparation method are basically the same as in Example 1.

[0074] Example 10 The difference between this embodiment and Example 1 is that in the androdenafil citrate tablets of this embodiment, the diluent is microcrystalline cellulose: lactose in a mass ratio of 1:1. The remaining components, contents, and preparation method are basically the same as in Example 1.

[0075] Example 11 The difference between this embodiment and Example 1 is that in the androdenafil citrate tablets of this embodiment, the mass ratio of internal disintegrant to external disintegrant is 1:2. The remaining components, contents, and preparation method are basically the same as in Example 1.

[0076] Example 12 The difference between this embodiment and Example 1 is that in the androdenafil citrate tablets of this embodiment, the mass ratio of internal disintegrant to external disintegrant is 2:1. The remaining components, contents, and preparation method are basically the same as in Example 1.

[0077] Example 13 The difference between this embodiment and Example 1 is that the coating material used in the androdenafil citrate tablets of this embodiment is Opadry 85G62549 (a common gastric-soluble type). The remaining components, contents, and preparation method are basically the same as in Example 1.

[0078] Example 14 The difference between this embodiment and Example 1 is that in the androdenafil citrate tablets of this embodiment, the mass ratio of microcrystalline cellulose to lactose in the diluent is microcrystalline cellulose: lactose = 1.5:1. The remaining components, contents, and preparation method are basically the same as in Example 1. The androdenafil citrate tablets of this embodiment exhibit better dissolution within 2 minutes than those of Examples 9 and 10.

[0079] Example 15 The difference between this embodiment and Example 1 is that in the androdenafil citrate tablets of this embodiment, the mass ratio of microcrystalline cellulose to lactose in the diluent is microcrystalline cellulose: lactose = 2.5:1. The remaining components, contents, and preparation method are basically the same as in Example 1. The androdenafil citrate tablets of this embodiment exhibit better dissolution within 2 minutes than those of Examples 9 and 10.

[0080] Example 16 The difference between this embodiment and Example 1 is that the mass ratio of internally added disintegrant to externally added disintegrant in the androdenafil citrate tablets of this embodiment is 0.8:1. The remaining components, contents, and preparation method are basically the same as in Example 1. The androdenafil citrate tablets of this embodiment exhibit better dissolution within 2 minutes than those of Examples 11 and 12.

[0081] Example 17 The difference between this embodiment and Example 1 is that the mass ratio of internally added disintegrant to externally added disintegrant in the androdenafil citrate tablets of this embodiment is 1.2:1. The remaining components, contents, and preparation method are basically the same as in Example 1. The androdenafil citrate tablets of this embodiment exhibit better dissolution within 2 minutes than those of Examples 11 and 12.

[0082] Example 18 In this embodiment, the solid oral dosage form comprises the following components by weight percentage: 10% androdenafil citrate; 60% diluent; 3% disintegrant; 2% binder; and 0.6% lubricant. The specific substances of each component are as described in Example 1.

[0083] Example 19 In this embodiment, the solid oral dosage form comprises the following components by weight percentage: androdenafil citrate 25%; diluent 80%; disintegrant 7%; binder 6%; and lubricant 2%. The specific substances of each component are as described in Example 1.

[0084] Comparative Example 1 The difference between this comparative example and Example 1 is that the androdenafil citrate tablets in this comparative example use lactose T80 instead of lactose G200 and sodium carboxymethyl starch instead of crospovidone XL. The remaining components, contents, and preparation methods are basically the same as in Example 1.

[0085] Comparative Example 2 The difference between this comparative example and Example 1 is that the total amount of the disintegrant crospovidone XL added to the androdenafil citrate tablets in this comparative example is 1%. The remaining components, contents, and preparation methods are basically the same as in Example 1.

[0086] Comparative Example 3 The difference between this comparative example and Example 1 is that in the androdenafil citrate tablets of this comparative example, all disintegrants are internally added, and no external disintegrants are added. The remaining components, contents, and preparation methods are basically the same as in Example 1.

[0087] Comparative Example 4 The difference between this comparative example and Example 1 is that in the androdenafil citrate tablets of this comparative example, all disintegrants are added externally, and no internal disintegrants are added. The remaining components, contents, and preparation methods are basically the same as in Example 1.

