Compound tablet for treating hypertension and its preparation method

Abstract

The application discloses a compound tablet for treating hypertension, which comprises telmisartan, benzenesulfonic acid amlodipine, an alkalizing agent, a binder, a filling agent, a lubricant and a flow aid, and is characterized in that: the benzenesulfonic acid amlodipine is externally attached with a coating film; the coating material of the coating film is a gastric soluble coating material stable under an alkaline condition; and the weight ratio of the coating material to the benzenesulfonic acid amlodipine is (1-2.5): 1. The coating material is one or more of hydroxypropyl methyl cellulose, Eudragit E series and hydroxypropyl cellulose. The application provides a telmisartan amlodipine tablet with high stability and outstanding dissolution performance.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology and relates to a compound tablet for treating hypertension, specifically a telmisartan amlodipine tablet. Background Technology

[0002] Telmisartan belongs to a group of drugs called "angiotensin II receptor antagonists." Angiotensin II is a substance formed in the body that can narrow blood vessels and thus raise blood pressure. Telmisartan blocks the action of angiotensin II. Amlodipine belongs to a group of drugs called "calcium channel blockers," which prevent calcium from flowing into the blood vessel walls, thereby preventing vasoconstriction.

[0003] Amlodipine besylate is a dihydropyridine calcium channel blocker that selectively inhibits the transmembrane entry of calcium ions into smooth muscle cells and cardiomyocytes. Its effect on smooth muscle is greater than that on cardiomyocytes. It is a peripheral artery vasodilator that acts directly on vascular smooth muscle to reduce peripheral vascular resistance and thus lower blood pressure.

[0004] Telmisartan is a white crystalline powder, practically insoluble in water but soluble in strong alkalis. To achieve good dissolution, telmisartan is usually combined with alkaline excipients or dissolved in an alkaline solution to prepare spray-dried granules. However, direct mixing of amlodipine with acidic or alkaline substances can lead to decreased stability, as the ester bonds of amlodipine are easily hydrolyzed. Therefore, currently marketed telmisartan-amlodipine combination formulations are all designed as double-layer tablets. The production process requires specialized tableting equipment (double-layer tablet presses), which is complex and has high manufacturing costs.

[0005] In Chinese patent CN115531331B, to simplify the process and reduce manufacturing costs, a single-layer tablet design is still used. Amlodipine besylate is coated with chitosan, which prevents direct contact between amlodipine besylate and the alkaline excipients of telmisartan, thus improving stability to some extent. However, chitosan has poor stability to acids, alkalis, and light; therefore, the stability of the prepared telmisartan-amlodipine tablets still needs improvement. Summary of the Invention

[0006] This application provides a telmisartan amlodipine tablet with high stability and outstanding dissolution performance.

[0007] This application provides a telmisartan-amlodipine tablet comprising telmisartan, amlodipine besylate, an alkalizing agent, a binder, a filler, a lubricant, and a flow aid. The tablet is characterized by having an outer coating film on the amlodipine besylate, wherein the coating material is a gastric-soluble coating material stable under alkaline conditions, and the weight ratio of the coating material to the amlodipine besylate is (1-2.5):1.

[0008] Preferably, the coating material is one or more of hydroxypropyl methylcellulose, E-series hydroxypropylcellulose, and hydroxypropyl methylcellulose.

[0009] Preferably, the coating material is one or more of Euclidean E100 and Euclidean EPO.

[0010] Preferably, the weight ratio of the coating material to amlodipine benzylsulfonate is (1.5-2):1.

[0011] Preferably, the weight ratio of the coating material to amlodipine benzylsulfonate is 1.5:1.

[0012] Preferably, the compound tablets comprise telmisartan, sodium hydroxide, meglumine, crospovidone, amlodipine besylate tablets, dimethicone, lactose, coating material, sorbitol, and magnesium stearate.

[0013] Preferably, the compound tablet is a single-layer tablet.

[0014] This application also provides a method for preparing telmisartan amlodipine tablets, the specific steps of which are as follows:

[0015] 1) Preparation of telmisartan granules: Telmisartan, alkalizing agent, and binder are dissolved in water to prepare an aqueous solution, which is then spray-dried.

[0016] 2) Preparation of amlodipine besylate granules: Amlodipine besylate was dissolved in a gliding agent, mixed with water, emulsified, and then granulated with a filler to obtain granules. The granules were coated with a coating material solution and dried for later use.

