A method for preparing a sustained-release tablet of sildenafil citrate and telmisartan

Abstract

The application provides a preparation method of sildenafil citrate and telmisartan sustained-release tablets, which comprises the following steps: obtaining a tablet core by wet granulation, drying, total mixing and tabletting of sildenafil citrate and auxiliary materials; adding telmisartan into an aqueous solution of sodium hydroxide and meglumine to prepare sodium telmisartan by granulation; forming a fast-release coating slurry by mixing the sodium telmisartan and coating materials; and coating the tablet core in a coating machine by using the prepared fast-release coating slurry to obtain the sildenafil citrate and telmisartan sustained-release tablets. The application adopts a unique microporous penetration controlled-release technology. When the drug is taken, water molecules penetrate into the tablet core through the membrane, the drug component is dissolved to generate osmotic pressure, and the drug is slowly and constantly released at a zero-order or near zero-order rate under the osmotic pressure in the membrane, thereby prolonging the sustained-release time of sildenafil citrate.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmacy, and particularly relates to a preparation method of a sildenafil citrate and telmisartan sustained-release tablet. BACKGROUND

[0002] Pulmonary arterial hypertension is a group of clinicopathophysiological syndromes characterized by the progressive increase in pulmonary vascular resistance due to functional and / or structural changes in pulmonary vessels, and is diagnosed according to hemodynamic criteria. That is, the mean pulmonary arterial pressure is higher than 25 mmHg when measured by right heart catheterization at rest, which is a disease of abnormal increase in pulmonary arterial pressure. Pulmonary arterial hypertension is a chronic and life-threatening disease, and common symptoms include shortness of breath after exercise, fatigue, and angina pectoris. As the pulmonary arterial pressure increases, the cardiac load of the patient will continue to increase, eventually leading to right ventricular hypertrophy, failure, and even death.

[0003] When the disease of a patient with pulmonary arterial hypertension reaches the middle and late stages, the patient will often have different degrees of blue and purple color on the nails, cheeks, and lips due to hypoxia, which is also the reason why these patients are called "blue-lipped". Due to the low social awareness, the rate of missed diagnosis and misdiagnosis in the clinic is relatively high, and many patients with pulmonary arterial hypertension are not diagnosed until they have progressed to cardiac function class III / IV, and the mortality rate is very high, and they are once called "cancer in the cardiovascular field".

[0004] Hypertension is the most common cardiovascular disease and a major public health problem worldwide.

[0005] Telmisartan is a new type of antihypertensive drug and is a specific angiotensin II receptor (AT1 type) antagonist. Telmisartan replaces the angiotensin II receptor and binds to the AT1 receptor subtype (the known angiotensin II action site) with high affinity. Telmisartan has no agonist effect at the AT1 receptor site, and telmisartan selectively binds to the AT1 receptor, and the binding is durable.

[0006] The final elimination half-life of telmisartan is about 24 hours, showing square decay kinetics. The antihypertensive effect gradually becomes obvious within 3 hours after the first dose of telmisartan, and the maximum antihypertensive effect can be obtained 4 weeks after the start of treatment and can be maintained in long-term treatment. If telmisartan treatment is suddenly discontinued, the blood pressure gradually returns to the pre-treatment level after a few days without rebound hypertension. Telmisartan has a good antihypertensive effect on both diastolic and systolic blood pressure, and the antihypertensive effect is stable and does not cause coughing. Telmisartan has few adverse reactions. Telmisartan has a kidney-protecting effect in patients with diabetes and improves the quality of life.

[0007] Sildenafil, brand name Viagra (Sildenafil), is widely used to treat male erectile dysfunction. Recent studies have shown it can also be used to treat pulmonary hypertension. Sildenafil is a selective phosphodiesterase inhibitor that increases the concentration of cyclic guanosine monophosphate (cGMP) in pulmonary blood vessels, thereby increasing endogenous NO and dilating pulmonary blood vessels. Sildenafil not only dilates normal pulmonary blood vessels but also dilates blood vessels in diseased lung tissue.

[0008] Sildenafil citrate is highly hygroscopic and easily deteriorates under normal conditions. The moisture content of the finished product should not be too high, as it significantly affects the drug's stability. Furthermore, hygroscopic sildenafil citrate is prone to sticking and clogging during tableting, which is detrimental to commercial production. Sildenafil citrate also has a short half-life, resulting in a rapid decline in efficacy, necessitating multiple administrations. Summary of the Invention

[0009] To address the problems in the prior art, this invention provides a method for preparing sildenafil citrate and telmisartan sustained-release tablets. The method employs microporous permeation controlled-release technology, where water molecules pass through a permeation membrane into the tablet core. The drug components dissolve and generate osmotic pressure, allowing the drug to be released slowly and at a constant rate. The resulting sustained-release tablets have good stability and are used to relieve, treat, or prevent hypertension.

[0010] The technical problem solved by this invention is achieved by the following technical solution:

[0011] The first objective of this invention is to provide a sildenafil citrate and telmisartan extended-release tablet, characterized in that it comprises an immediate-release layer and a sustained-release layer.

[0012] The immediate-release layer comprises telmisartan sodium and a pharmaceutically acceptable coating material, wherein the telmisartan sodium and the coating material together form a microporous film to coat the tablet core.

[0013] The sustained-release layer is a tablet core comprising sildenafil citrate and pharmaceutically acceptable excipients, wherein the sildenafil citrate is attached to the sustained-release matrix composed of the excipients.

[0014] Furthermore, the immediate-release layer includes an insoluble film-forming agent, a water-soluble pore-forming agent, and a filler.

[0015] Furthermore, the film-forming agent is ethyl cellulose.

[0016] Furthermore, the pore-forming agent is telmisartan sodium and polyethylene glycol.

[0017] Furthermore, the filler is hydroxypropyl methylcellulose and lactose.

[0018] Further, the immediate release layer comprises 5-20 parts of telmisartan sodium, 5-25 parts of lactose, 2-5 parts of hypromellose, 8-10 parts of ethyl cellulose, 1-5 parts of cetanol and 1-5 parts of polyethylene glycol 6000.