[0088] Comparative Example 5 The difference between this comparative example and Example 1 is that the binder in the androdenafil citrate tablets of this comparative example is a 50% ethanol solution containing 10% PVP K30. The remaining components, contents, and preparation methods are basically the same as in Example 1.

[0089] Comparative Example 6 The difference between this comparative example and Example 1 is that in the androdenafil citrate tablets of this comparative example, the binder is formed by a 70% ethanol solution containing 10% PVP K30. The remaining components, contents, and preparation methods are basically the same as in Example 1.

[0090] Comparative Example 7 The difference between this comparative example and Example 1 is that the binder in the androdenafil citrate tablets of this comparative example is pure water. The remaining components, contents, and preparation methods are basically the same as in Example 1.

[0091] Comparative Example 8 The difference between this comparative example and Example 1 is that the androdenafil citrate tablets in this comparative example are plain tablets, without coating, coating material, or a corresponding coating layer. The remaining components, contents, and preparation methods are basically the same as in Example 1.

[0092] Comparative Example 9 The difference between this comparative example and Example 1 is that the diluent in the androdenafil citrate tablets of this comparative example is replaced with anhydrous calcium hydrogen phosphate. The remaining components, contents, and preparation methods are basically the same as in Example 1.

[0093] The compatibility test of raw materials and excipients showed that anhydrous dicalcium phosphate has an adsorption effect on androdenafil citrate. The drug content determination could only extract 46%, which could not meet the requirements of the formulation and therefore could not be used as a diluent.

[0094] Tests and Results 1) Material screening Corresponding to Examples 1, 7, 8 and Comparative Example 1, the substances were screened using prescriptions 1, 2, 3 and 4 in Table 2.

[0095] Table 2 Preliminary screening of androdenafil citrate tablet formulations Table 3 Test Results According to the test results in Table 3 above: the granules prepared by Formula 1 have good integrity and appearance, while the granules prepared by Formula 2 have poor granulation properties. This indicates that the granulation effect is not good when using lactose T80 as a filler. This may be because T80 is pre-granulated lactose with a larger particle structure, which is more suitable for direct compression of powder and not suitable for wet granulation. G200, on the other hand, is a finer-mesh lactose, which is more conducive to wet granulation after uniform mixing. From the test results of Formula 1 and Formula 4, it can be seen that when lactose G200 and microcrystalline cellulose PH101 are used together as fillers, the granules have better formability, compressibility, and tablet appearance hardness. Compared with Formula 1, the granules prepared by Formula 3 are loose and have poor flowability. The only difference between the two formulas is that the binder is changed from povidone K30 to povidone S630. Povidone S630 was chosen for investigation because its hygroscopicity is weaker than that of povidone K30, which can reduce the moisture absorption of the granules. However, experimental results showed that while granulation with a 10% povidone S630 aqueous solution could form drug particles, the particles were loose, contained a lot of fine powder, had a 45° angle of repose, poor compressibility, and the appearance of the tablets / dispersible tablets was generally poor, with poor adhesion, failing to meet the requirements for particle quality. Formulation 4 used HPMC (hydroxypropyl methylcellulose) E15 as the binder, which had a similar granulation effect to K30 as a binder, producing better particle quality. However, HPMC E15 has poor water solubility, often requiring overnight stirring to dissolve, and the tablets disintegrated slowly. Tablets prepared with crospovidone XL as the disintegrant disintegrated faster than those prepared with sodium carboxymethyl starch; moreover, the particles prepared with sodium carboxymethyl starch were finer, making them difficult to mix evenly when added externally. Therefore, crospovidone XL was chosen as the disintegrant. Increasing magnesium stearate can reduce friction and lower the angle of repose, but it will have a certain impact on the disintegration rate of the tablets, so the dosage should not be too high.

[0096] Therefore, the preferred excipients for androdenafil citrate tablets are: lactose and microcrystalline cellulose used together as diluents, povidone K30 as a binder, crospovidone XL as a disintegrant, and magnesium stearate as a lubricant.