[0017] 3) After mixing telmisartan granules and amlodipine besylate granules, compress them into tablets. In the emulsification step, use a high-shear emulsifier or an ultrasonic mixer for emulsification and dispersion.

[0018] Preferably, the coating material solution is a coating aqueous solution or a coating organic solution.

[0019] Beneficial effects:

[0020] The inventors discovered that using chitosan as a coating for amlodipine besylate did not result in high stability of amlodipine, primarily because chitosan is unstable under alkaline conditions, exposing amlodipine. This exposed amlodipine, upon contact with the alkaline excipients of telmisartan, undergoes hydrolysis, leading to increased impurities. Through extensive experimentation, the inventors optimized a gastric-soluble coating material stable under alkaline conditions and determined the optimal amount of coating material, significantly improving the stability of telmisartan-amlodipine tablets while ensuring adequate dissolution. The telmisartan-amlodipine tablets provided by this invention utilize a single-layer tablet manufacturing process, reducing production costs and facilitating large-scale industrial production. Detailed Implementation

[0021] The technical solutions in the embodiments of this application are clearly described below. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0022] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those described, and the objects distinguished by "first," "second," etc., are generally of the same class, without limiting the number of objects; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0023] This application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

[0024] This application provides a telmisartan-amlodipine tablet comprising telmisartan, amlodipine besylate, an alkalizing agent, a binder, a filler, a lubricant, and a flow aid. The tablet is characterized by having an outer coating film around the amlodipine besylate. The coating material is a gastrosoluble coating material stable under alkaline conditions. The weight ratio of the coating material to amlodipine besylate is (1-2.5):1, which can be 1:1, 1.5:1, 2:1, or 2.5:1, but is not limited to these. The alkalizing agent can be sodium hydroxide or meglumine. The binder can be povidone K25, povidone K30, or cross-linked povidone. The flow aid can be silica or dimethicone. The filler can be lactose, corn starch, or microcrystalline cellulose. The lubricant can be magnesium stearate, colloidal silica, or talc, but is not limited to these.

[0025] Preferably, the coating material is one or more of hydroxypropyl methylcellulose, E-series hydroxypropylcellulose, and E-series hydroxypropylcellulose, and the coating material is one or more of E-series hydroxypropylcellulose and E-series hydroxypropylcellulose.

[0026] Preferably, the compound tablets comprise telmisartan, sodium hydroxide, meglumine, crospovidone, amlodipine besylate tablets, dimethicone, lactose, coating material, sorbitol, and magnesium stearate.

[0027] This application also provides a method for preparing telmisartan amlodipine tablets, the specific steps of which are as follows:

[0028] 1) Preparation of telmisartan granules: Telmisartan, alkalizing agent, and binder are dissolved in water to prepare an aqueous solution, which is then spray-dried.

[0029] 2) Preparation of amlodipine besylate granules: Amlodipine besylate was dissolved in a gliding agent, mixed with water, emulsified, and then granulated with a filler to obtain granules. The granules were coated with a coating material solution and dried for later use.

[0030] 3) After mixing telmisartan granules and amlodipine besylate granules, compress them into tablets. In the emulsification step, use a high-shear emulsifier or an ultrasonic mixer for emulsification and dispersion.

[0031] Preferably, the coating material solution is a coating aqueous solution or a coating organic solution.

[0032] This application provides a telmisartan amlodipine tablet with high stability and outstanding dissolution performance.

[0033] The following examples further illustrate the proportions:

[0034] Example 1

[0035] The prescription composition and dosage for 1000 compound tablets are shown in Table 1:

[0036] Table 1. Prescription composition and dosage for Example 1

[0037] Prescription composition Prescription dosage (g) Telmisartan 80 Sodium hydroxide 10 meglumine 12 Cross-linked polyvinylpyrrolidone 5 Amlodipine besylate 5 Dimethicone 5 lactose 80 HPMC 7.5 Sorbitol 336 magnesium stearate 10

[0038] Preparation process:

[0039] (1) Dissolve the prescribed amounts of telmisartan, sodium hydroxide, meglumine and crospovidone in water in sequence to prepare an aqueous solution for later use;

[0040] (2) The above aqueous solution was spray-dried using a spray dryer. The atomizer frequency was set to 450±10Hz, the inlet air temperature to 190℃, the peristaltic pump speed to 5~15rpm, and the outlet air temperature to be controlled at 80~110℃. The material was discharged after spray drying. The telmisartan spray-dried material was passed through an 80-mesh sieve. After sieving, a sample was taken to measure the particle size. The particle size was D90: 50μm~150μm.