[0019] Further, the tablet core comprises a tablet core filler, a disintegrant, a sustained release matrix, a tablet core film forming agent and a lubricant.

[0020] Further, the tablet core filler comprises microcrystalline cellulose.

[0021] Further, the disintegrant is sodium croscarmellose.

[0022] Further, the sustained release matrix is hypromellose and lactose.

[0023] Further, the tablet core film forming agent is glycerol.

[0024] Further, the lubricant is magnesium stearate.

[0025] Further, the tablet core comprises 10-15 parts of sildenafil citrate, 30-40 parts of microcrystalline cellulose, 12-18 parts of hypromellose, 20-30 parts of lactose, 2-3 parts of sodium croscarmellose, 3-5 parts of glycerol and 5-8 parts of magnesium stearate.

[0026] Further, the mass ratio of the immediate release layer to the sustained release layer is 1:2-4.

[0027] A second object of the present application is to provide a preparation method of the sildenafil citrate and telmisartan sustained release tablet.

[0028] Preparation of the tablet core:

[0029] The sildenafil citrate and the excipients are subjected to wet granulation, drying, total mixing and tabletting to obtain the tablet core.

[0030] Preparation of the immediate release coating slurry:

[0031] The telmisartan is added to the aqueous solution of sodium hydroxide and meglumine to obtain the telmisartan sodium; the telmisartan sodium and the coating material are combined to form the immediate release coating slurry.

[0032] Coating:

[0033] The tablet core is placed in a coating machine, and the prepared immediate release coating slurry is used to coat the tablet core to obtain the sildenafil citrate and telmisartan sustained release tablet.

[0034] Further, the preparation method of the tablet core is as follows: after the proportionally weighed sildenafil citrate and tablet core filler are added into a granulator and premixed, a sustained-release matrix is further premixed, then a film-forming agent is added, and after mixing, the soft material is obtained by high-speed shearing in the granulator; the soft material is granulated to obtain wet granules; after drying and granulating the wet granules, a disintegrating agent is added for mixing, then a lubricant is added to obtain total mixed granules; and after tabletting, the tablet core is obtained.

[0035] Further, the preparation method of the sodium telmisartan is as follows: under stirring, sodium hydroxide and meglumine are added into purified water to dissolve, then the telmisartan is added for mixing to obtain a sodium salt solution for standby; polyvinylpyrrolidone is added into purified water to dissolve, then the above sodium salt solution is added for stirring to be uniform; and the sodium telmisartan is obtained by spray granulation.

[0036] Further, the mass ratio of the added sodium hydroxide, meglumine and telmisartan is 1.32:4.8:16.

[0037] Further, the spray granulation conditions are as follows: the inlet air temperature is 70-75℃, the inlet air frequency is 30-35Hz, the spray pressure is 0.3-0.5MPa, and the spray liquid rotation speed is 60-70rpm.

[0038] Further, the preparation method of the immediate-release layer coating solution is as follows: under stirring, ethyl cellulose, polyethylene glycol and cetyl alcohol are added into an ethanol solution A to completely dissolve to obtain solution A; under stirring, a mixed powder of sodium telmisartan, lactose and hydroxypropyl cellulose is added into an ethanol solution B to completely dissolve to obtain solution B; under stirring, the solution B is added into the solution A to obtain the immediate-release layer coating solution.

[0039] Further, the mass ratio of the total mass of the ethyl cellulose, polyethylene glycol and cetyl alcohol to the mass of the ethanol solution A is 1:3-5.

[0040] Further, the mass ratio of the total mass of the mixed powder of sodium telmisartan, lactose and hydroxypropyl cellulose to the mass of the ethanol solution B is 1:2-3.

[0041] Further, the ethanol solution A and the ethanol solution B are ethanol solutions with a volume fraction of 30-50%.

[0042] Further, the coating conditions are as follows: the hot air temperature is 100-120℃; the exhaust fan rotation speed is 1600-2800rpm; the air source pressure is 0.30-0.50Mpa; the outlet air temperature is 40-90℃; the coating solution flow rate is 0.08-0.20kg / min; and the main machine rotation speed is 3-5rpm.

[0043] Further, the coating weight gain is 3.5%-4.0%.

[0044] In the tablet core of the present application, hydroxypropyl methyl cellulose and lactose are used as tablet core fillers to form a sustained release matrix, and after the tablet core is contacted with water, glycerol with strong hydrophilicity rapidly leads water into the tablet core, so that crosslinked sodium carboxymethyl cellulose between the particles as a disintegrating agent rapidly expands, which promotes the rapid formation of the matrix of hydroxypropyl methyl cellulose and lactose, and sildenafil citrate adheres to the matrix to achieve slow release. In the preparation process, microcrystalline cellulose is used as a filler and mixed with sildenafil citrate, and the hygroscopicity of microcrystalline cellulose is weaker than that of sildenafil citrate, so the hygroscopicity of sildenafil citrate is reduced. At the same time, due to the presence of glycerol, glycerol has a certain film-forming property, and after drying, it can be distributed on the surface of sildenafil citrate and microcrystalline cellulose. Magnesium stearate is used as a lubricant to further wrap the formed particles, which can reduce the contact of sildenafil citrate with moisture in the air, reduce the hygroscopicity, and finally make the tabletting process no longer sticky, and the tablet weight difference is small.

[0045] The immediate release layer of the present application is prepared by a specific prescription and process, and the film-forming property and insolubility of ethyl cellulose are used to wrap the tablet core, and telmisartan sodium is used as the main component. At the same time, due to its water-soluble property, it forms a pore-forming agent with polyethylene glycol 6000, and forms a film with ethyl cellulose. After contacting with water, the pore-forming agent rapidly dissolves, that is, a plurality of small holes are formed on the film formed by ethyl cellulose, so that the drug components in the tablet core part dissolve to produce osmotic pressure when contacted with water. Under the osmotic pressure in the film, the drug is slowly and constantly released at zero order or near zero order rate.