[0097] 2) Different diluent ratios Corresponding to Examples 1, 9, and 10, 1.26g of androdenafil citrate, 0.37g of PVPP-XL, and 5.6g of the excipients under investigation (microcrystalline cellulose PH101 and lactose G200) were granulated using a 10% PVP K30 aqueous solution as a binder. After drying at 60℃, the granules were sized and compressed into tablets (30 tablets in total), with the hardness controlled at 70N. The ratio of diluent mainly affects the quality of granules, the appearance of tablets, and dissolution. Therefore, the granule properties, tablet appearance, and dissolution rate of the active ingredient in simulated gastric fluid (0.1N HCl) (dissolution conditions: basket method, 900mL pH1.2 HCl, 100rpm, 37℃) were selected as the main evaluation indicators. Only the mass ratio of microcrystalline cellulose PH101 to lactose G200 was changed to screen different diluent ratios. The results are shown in Table 4. Figure 1 As shown, when the mass ratio of microcrystalline cellulose to lactose is 2:1, the dissolution rate reaches 70% in 2 minutes, which is significantly higher than that of 1:1 and 1:2, and superior to the dissolution rate of commercially available Viagra. Since the granule properties and tablet appearance are not significantly different, a mass ratio of microcrystalline cellulose to lactose of 2:1 is preferred.

[0098] Table 4 Dissolution rate at 2 minutes with different diluent ratios 3) Effect of disintegrant dosage Corresponding to Examples 1, 5, 6, and Comparative Example 2, 1.26g of androdenafil citrate, 5.6g of microcrystalline cellulose and lactose (2:1) were used, the difference being the total amount of crospovidone: the addition amount of crospovidone XL was set to 1%, 3%, 5%, and 7% (by tablet weight), respectively. After being mixed evenly, granulation was performed using 10% PVP K30 aqueous solution as a binder, followed by drying and compression into tablets (30 tablets per tablet), with the hardness controlled at 70N. The amount of disintegrant mainly affects the disintegration of the tablets and the dissolution of the active ingredient; therefore, the dissolution of androdenafil citrate was the main evaluation indicator.

[0099] The results are as follows Figure 2 As shown, the dissolution rate of androdenafil citrate from tablets increases with increasing disintegrant dosage, with a dissolution curve at 7% dosage, which is significantly better than that at 1% and 3%. The preferred disintegrant dosage is 7% crospovidone.

[0100] 4) The effect of the ratio of internal to external disintegrants Corresponding to Examples 1, 11, 12, Comparative Example 3, and Comparative Example 4, 1.26g of androdenafil citrate, 5.6g of microcrystalline cellulose and lactose (2:1), and a total addition of 0.37g of crospovidone XL (7% of tablet weight) were used. Granulation was performed using 10% PVPK30 aqueous solution as a binder, followed by drying and compression into tablets (30 tablets per tablet), with a hardness controlled at 70N. The ratio of internal to external disintegrant mainly affects the disintegration rate of the tablet and the dissolution rate of the active pharmaceutical ingredient. Therefore, the dissolution of androdenafil citrate was selected as the main indicator. In this test, the total amount of disintegrant accounted for 7% of the weight of the unprocessed tablets. The difference lay in the ratio of internal to external crospovidone XL: the mass ratio of internal to external disintegrant was 1:1, 1:2, 2:1, all internal, and all external. Dissolution tests were then performed on the corresponding tablets. The results are as follows: Figure 3 As shown.

[0101] The results showed that the fastest dissolution was achieved when the ratio of internal disintegrant to external disintegrant was 1:2, but the difference was not significant compared to 1:1. Furthermore, the larger the amount of external disintegrant, the more fine powder was present in the tablets before compression, making uniform mixing more difficult. Therefore, a mass ratio of internal disintegrant to external disintegrant of 1:1 is preferred.

[0102] 5) The effect of adhesives An aqueous solution containing 10% PVP K30 (Example 1), a 50% ethanol solution containing 10% PVP K30 (Comparative Example 5), a 70% ethanol solution containing 10% PVP K30 (Comparative Example 6), and water (Comparative Example 7) were selected as adhesives, and the test results are shown in Table 5.