[0041] (3) Amlodipine besylate was slowly added to dimethicone to obtain a suspension;

[0042] (4) Add the above suspension to water to prepare a 10wt% amlodipine besylate suspension, and disperse it fully using a high-shear emulsion disperser for later use.

[0043] (5) Weigh the prescribed amount of lactose into a fluidized bed, and use the drug-containing suspension from step (4) to perform fluidized bed granulation and drying; set the air inlet temperature to 60℃, the material temperature to 55℃, and the fan frequency to 15-25Hz. After the material temperature reaches 55℃, stop heating after drying for 40 minutes.

[0044] (6) Add the prescribed amount of HPMC to water to prepare a 10wt% HPMC aqueous solution;

[0045] (7) After the operation in step (5) is completed, the HPMC aqueous solution in step (6) is then sprayed into the fluidized bed to coat and dry the granules prepared in step (5). The granules are discharged when the moisture content is measured to be 3.0%-5.0%. Amlodipine besylate granules are obtained.

[0046] (8) Add the telmisartan granules prepared in step (2), the amlodipine granules prepared in step (7), sorbitol, and magnesium stearate into a mixer and mix evenly.

[0047] (9) Compress the granules prepared in step (8) into tablets to obtain the compound tablets.

[0048] Example 2

[0049] The prescription composition and dosage for 1000 compound tablets are shown in Table 2:

[0050] Table 2. Prescription composition and dosage for Example 2

[0051] Prescription composition Prescription dosage (g) Telmisartan 80 Sodium hydroxide 10 meglumine 12 Cross-linked polyvinylpyrrolidone 5 Amlodipine besylate 5 Dimethicone 5 lactose 80 E100 7.5 Sorbitol 336 magnesium stearate 10

[0052] Preparation process:

[0053] (1) Dissolve the prescribed amounts of telmisartan, sodium hydroxide, meglumine and crospovidone in water in sequence to prepare an aqueous solution for later use;

[0054] (2) The above aqueous solution was spray-dried using a spray dryer. The atomizer frequency was set to 450±10Hz, the inlet air temperature to 190℃, the peristaltic pump speed to 5~15rpm, and the outlet air temperature to be controlled at 80~110℃. The material was discharged after spray drying. The telmisartan spray-dried material was passed through an 80-mesh sieve. After sieving, a sample was taken to measure the particle size. The particle size was D90: 50μm~150μm.

[0055] (3) Amlodipine besylate was slowly added to dimethicone to obtain a suspension;

[0056] (4) Add the above suspension to water to prepare a 10wt% amlodipine besylate suspension, and disperse it fully using a high-shear emulsion disperser for later use.

[0057] (5) Weigh the prescribed amount of lactose into a fluidized bed, and use the drug-containing suspension from step (4) to perform fluidized bed granulation and drying; set the air inlet temperature to 60℃, the material temperature to 55℃, and the fan frequency to 15-25Hz. After the material temperature reaches 55℃, stop heating after drying for 40 minutes.

[0058] (6) Add the prescribed amount of Euclide E100 to ethanol to prepare a 10wt% ethanol solution of Euclide E100.

[0059] (7) After the operation in step (5) is completed, the ethanol solution of E100 in step (6) is continued to be sprayed into the fluidized bed in step (5). At the same time, the air inlet temperature is adjusted to 95°C, the material temperature is 85°C, and the fan frequency is 15-25Hz. After the material temperature reaches 85°C, it is continuously heated. When the ethanol content is measured to be 3.0%-5.0%, the material is discharged to obtain amlodipine besylate granules.

[0060] (8) Add the telmisartan granules prepared in step (2), the amlodipine granules prepared in step (7), sorbitol, and magnesium stearate into a mixer and mix evenly.

[0061] (9) Compress the granules prepared in step (8) into tablets to obtain the compound tablets.

[0062] Example 3

[0063] The prescription composition and dosage for 1000 compound tablets are shown in Table 3:

[0064] Table 3. Prescription composition and dosage for Example 3

[0065]

[0066]

[0067] Preparation process:

[0068] (1) Dissolve the prescribed amounts of telmisartan, sodium hydroxide, meglumine and crospovidone in water in sequence to prepare an aqueous solution for later use;

[0069] (2) The above aqueous solution was spray-dried using a spray dryer. The atomizer frequency was set to 450±10Hz, the inlet air temperature to 190℃, the peristaltic pump speed to 5~15rpm, and the outlet air temperature to be controlled at 80~110℃. The material was discharged after spray drying. The telmisartan spray-dried material was passed through an 80-mesh sieve. After sieving, a sample was taken to measure the particle size. The particle size was D90: 50μm~150μm.