[0046] Compared with the prior art, the present application has the beneficial technical effects that:

[0047] The auxiliary materials used in the present application are stable, almost no hygroscopicity during storage, which can ensure the stability of the product during storage, reduce the influence of water on sildenafil citrate, and adopt a unique microporous osmotic controlled release technology. There is a thin osmotic membrane on the surface of the drug. When the drug is taken, a plurality of small holes are formed on the surface of the osmotic membrane under the action of water molecules. Water molecules enter the tablet core through the osmotic membrane containing small holes, and the drug components dissolve to produce osmotic pressure. Under the osmotic pressure in the film, the drug is slowly and constantly released at zero order or near zero order rate, which prolongs the slow release time of sildenafil citrate, alleviates the shortcoming of short half-life of sildenafil citrate, and avoids repeated administration during treatment. The product of the present application has good stability, and the properties, moisture, identification, content, related substances, and microbial limit of the product are not significantly changed after 36 months of long-term storage. The maximum increase of moisture is only 0.23% after 36 months of long-term storage, the increase is small, the maximum increase of related substances is only 0.12% after 36 months of long-term storage, and all meet the requirements of products on the market. Therefore, the shelf life of the product is up to 36 months. The sildenafil citrate and telmisartan sustained release tablets of the present application can be used for alleviating, treating or prophylactic treatment of hypertension, and the hypertension includes primary / secondary hypertension, pulmonary arterial hypertension, and simple systolic hypertension.

[0048] The above description is only a summary of the technical solutions of the present application. In order to make the technical solutions of the present application more clearly understood and implemented, and to make the above content and purposes, characteristics and advantages of the present application more apparent and easy to understand, the specific embodiments of the present application are described below. BRIEF DESCRIPTION OF DRAWINGS

[0049] Figure 1 Figure 1 is a dissolution curve diagram of the sample prepared in Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 3 in the preparation method of the sildenafil citrate and telmisartan sustained-release tablet according to the present application.

[0050] Figure 2 Figure 1 is a dissolution curve diagram of the sample prepared in Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 3 in the preparation method of the sildenafil citrate and telmisartan sustained-release tablet according to the present application. DETAILED DESCRIPTION

[0051] The technical solutions of the present application are further described in detail below in combination with the drawings and specific embodiments. It should be understood that the following examples are only exemplary and are used to illustrate and explain the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology implemented based on the above content of the present application is covered within the scope of protection intended by the present application.

[0052] In addition, unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present application can be purchased from the market or prepared by existing methods.

[0053] Example 1:

[0054] A preparation method of a sildenafil citrate and telmisartan sustained-release tablet, comprising the following steps:

[0055] (1) Preparation of the tablet core:

[0056] Take 12 parts of sildenafil citrate, 35 parts of microcrystalline cellulose, add them into a high-efficiency wet granulator, stir at low speed, pre-mix for 3 minutes, then add 16 parts of hydroxypropyl cellulose and 25 parts of lactose, pre-mix again for 12 minutes, under stirring, add 4 parts of glycerol, continue to mix for 4 minutes, then add 27 parts of purified water into the high-efficiency wet granulator within 1 minute, after the addition is completed, open the high shear for 2 minutes to obtain soft material;

[0057] Place the soft material in a swing granulator, granulate with a 20-mesh screen to obtain wet granules;

[0058] The wet granules are placed in a fluidized bed granulator, the inlet air temperature is set to 75°C, the inlet air frequency is set to 40Hz, the granules are in a fluidized state, drying is carried out, and the drying is stopped when the moisture content is 1.53%; the dry granules are collected;

[0059] The dry granules are sieved with a 20-mesh screen to obtain the whole granules, and the whole granules are collected for standby;

[0060] The dry granules are placed in a three-dimensional motion mixer, 2.5 parts of cross-linked sodium carboxymethyl cellulose are added, and mixing is started for 7 minutes; then, 7 parts of magnesium stearate are added, and mixing is continued for 18 minutes; and the total mixed granules are obtained.

[0061] The total mixed granules are added to a rotary tablet press to obtain the tablet cores, and the hardness of the tablet cores is 8-15kg.

[0062] (2) Preparation of the immediate-release coating solution:

[0063] a) Preparation of telmisartan sodium: purified water is added to a preparation barrel, sodium hydroxide and meglumine are added under stirring to dissolve them, and telmisartan is gradually added under stirring; the mass ratio of the purified water, sodium hydroxide, meglumine, and telmisartan is 50:1.32:4.8:16; another preparation barrel is added with purified water, and povidone K30 is gradually added; after stirring and dissolving, the solution is poured into the sodium salt solution, and stirring is performed until the solution is uniform; the mass ratio of the purified water and povidone K30 is 30:4.8; the solution is placed in a fluidized bed granulator, the inlet air temperature of the fluidized bed is set to 72°C, the inlet air frequency is set to 33Hz, the spray pressure is 0.4MPa, the liquid spray speed is 65rpm, and spray granulation is performed to obtain telmisartan sodium.

[0064] b) The preparation of the coating liquid: First, the volume fraction 40% ethanol solution A was placed in a stirring tank, and the stirring was started. The ethanol solution formed a vortex without splashing, and the weight parts of ethyl cellulose 9 parts, polyethylene glycol 6000 3 parts, and cetyl alcohol 3 parts were slowly added to the vortex surface in turn. The powders were quickly stirred into the vortex. After the completion of the feeding, the stirring was continued to completely dissolve the powders for standby. The solution A was obtained. The mass ratio of the total mass of the ethyl cellulose, polyethylene glycol 6000, and cetyl alcohol to the mass of the volume fraction 40% ethanol solution A was 1:4. Another weight parts of telmisartan sodium 15 parts, lactose 18 parts, and hydroxypropyl cellulose 3 parts were placed in a three-dimensional motion mixer, and the frequency was set to 13 Hz. The mixing was performed for 18 minutes to obtain a mixed powder for standby. Another volume fraction 40% ethanol solution B was placed in a stirring tank, and the stirring was started. The ethanol solution formed a vortex without splashing, and the mixed powder was slowly added. After the completion of the addition, the stirring was continued to completely dissolve the mixed powder to obtain the solution B for standby. The mass ratio of the mixed powder to the volume fraction 40% ethanol solution B was 1:2.5. Under the condition of continuous stirring, the solution B was added to the solution A. After the completion of the addition, the stirring was continued for 25 minutes to obtain the immediate-release layer coating slurry.