[0103] Table 5 Test results of adhesives According to the experimental results in Table 5, using pure water as a binder resulted in insufficient adhesion, leading to granule failure and inability to compress tablets. While using an ethanol solution containing PVP K30 as a binder increased the dissolution rate of PVP K30 and shortened the drying time with increasing ethanol concentration, the binder's adhesion remained poor due to the low viscosity of ethanol, resulting in a high concentration of fine powder. Furthermore, the rapid evaporation of ethanol made granulation time difficult to control under high-speed stirring. In contrast, an aqueous solution containing 10% PVP K30 provided a faster granulation speed, better adhesion, and fewer fine powder particles in the granules. Therefore, an aqueous solution containing 10% PVP K30 was selected as the binder.

[0104] 6) Orthogonal experiment on diluent ratio, disintegrant dosage, and internal / external disintegrant addition ratio The results of the aforementioned single-factor investigation show that the factors affecting the quality and dissolution of androdenafil citrate tablets include the diluent ratio, disintegrant dosage, and the ratio of internal to external disintegrant addition. Furthermore, there may be interactions and influences among these factors. Therefore, a three-factor, three-level orthogonal experimental design was used to further optimize the androdenafil citrate formulation. The L9(3)2 model was employed. 4 The experiment was arranged according to the table, and different levels of the three factors were set with reference to the results of the single-factor experiment. The factor level table for the orthogonal experiment is shown in Table 6, and the orthogonal experimental design and results are shown in Table 7.

[0105] Table 6. Factor Level Table for Orthogonal Experiments Following the orthogonal experimental design, androdenafil citrate tablets were prepared using different formulations and the aforementioned process. Since the granules and tablets obtained from different formulations all exhibited good appearances, making comparison difficult, the dissolution behavior of androdenafil citrate from the tablets was used as the primary evaluation indicator. Because the drug dissolves rapidly from the tablets, reaching over 85% within 5 minutes, the dissolution percentage at 2 minutes was used as the evaluation indicator. The experimental results are shown in Table 7.

[0106] Table 7 Orthogonal Experimental Design and Results Analysis of the orthogonal experimental results showed that the proportion of disintegrant in the formulation had the greatest impact on the dissolution rate of the active pharmaceutical ingredient from the tablets. Analysis of variance was performed on the results, which are as follows: Table 8 Results of Analysis of Variance It is evident that the ratio of disintegrants significantly affects dissolution results. As the amount of disintegrant increases, the disintegration time of the tablets shortens, and the dissolution rate of the active pharmaceutical ingredient (API) increases. The ratio of internally and externally added disintegrants, as well as the ratio of microcrystalline cellulose to lactose, also have a certain impact on the formulation's dissolution. The fastest dissolution occurs when the ratio of internally and externally added disintegrants is 1:1 and the ratio of microcrystalline cellulose to lactose is 2:1. Considering factors such as particle quality, fine powder content, tablet appearance, and hardness during tablet preparation, the final selected disintegrant dosage is 7%, the ratio of internally and externally added disintegrants is 1:1, and the ratio of microcrystalline cellulose to lactose is 2:1.

[0107] By optimizing the formulation through orthogonal experimental design, it was determined that when the ratio of microcrystalline cellulose to lactose was 2:1, the amount of disintegrant was 7%, and the ratio of internal to external disintegrant addition was 1:1, the tablets dissolved fastest, with a dissolution rate of over 75% in 2 minutes and over 85% in 5 minutes, thus meeting the requirements for rapid onset of action.

[0108] 7) The influence of coating materials Example 1 used Opadry 200F220031 (moisture-resistant, stomach-coated) to coat uncoated tablets, while Example 13 used Opadry 85G62549 (regular stomach-coated) to coat uncoated tablets. Dissolution and moisture-resistant properties were compared, and neither coating affected rapid dissolution. A high humidity test (RH 92.5%, 10 days) showed that the regular coated tablets (Opadry 85G62549) exhibited some discoloration and moisture absorption swelling, while the moisture-resistant coated tablets (Opadry 200F220031) showed no change in appearance. After a strong light test (4500 Lx, 10 days), the levels of related substances in the coated tablets were significantly lower than those in the uncoated tablets. Therefore, the moisture-resistant, stomach-coated Opadry 200F220031 was selected as the coating material.

[0109] Table 9. Test results of related substances in tablets under strong light conditions (4500 Lx, 10 days) 8) The effect of different screen mesh sizes on granulation effect According to the compatibility test results of raw materials and excipients, the related substances of androdenafil citrate API showed no significant changes after being placed at 60℃ for 10 days, indicating its relative stability at high temperatures. Crosslinked povidone aqueous solution was used as a binder in granulation, and moisture should be removed as much as possible during drying. To ensure drying efficiency, the proposed drying temperature for wet granules was 60℃, and the moisture content of dry granules was controlled at approximately 3%. The drying endpoint of multiple batches of small-scale samples was confirmed based on moisture content determination results (loss on drying method). When the moisture content was between 1% and 2%, there were no significant differences in tablet appearance and hardness. Therefore, the drying moisture content was controlled to not exceed 3.0%, and the drying endpoint was determined based on the moisture control results.

[0110] During the drying process, wet granules or powder may clump together. Further granulation can disperse the clumps and obtain granules of uniform size. Granulation was carried out using 20, 24, and 30 mesh sieves, and the bulk density, angle of repose, compressibility, and weight variation of the granules were used as indicators for evaluation. The results are shown in Table 10.

[0111] Table 10. Results of the effect of different sieve mesh sizes on granulation effect The experimental results show that, compared with the raw drug, the flowability of granulated tablets is significantly improved, and the angle of repose decreases from 54° to about 34°. The granulation effect of different mesh sizes is similar. However, smaller mesh sizes produce more fine powder. During the later coating process, it was found that tablets prepared with granules containing more fine powder are prone to powder loss due to friction, resulting in blurred lettering, possibly due to poorer interparticle forces. Granules prepared using a 20-mesh sieve exhibit good compressibility and flowability, and are less prone to powder loss during coating. Therefore, the drying temperature for wet granules was determined to be 60℃, and a 20-mesh sieve was used for granulation.

[0112] Example 7: Pilot-scale amplification According to the formulation ratio of Example 1, 336g of androdenafil citrate was added, and other excipients were scaled up proportionally. Using an HLSH2-6A wet granulation machine, the mixture was granulated, and the granules were dried at 60℃ to a moisture content of 1.5%. The granules were then sized, mixed, and finally compounded to obtain drug granules, which were then compressed into ordinary tablets or dispersible tablets for coating. The pilot-scale samples all met quality standards, with a 10-minute dissolution rate >98%, related substances <0.09%, and content between 99.5% and 101.8%. Simultaneously, in accordance with the guidelines for drug stability testing in Appendix XIXC of the 2010 edition of the Chinese Pharmacopoeia, influencing factor tests (high temperature 60℃, high humidity 75%~92.5%, strong light 4500Lx) were conducted on the pilot-scale samples. The results showed that: At a high temperature of 60℃: after 10 days, the levels of related substances increased slightly but remained below 0.12%, with no significant changes in content or dissolution.

[0113] High humidity 92.5%: Tablets and dispersible tablets absorb moisture and swell, but the intrinsic quality (content, dissolution, related substances) of coated tablets is not affected, and moisture-proof packaging is preferred.

[0114] Strong light: The related substances of the coated tablets remain basically unchanged, indicating that the coating effectively protects the active ingredient.

[0115] The influencing factor test showed that the tablets and dispersible tablets were stable in quality under conditions of 60°C, high humidity, and strong light, and the quality of the formulation of the present invention was stable and controllable.

[0116] This invention relates to a solid oral dosage form containing androdenafil citrate, its preparation method, and its uses, belonging to the field of pharmaceutical formulation technology. The solid oral dosage form uses androdenafil citrate as the active ingredient, combined with microcrystalline cellulose and lactose as diluents, crospovidone as a disintegrant, povidone K30 as a binder, and magnesium stearate as a lubricant, and can be prepared into tablets, dispersible tablets, capsules, and granules. The androdenafil citrate solid oral dosage form provided by this invention has advantages such as rapid disintegration, rapid dissolution, good stability, comprehensive dosage forms, and simple process. It can be used to prepare drugs for treating male erectile dysfunction, pulmonary hypertension, benign prostatic hyperplasia, combined tumor treatment, and Alzheimer's disease. The formulation process is mature, excipients are readily available, and equipment is universal, making it suitable for large-scale industrial production, with significant clinical value and market prospects. Compared with the prior art, this invention has the following beneficial effects: 1. Rapid disintegration and dissolution: The preferred formulation of the present invention has a dissolution rate of more than 75% within 2 minutes and more than 85% within 5 minutes. The dispersible tablets can completely disintegrate and disperse in water within 3 minutes, meeting the requirements for rapid onset of action.