[0065] (3) Coating

[0066] The tablet core prepared in step (1) was placed in a coating machine, and the hot air temperature of the coating machine was set to 110°C. The fan speed was 2000 rpm. The air source pressure was 0.40 Mpa. The air outlet temperature was 67°C. The coating liquid flow rate was 1.15 kg / minute. The main machine speed was 4 revolutions / minute. The immediate-release layer coating slurry prepared in step (2) was used for coating. The coating weight gain was 3.82%, and the coated tablet was obtained.

[0067] Example 2:

[0068] A preparation method of a sildenafil citrate and telmisartan sustained-release tablet, comprising the following steps:

[0069] (1) Preparation of the tablet core:

[0070] Weight parts of sildenafil citrate 10 parts, microcrystalline cellulose 30 parts, hydroxypropyl cellulose 12 parts, and lactose 20 parts were added to a high-efficiency wet granulator. Low-speed stirring was performed for 2 minutes. Then, glycerol 3 parts was added under stirring. The mixing was continued for 3 minutes. Then, purified water 25 parts was added to the high-efficiency wet granulator within 1 minute. After the completion of the addition, high shear was started for 2 minutes to obtain soft material.

[0071] The soft material was placed in a swing granulator, and granulation was performed with a 20-mesh sieve to obtain wet granules.

[0072] The wet granules are placed in a fluidized bed granulator, the inlet air temperature is set to 70°C, the inlet air frequency is set to 30Hz, the granules are in a fluidized state, drying is carried out, and the drying is stopped when the moisture content is 1.03%; the dry granules are collected;

[0073] The dry granules are sieved with a 20-mesh screen to obtain the whole granules, and the whole granules are collected for standby;

[0074] The dry granules are placed in a three-dimensional motion mixer, 2 parts of cross-linked sodium carboxymethyl cellulose are added, the mixer is started for 5 minutes, the mixing is stopped, 5 parts of magnesium stearate are added, and the mixing is continued for 15 minutes to obtain the total mixed granules;

[0075] The total mixed granules are added to a rotary tablet press to obtain the tablet cores with a hardness of 8-15 kg;

[0076] (2) Preparation of the immediate-release coating solution:

[0077] a) Preparation of telmisartan sodium: purified water is added to a preparation barrel, sodium hydroxide and meglumine are added under stirring to dissolve, and telmisartan is gradually added under stirring, the mass ratio of the purified water, sodium hydroxide, meglumine, and telmisartan is 50:1.32:4.8:16; another preparation barrel is added with purified water, and povidone K30 is gradually added, stirred and dissolved, and then poured into the sodium salt solution, stirred and mixed uniformly to obtain a solution, the mass ratio of the purified water and povidone K30 is 30:4.8; the solution is placed in a fluidized bed granulator, the inlet air temperature of the fluidized bed is set to 70°C, the inlet air frequency is set to 30Hz, the spray pressure is 0.3MPa, the liquid spray speed is 60rpm, and spray granulation is carried out to obtain telmisartan sodium;

[0078] b) The preparation of the coating liquid: First, the volume fraction 30% ethanol solution A was placed in a stirring tank, and the stirring was started. The ethanol solution formed a vortex without splashing. The weight parts of ethyl cellulose 8 parts, polyethylene glycol 6000 1 part, and cetyl alcohol 1 part were slowly added to the vortex surface in turn, so that the powder was quickly stirred into the vortex. After the completion of the feeding, the stirring was continued to completely dissolve the mixture, and solution A was obtained. The total mass of ethyl cellulose, polyethylene glycol 6000, and cetyl alcohol was 1:3 by mass ratio to the volume fraction 30% ethanol solution A. Another weight parts of telmisartan sodium 5 parts, lactose 5 parts, and hydroxypropyl cellulose 2 parts were placed in a three-dimensional motion mixer, and the frequency was set to 12 Hz. The mixing was carried out for 15 minutes to obtain a mixed powder. Another volume fraction 30% ethanol solution B was placed in a stirring tank, and the stirring was started. The ethanol solution formed a vortex without splashing. The mixed powder was slowly added. After the completion of the addition, the stirring was continued to completely dissolve the mixture, and solution B was obtained. The mass ratio of the mixed powder to the volume fraction 30% ethanol solution B was 1:2. Under the condition of continuous stirring, solution B was added to solution A. After the completion of the addition, the stirring was continued for 20 minutes to obtain a fast-release layer coating slurry.

[0079] (3) Coating

[0080] The tablet core prepared in step (1) was placed in a coating machine. The hot air temperature of the coating machine was set to 100°C. The fan speed was 1600 rpm. The air source pressure was 0.30 Mpa. The air outlet temperature was 40°C. The coating liquid flow rate was 0.08 kg / minute. The main machine speed was 3 revolutions / minute. The fast-release layer coating slurry prepared in step (2) was used for coating. The coating weight gain was 3.56%. The preparation of the sustained-release layer coating slurry was completed.

[0081] Example 3:

[0082] A method for preparing a sildenafil citrate and telmisartan sustained-release tablet is prepared according to the following formula and process:

[0083] (1) Preparation of the tablet core:

[0084] Weight parts of sildenafil citrate 15 parts, microcrystalline cellulose 40 parts were added to a high-efficiency wet granulator. Low-speed stirring was carried out for 5 minutes. Then hydroxypropyl cellulose 18 parts and lactose 30 parts were added. The mixing was carried out for another 15 minutes. Under the condition of stirring, glycerol 5 parts was added. The mixing was continued for 5 minutes. Then purified water 28 parts was added to the high-efficiency wet granulator within 1 minute. After the completion of the addition, the high-shear stirring was started for 3 minutes to obtain soft material.

[0085] The soft material was placed in a swing granulator for granulation with a 20-mesh sieve to obtain wet granules.

[0086] The wet granules are placed in a fluidized bed granulator, the inlet air temperature is set to 80°C, the inlet air frequency is set to 50Hz, the granules are in a fluidized state, drying is carried out, and the drying is stopped when the moisture content is 1.97%; the dry granules are collected;

[0087] The dry granules are sieved with a 20-mesh screen to obtain the whole granules, and the whole granules are collected for standby;

[0088] The dry granules are placed in a three-dimensional motion mixer, 3 parts of cross-linked sodium carboxymethyl cellulose are added, and mixing is started for 8 minutes; then, 8 parts of magnesium stearate are added, and mixing is continued for 20 minutes; and the total mixed granules are obtained;

[0089] The total mixed granules are added to a rotary tablet press to obtain the tablet cores, and the hardness of the tablet cores is 8-15kg;

[0090] (2) Preparation of the immediate-release coating solution:

[0091] a) Preparation of the sodium telmisartan: purified water is added to a preparation barrel, sodium hydroxide and meglumine are added under stirring to dissolve them, and telmisartan is gradually added under stirring; the mass ratio of the purified water, sodium hydroxide, meglumine, and telmisartan is 50:1.32:4.8:16; another preparation barrel is added with purified water, and povidone K30 is gradually added; after stirring and dissolving, the solution is poured into the sodium salt solution, and stirring is performed to obtain a uniform solution; the mass ratio of the purified water and povidone K30 is 30:4.8; the solution is placed in a fluidized bed granulator, the inlet air temperature of the fluidized bed is set to 75°C, the inlet air frequency is set to 35Hz, the spray pressure is 0.5MPa, the liquid spray speed is 70rpm, and spray granulation is performed to obtain the sodium telmisartan;

[0092] b) The preparation of the coating liquid: first, 50% by volume of ethanol solution A was placed in a stirring tank, and the stirring was started to make the ethanol solution form a vortex without splashing. Then, 10 parts of ethyl cellulose, 5 parts of polyethylene glycol 6000, and 5 parts of cetyl alcohol were slowly added to the vortex page in sequence, and the powders were quickly stirred into the vortex. After the addition was completed, the stirring was continued to completely dissolve the powders, and solution A was obtained for standby use. The total mass of the ethyl cellulose, polyethylene glycol 6000, and cetyl alcohol was in a mass ratio of 1:5 to the mass of 50% by volume of ethanol solution A. Then, 20 parts of telmisartan sodium, 25 parts of lactose, and 5 parts of hydroxypropyl cellulose were placed in a three-dimensional motion mixer, and the frequency was set to 15 Hz for mixing for 20 minutes to obtain mixed powders for standby use. Then, 50% by volume of ethanol solution B was placed in a stirring tank, and the stirring was started to make the ethanol solution form a vortex without splashing. Then, the mixed powders were slowly added, and after the addition was completed, the stirring was continued to completely dissolve the mixed powders to obtain solution B for standby use. The mass ratio of the mixed powders to 50% by volume of ethanol solution B was 1:3. Under the condition of continuous stirring, solution B was added to solution A, and after the addition was completed, the stirring was continued for 30 minutes to obtain a quick-release layer coating slurry.

[0093] (3) Coating

[0094] The tablet core prepared in step (1) was placed in a coating machine, and the hot air temperature of the coating machine was set to 120°C; the fan speed was 2800 rpm; the air source pressure was 0.50 Mpa; the air outlet temperature was 90°C; the coating liquid flow rate was 0.20 kg / minute; and the main machine speed was 5 revolutions / minute. The quick-release layer coating slurry prepared in step (2) was used for coating, and the coating weight gain was 3.97%, and the coating was completed.

[0095] Comparative Example 1

[0096] A preparation method of a sildenafil citrate and telmisartan sustained-release tablet, compared with Example 1, the multiple premixing processes in the tablet core preparation process were improved, and the specific preparation process was as follows:

[0097] (1) Preparation of the tablet core:

[0098] Twelve parts of sildenafil citrate, 35 parts of microcrystalline cellulose, 16 parts of hydroxypropyl cellulose, 25 parts of lactose, and 4 parts of glycerol were weighed, and premixed for 19 minutes. Under the condition of stirring, 27 parts of purified water was added to the high-efficiency wet granulator within 1 minute, and after the addition was completed, the high shear was started for 2 minutes to obtain soft material.

[0099] The soft material was placed in a swing granulator and granulated with a 20-mesh screen to obtain wet granules.

[0100] The wet granules are placed in a fluidized bed granulator, the inlet air temperature is set to 75°C, the inlet air frequency is set to 40Hz, the granules are in a fluidized state, drying is carried out, and the drying is stopped when the moisture content is 1.53%; the dry granules are collected;

[0101] The dry granules are sieved with a 20-mesh screen to obtain the whole granules, and the whole granules are collected for standby;

[0102] The dry granules are placed in a three-dimensional motion mixer, 2.5 parts of cross-linked sodium carboxymethyl cellulose are added, and mixing is started for 7 minutes; then, 7 parts of magnesium stearate are added, and mixing is continued for 18 minutes; and the total mixed granules are obtained;

[0103] The total mixed granules are added to a rotary tablet press to obtain the tablet cores, and the hardness of the tablet cores is 8-15kg;

[0104] (2) Preparation of the immediate-release coating solution:

[0105] a) Preparation of telmisartan sodium: purified water, sodium hydroxide, meglumine, and telmisartan are added to a preparation barrel under stirring, and the mass ratio of the purified water, sodium hydroxide, meglumine, and telmisartan is 50:1.32:4.8:16; another preparation barrel is added with purified water, and povidone K30 is gradually added; after stirring and dissolving, the solution is poured into the sodium salt solution, and stirring is performed until the solution is uniformly mixed; the mass ratio of the purified water and povidone K30 is 30:4.8; the solution is placed in a fluidized bed granulator, the inlet air temperature of the fluidized bed is set to 72°C, the inlet air frequency is set to 33Hz, the spray pressure is 0.4MPa, the liquid spray speed is 65rpm, and spray granulation is performed to obtain telmisartan sodium;