[0117] 2. Good stability: Excipients with good compatibility with the active pharmaceutical ingredient are selected through raw material compatibility tests, and light and moisture are effectively isolated through film coating technology, so the formulation is stable under high temperature, high humidity and strong light conditions.

[0118] 3. Simple process, suitable for industrial production: It adopts conventional wet granulation process, and the excipients used are all commonly used pharmaceutical excipients. The equipment is highly versatile and easy to scale up production.

[0119] 4. Multi-dosage form coverage: This invention protects tablets, dispersible tablets, capsules, and granules, covering all mainstream solid oral dosage forms to meet the needs of patients of different ages and swallowing abilities.

[0120] 5. Wide range of indications: Expanded from andrological diseases to respiratory, urological, oncological and neurological diseases, achieving multiple uses for one drug and significantly enhancing its clinical application value.

[0121] The above embodiments prepared by the method of the present invention are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

[0122] The equipment and raw materials used in the above embodiments are all commercially available or commonly used in the art. Unless otherwise specified, the methods in the above embodiments are conventional methods in the art. Raw materials not specifically mentioned in the embodiments are all commercially available. Operations without a specific temperature are performed at room temperature. Operating methods and conditions not specifically mentioned can employ well-known or conventional means and conditions in the art. The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values; these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and individual point values, and individual point values ​​can be combined to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

Claims

1. A method for preparing a solid oral dosage form containing androdenafil citrate, characterized in that, Includes the following steps: Mix and homogenize androgen citrate, diluent, and first-part disintegrant. Add adhesive and mix to obtain a soft material; The soft material is sieved to prepare wet granules; The wet granules are dried to prepare dry granules; Add the second disintegrant and lubricant, mix again to obtain drug particles, which are the solid oral dosage form; The first portion of the disintegrant is 30% to 70% of the total mass of the disintegrant, and the second portion of the disintegrant is 30% to 70% of the total mass of the disintegrant.

2. The preparation method according to claim 1, characterized in that, The mass ratio between the first and second disintegrants is 1:2 to 2:

1.

3. The preparation method according to claim 1, characterized in that, The diluent is a mixture of microcrystalline cellulose and lactose, wherein the mass ratio of microcrystalline cellulose to lactose in the diluent is microcrystalline cellulose: lactose = 1:2~3:

1.

4. The preparation method according to claim 1, characterized in that, By weight percentage, the solid oral dosage form comprises the following components: androdenafil citrate 10%~25%; diluent 60%~80%; disintegrant 3%~7%; binder 2%~6%; lubricant 0.5%~2%.

5. The preparation method according to claim 1, characterized in that, The solid oral preparation is a granule; or, When the solid oral dosage form is a tablet or a dispersible tablet, the step includes compressing the drug particles to obtain a tablet or a dispersible tablet; or, When the solid oral dosage form is a capsule, the step includes filling the drug particles into an empty capsule to obtain the capsule.

6. The preparation method according to claim 5, characterized in that, When the solid oral dosage form is a tablet or a dispersible tablet, the step further includes coating the tablet or dispersible tablet to obtain a coating layer for encapsulating the tablet or dispersible tablet.

7. A solid oral dosage form containing androdenafil citrate prepared by the preparation method according to any one of claims 1-6.

8. A solid oral dosage form containing androdenafil citrate, characterized in that, By weight percentage, the solid oral dosage form comprises the following components: androdenafil citrate 10%~25%; diluent 60%~80%; disintegrant 3%~7%; binder 2%~6%; lubricant 0.5%~2%.

9. The solid oral dosage form according to claim 8, characterized in that, The solid oral dosage form is a tablet, dispersible tablet, capsule, or granule; when the solid oral dosage form is a tablet or dispersible tablet, the solid oral dosage form includes a coating layer on the outer surface of the tablet or dispersible tablet.

10. The use of a solid oral dosage form as described in claim 8 or 9 in the preparation of a medicament for treating at least one of erectile dysfunction, pulmonary hypertension, benign prostatic hyperplasia, tumor, and neurodegenerative disease in men.

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