[0106] b) The preparation of coating liquid: firstly, put the ethanol solution A with volume fraction of 40% into the stirring tank, and start stirring to make the ethanol solution form vortex without splashing. Then, slowly add ethyl cellulose 9 parts, polyethylene glycol 6000 3 parts, and cetyl alcohol 3 parts in sequence on the vortex surface under the condition of continuous stirring, so that the powder is quickly stirred into the vortex. After the completion of feeding, continue to stir until the powder is completely dissolved for standby. The mass ratio of the total mass of ethyl cellulose, polyethylene glycol 6000, and cetyl alcohol to the mass of ethanol solution A with volume fraction of 40% is 1:4. Then, take sodium temsiartan 15 parts, lactose 18 parts, and hydroxypropyl cellulose 3 parts by weight and put them into a three-dimensional motion mixer, set the frequency to 13 Hz, and mix for 18 minutes to obtain mixed powder for standby. Take ethanol solution B with volume fraction of 40% and put it into the stirring tank, and start stirring to make the ethanol solution form vortex without splashing. Then, slowly add the mixed powder, continue to stir until the powder is completely dissolved to obtain solution B for standby. The mass ratio of the mixed powder to the ethanol solution B with volume fraction of 40% is 1:2.5. Under the condition of continuous stirring, add solution B into solution A, and continue to stir for 25 minutes to obtain the immediate-release layer coating slurry.

[0107] (3) Coating

[0108] Put the tablet core prepared in step (1) into a coating machine, set the hot air temperature of the coating machine to 110°C, the blower speed to 2000 rpm, the air source pressure to 0.40 Mpa, the air outlet temperature to 67°C, the coating liquid flow rate to 1.15 kg / min, and the main machine speed to 4 revolutions / min, and coat the immediate-release layer coating slurry prepared in step (2) to obtain a tablet with a coating weight gain of 3.87%.

[0109] Comparative Example 2

[0110] A preparation method of a sildenafil citrate and temsiartan sustained-release tablet, wherein, compared with Example 1, the auxiliary materials in the tablet core preparation process are changed, the microcrystalline cellulose is replaced by starch, the glycerol is replaced by propylene glycol, and the magnesium stearate is replaced by silicon dioxide. The specific preparation process is as follows:

[0111] (1) Preparation of tablet core:

[0112] Take sildenafil citrate 12 parts and starch 35 parts by weight, add them into a high-efficiency wet granulator, stir at low speed, and premix for 3 minutes. Then, add hydroxypropyl cellulose 16 parts and lactose 25 parts, and premix for 12 minutes. Under the condition of stirring, add propylene glycol 4 parts, continue to mix for 4 minutes, and then add purified water 27 parts into the high-efficiency wet granulator within 1 minute. After the completion of feeding, start high shear for 2 minutes to obtain soft material.

[0113] Put the soft material into a swing granulator, and granulate with a 20-mesh sieve to obtain wet granules.

[0114] The wet granules were placed in a fluidized bed dryer, the inlet temperature was set at 75°C, the inlet frequency was set at 40Hz, the granules were in fluidized state, drying was carried out, and the drying was stopped when the moisture content was 1.53%, and the dry granules were collected;

[0115] The dry granules were sieved with a 20 mesh screen to obtain the sized granules, and the sized granules were collected for later use;

[0116] The sized dry granules were placed in a three-dimensional motion mixer, 2.5 parts of cross-linked sodium carboxymethyl cellulose was added, and the mixture was stirred for 7 minutes, then 7 parts of silicon dioxide was added, and the mixture was stirred for another 18 minutes to obtain the total mixed granules;

[0117] The total mixed granules were added to a rotary tablet press to obtain the tablet cores, and the hardness of the tablet cores was 8-15kg;

[0118] (2) Preparation of the immediate-release coating solution:

[0119] a) Preparation of telmisartan sodium: purified water was added to a preparation barrel, sodium hydroxide and meglumine were added under stirring to dissolve, and telmisartan was gradually added under stirring, and the mass ratio of the purified water, sodium hydroxide, meglumine, and telmisartan was 50:1.32:4.8:16; another preparation barrel was added with purified water, and povidone K30 was gradually added, and the mixture was stirred and dissolved, and then poured into the sodium salt solution, and stirred to mix uniformly to obtain a solution, and the mass ratio of the purified water and povidone K30 was 30:4.8; the solution was placed in a fluidized bed dryer, the inlet temperature was set at 72°C, the inlet frequency was set at 33Hz, the spray pressure was 0.4MPa, the liquid spray speed was 65rpm, and spray granulation was carried out to obtain telmisartan sodium;

[0120] b) The preparation of the coating liquid: First, put the 40% ethanol solution A into the stirring tank, and start stirring. The ethanol solution forms a vortex without splashing. Slowly add the ethyl cellulose 9 parts, polyethylene glycol 6000 3 parts, and cetyl alcohol 3 parts to the vortex surface under continuous stirring. The powders are quickly stirred into the vortex. After the ingredients are added, continue stirring until they are completely dissolved. The resulting solution A is ready for use. The total mass of ethyl cellulose, polyethylene glycol 6000, and cetyl alcohol is 1:4 by mass compared to the 40% ethanol solution A. Take another 15 parts of telmisartan sodium, 18 parts of lactose, and 3 parts of hydroxypropyl cellulose by weight and place them in a three-dimensional motion mixer. Set the frequency to 13 HZ and mix for 18 minutes to obtain a mixture of powders. Take another 40% ethanol solution B and place it in a stirring tank. Start stirring to form a vortex without splashing. Slowly add the mixed powder. After adding, continue stirring until it is completely dissolved to obtain solution B. The mass ratio of the mixed powder to the 40% ethanol solution B is 1:2.5. Under continuous stirring, add solution B to solution A. After adding, continue stirring for 25 minutes to obtain the immediate-release layer coating slurry.

[0121] (3) Coating

[0122] Place the tablet core prepared in step (1) in the coating machine. Set the hot air temperature to 110°C, the blower speed to 2000 rpm, the air source pressure to 0.40 Mpa, the air outlet temperature to 67°C, the coating liquid flow rate to 1.15 kg / min, and the main machine speed to 4 revolutions / min. Coat the immediate-release layer coating slurry prepared in step (2). The coating weight gain is 3.82%, and the process is complete.

[0123] Comparative Example 3:

[0124] A method for preparing a sildenafil citrate and telmisartan sustained-release tablet. The method for preparing the immediate-release layer coating slurry is improved compared to Example 1. The method includes the following steps:

[0125] (1) Preparation of the tablet core:

[0126] Take 12 parts of sildenafil citrate and 35 parts of microcrystalline cellulose by weight and add them to a high-efficiency wet granulator. Stir at low speed for 3 minutes. Then add 16 parts of hydroxypropyl cellulose and 25 parts of lactose. Mix again for 12 minutes. Under stirring, add 4 parts of glycerol. Continue mixing for 4 minutes. Then add 27 parts of purified water to the high-shear granulator within 1 minute. Start the high-shear granulator for 2 minutes to obtain soft material.

[0127] Place the soft material in a swing granulator and granulate with a 20-mesh sieve to obtain wet granules.

[0128] The wet granules are placed in a fluidized bed granulator, the inlet air temperature is set to 75°C, and the inlet air frequency is set to 40 Hz to make the granules in a fluidized state, and the granules are dried until the moisture content is 1.53%. The drying is stopped, and the dry granules are collected;

[0129] The dry granules are sieved with a 20-mesh sieve to make the granules uniform in size. The granules are collected and used as needed.

[0130] The dry granules are placed in a three-dimensional motion mixer, 2.5 parts of cross-linked sodium carboxymethyl cellulose are added, and the mixture is mixed for 7 minutes. Then, 7 parts of magnesium stearate are added, and the mixture is continuously mixed for 18 minutes to obtain the total mixed granules.

[0131] The total mixed granules are added to a rotary tablet press to press the tablets. The hardness of the tablets is 8-15 kg. The tablet cores are obtained.

[0132] (2) Preparation of the immediate-release coating solution:

[0133] a) Preparation of telmisartan sodium: In a preparation barrel, purified water is added, and sodium hydroxide and meglumine are added under stirring to dissolve them. Telmisartan is gradually added under stirring. The mass ratio of the purified water, sodium hydroxide, meglumine, and telmisartan is 50:1.32:4.8:16. Another preparation barrel is added with purified water, and povidone K30 is gradually added. After stirring and dissolving, the solution is poured into the sodium salt solution, and stirring is performed to mix uniformly. The mass ratio of the purified water and povidone K30 is 30:4.8. The solution is placed in a fluidized bed granulator, the inlet air temperature of the fluidized bed is set to 72°C, the inlet air frequency is set to 33 Hz, the spray pressure is 0.4 MPa, and the liquid spray speed is 65 rpm. Spray granulation is performed to obtain telmisartan sodium.

[0134] b) Preparation of the coating solution: First, 90 parts of an ethanol solution with a volume fraction of 40% is placed in a stirring tank. The stirring is started to make the ethanol solution form a vortex without splashing. Under continuous stirring, 9 parts of ethyl cellulose, 3 parts of cetyl alcohol, and 3 parts of polyethylene glycol 6000 are slowly added to the vortex surface in sequence. The powder is quickly stirred into the vortex. After the addition is completed, the stirring is continued to completely dissolve the powder. After dissolution, 15 parts of telmisartan sodium, 18 parts of lactose, and 3 parts of hydroxypropyl cellulose are added under stirring. The addition is completed, and the stirring is continued to completely dissolve the powder. The immediate-release layer coating solution is obtained.

[0135] (3) Coating

[0136] The tablet cores prepared in step (1) are placed in a coating machine, and the hot air temperature of the coating machine is set to 110°C. The blower speed is 2000 rpm, the air source pressure is 0.40 MPa, the outlet air temperature is 67°C, the coating liquid flow rate is 1.15 kg / min, and the main machine speed is 4 revolutions / min. The immediate-release layer coating solution prepared in step (2) is used for coating. The coating weight gain is 3.79%, and the coating is completed.

[0137] Experimental Example 1

[0138] The samples prepared in Examples 1-3 were subjected to long-term stability test according to the second part of the 2015 edition of the Chinese Pharmacopoeia.

[0139] Test conditions:

[0140] Long-term test temperature: 25±2℃

[0141] Long-term test humidity: RH 60%±10%

[0142] Long-term test observation time: 0, 3, 6, 9, 12, 18, 24, 36 months.

[0143] The long-term stability test results of Examples 1-3 are shown in Table 1. It can be seen that the properties, moisture, identification, content, related substances, and microbial limit of the samples of Examples 1, 2, and 3 after 36 months of long-term test did not change significantly, and the maximum increase in moisture was only 0.23% (Example 1 sample) after 36 months of long-term test, and the increase was small. In addition, the maximum increase in related substances was only 0.12% (Example 1 sample) after 36 months of long-term test, and the increase was small. Therefore, the product is stable in quality after 36 months of long-term test, and the shelf life is up to 36 months.

[0144] Table 1

[0145]

[0146]

[0147] Experimental Example 2

[0148] The samples obtained from Examples 1, Comparative Example 1, Comparative Example 2, and Comparative Example 3 were subjected to tabletting process monitoring, and the tablet weight difference and the content of main raw materials were compared. The results are shown in Table 2. It can be seen that after changing the multiple premixing to single premixing in Comparative Example 1, the tablet core tablet weight difference increased significantly, the sticking and clashing phenomenon was serious during the tabletting process, and the content uniformity of telmisartan and sildenafil citrate was poor, especially the content uniformity of sildenafil citrate was very poor. This is mainly because during multiple premixing, sildenafil citrate is first mixed with microcrystalline cellulose, and then premixed with hydroxypropyl cellulose, lactose, and release matrix, so that sildenafil citrate adheres to the matrix. Then through premixing with glycerol, glycerol is distributed on the surface of sildenafil citrate to prevent sildenafil citrate from sticking to the tablet after absorbing moisture, and the strong hydrophilicity of glycerol is used to guide water to the inside of the tablet core when it encounters water during use.

[0149] The tablet weight, sticking phenomenon, and content uniformity of Comparative Example 2 and Comparative Example 1 are similar to those of Comparative Example 1. This is mainly because after the tablet core excipients were changed, the original microcrystalline cellulose, glycerol, and magnesium stearate could not play their roles and could not change the problem of sildenafil citrate being hygroscopic and sticking during tableting, which resulted in poor content stability of sildenafil citrate.

[0150] After modifying the preparation method of the coating paste in Comparative Example 3, the telmisartan content uniformity was poor compared with that in Example 1. This was mainly because the present invention first fully dissolves telmisartan sodium, lactose, and hydroxypropyl cellulose in ethanol, mixes them evenly, and then mixes them with a mixed solution of ethyl cellulose, polyethylene glycol, and cetyl alcohol, thereby making the telmisartan distribution more uniform and forming a uniformly distributed pore-forming agent on the surface of the tablet core after coating.

[0151] Table 2

[0152]

[0153] Experimental Example 3:

[0154] The release curves of the samples obtained in Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 3 were detected. The sustained-release properties of telmisartan and sildenafil citrate at different time points are shown in Table 3. The release curve of telmisartan is shown in Appendix 1. Figure 1 The release curve of sildenafil citrate is attached. Figure 2 Combine Table 3 and Appendix Figure 1 Appendix Figure 2 It can be seen that the release rate of telmisartan in the sample of Example 1 of this invention is relatively fast, reaching 62% in 5 minutes, while the release rate of telmisartan in Comparative Examples 2 and 3 is only about 30% in 5 minutes. The release rate of sildenafil citrate in the sample of Example 1 is slow, starting to be released after nearly 15 minutes, reaching only 53% in 1.5 hours and only 72% in 4 hours, while Comparative Example 1 reaches 76% in 1.5 hours. It is evident that the release rate of sildenafil citrate in Example 1 is much lower than that of the three comparative examples.

[0155] Table 3

[0156]

[0157] This invention improves the sustained-release rate of telmisartan and reduces the sustained-release efficiency of sildenafil citrate by studying the composition of tablet core and coating paste raw materials and preparation process. It combines telmisartan and sildenafil citrate to form sustained-release tablets, solving the problems of rapid efficacy reduction and severe moisture absorption and sticking caused by the short half-life of sildenafil citrate, which makes it difficult to form tablets. The tablets are easy to store and can be directly used to relieve, treat or prevent hypertension.

[0158] The above-mentioned serial numbers of the embodiments of the present application are only for description, and do not represent the advantages and disadvantages of the embodiments.

[0159] The embodiments of the present application are described above with reference to the accompanying drawings, but the present application is not limited to the above-mentioned specific embodiments, and the above-mentioned specific embodiments are only illustrative, but not restrictive. Those skilled in the art can make many forms under the inspiration of the present application without departing from the purpose of the present application and the scope protected by the claims, and these all belong to the protection of the present application.

Claims

1. A sustained-release tablet of sildenafil citrate and telmisartan, characterized in that, Includes immediate-release and sustained-release layers. The immediate-release layer comprises telmisartan sodium and a pharmaceutically acceptable coating material, wherein the telmisartan sodium and the coating material together form a microporous film to coat the tablet core. The sustained-release layer is a tablet core comprising sildenafil citrate and pharmaceutically acceptable excipients, wherein the sildenafil citrate is attached to the sustained-release matrix composed of the excipients; the tablet core comprises 10-15 parts of sildenafil citrate, 30-40 parts of microcrystalline cellulose, 12-18 parts of hydroxypropyl methylcellulose, 20-30 parts of lactose, 2-3 parts of croscarmellose sodium, 3-5 parts of glycerin, and 5-8 parts of magnesium stearate; The method for preparing the sustained-release tablets is as follows: Preparation of chip core: Sildenafil citrate and tablet core filler, weighed according to the proportion, are added to a granulator for premixing. Then, a sustained-release matrix is ​​added for further premixing. Finally, a film-forming agent is added, and the mixture is subjected to high-speed shearing in a granulator to obtain a soft mass. The soft mass is granulated to obtain wet granules. The wet granules are dried, sized, and then mixed with a disintegrant. Finally, a lubricant is added to obtain a total mixed granule. After tableting, a tablet core is obtained. Preparation of immediate-release coating: Telmisartan was added to an aqueous solution of sodium hydroxide and meglumine, and granulation was performed to obtain telmisartan sodium. Ethyl cellulose, polyethylene glycol, and hexadecyl alcohol were added to an ethanol solution A under stirring and dissolved completely to obtain solution A. A mixed powder of telmisartan sodium, lactose, and hydroxypropyl cellulose was added to an ethanol solution B under stirring and dissolved completely to obtain solution B. Solution B was added to solution A under stirring to obtain an immediate-release coating slurry. Coating: The tablet core is placed in a coating machine, and the tablet core is coated with the prepared immediate-release coating slurry to obtain sildenafil citrate and telmisartan extended-release tablets, so that a water-soluble pore-forming agent is uniformly distributed on the surface of the coated extended-release tablets.

2. The sildenafil citrate and telmisartan sustained-release tablet as described in claim 1, characterized in that: The immediate-release layer comprises an insoluble film-forming agent, a water-soluble pore-forming agent, and a filler.

3. The sildenafil citrate and telmisartan sustained-release tablet as described in claim 2, characterized in that: The immediate-release layer comprises 5-20 parts of telmisartan sodium, 5-25 parts of lactose, 2-5 parts of hydroxypropyl methylcellulose, 8-10 parts of ethylcellulose, 1-5 parts of polyethylene glycol 6000, and 1-5 parts of cetyl alcohol.

4. The sildenafil citrate and telmisartan extended-release tablet as described in claim 1, characterized in that, The preparation method of telmisartan sodium is as follows: sodium hydroxide and meglumine are added to purified water under stirring to dissolve them, and then telmisartan is added and mixed to obtain a sodium salt solution for later use; povidone is added to purified water, dissolved, and then added to the above sodium salt solution and stirred evenly; telmisartan sodium is obtained by spray granulation.

5. The sildenafil citrate and telmisartan sustained-release tablet as described in claim 1, characterized in that: The total mass ratio of ethyl cellulose, polyethylene glycol, and hexadecyl alcohol to ethanol solution A is 1:3~5; The total mass ratio of the mixed powder of telmisartan sodium, lactose, and hydroxypropyl cellulose to the mass ratio of ethanol solution B is 1:2~3.

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