[0070] (3) Amlodipine besylate was slowly added to dimethicone to obtain a suspension;

[0071] (4) Add the above suspension to water to prepare a 10wt% amlodipine besylate suspension, and disperse it fully using a high-shear emulsion disperser for later use.

[0072] (5) Weigh the prescribed amount of lactose into a fluidized bed, and use the drug-containing suspension from step (4) to perform fluidized bed granulation and drying; set the air inlet temperature to 60℃, the material temperature to 55℃, and the fan frequency to 15-25Hz. After the material temperature reaches 55℃, stop heating after drying for 40 minutes.

[0073] (6) Add the prescribed amount of Euclidean EPO to ethanol to prepare a 10wt% ethanol solution of Euclidean EPO;

[0074] (7) After the operation in step (5) is completed, the ethanol solution of EPO in step (6) is continued to be sprayed into the fluidized bed in step (5). At the same time, the air inlet temperature is adjusted to 95°C, the material temperature is 85°C, and the fan frequency is 15-25Hz. After the material temperature reaches 85°C, it is continuously heated. When the ethanol content is measured to be 3.0%-5.0%, the material is discharged to obtain amlodipine besylate granules.

[0075] (8) Add the telmisartan granules prepared in step (2), the amlodipine granules prepared in step (7), sorbitol, and magnesium stearate into a mixer and mix evenly.

[0076] (9) Compress the granules prepared in step (8) into tablets to obtain the compound tablets.

[0077] Example 4

[0078] The prescription composition and dosage for 1000 compound tablets are shown in Table 4:

[0079] Table 4. Prescription composition and dosage for Example 4

[0080] Prescription composition Prescription dosage (g) Telmisartan 80 Sodium hydroxide 10 meglumine 12 Cross-linked polyvinylpyrrolidone 5 Amlodipine besylate 5 Dimethicone 5 lactose 80 HPC 7.5 Sorbitol 336 magnesium stearate 10

[0081] Preparation process:

[0082] (1) Dissolve the prescribed amounts of telmisartan, sodium hydroxide, meglumine and crospovidone in water in sequence to prepare an aqueous solution for later use;

[0083] (2) The above aqueous solution was spray-dried using a spray dryer. The atomizer frequency was set to 450±10Hz, the inlet air temperature to 190℃, the peristaltic pump speed to 5~15rpm, and the outlet air temperature to be controlled at 80~110℃. The material was discharged after spray drying. The telmisartan spray-dried material was passed through an 80-mesh sieve. After sieving, a sample was taken to measure the particle size. The particle size was D90: 50μm~150μm.

[0084] (3) Amlodipine besylate was slowly added to dimethicone to obtain a suspension;

[0085] (4) Add the above suspension to water to prepare a 10wt% amlodipine besylate suspension, and disperse it fully using a high-shear emulsion disperser for later use.

[0086] (5) Weigh the prescribed amount of lactose into a fluidized bed, and use the drug-containing suspension from step (4) to perform fluidized bed granulation and drying; set the air inlet temperature to 60℃, the material temperature to 55℃, and the fan frequency to 15-25Hz. After the material temperature reaches 55℃, stop heating after drying for 40 minutes.

[0087] (6) Add the prescribed amount of HPC to ethanol to prepare a 10wt% HPC ethanol solution;

[0088] (7) After the operation in step (5) is completed, the ethanol solution of HPC in step (6) is then sprayed into the fluidized bed in step (5). At the same time, the air inlet temperature is adjusted to 95°C, the material temperature is 85°C, and the fan frequency is 15-25Hz. After the material temperature reaches 85°C, the heating continues. When the ethanol content is measured to be 3.0%-5.0%, the material is discharged to obtain amlodipine besylate granules.

[0089] (8) Add the telmisartan granules prepared in step (2), the amlodipine granules prepared in step (7), sorbitol, and magnesium stearate into a mixer and mix evenly.

[0090] (9) Compress the granules prepared in step (8) into tablets to obtain the compound tablets.

[0091] Example 5

[0092] The prescription composition and dosage for 1000 compound tablets are shown in Table 5:

[0093] Table 5. Prescription composition and dosage for Example 5

[0094] Prescription composition Prescription dosage (g) Telmisartan 80 Sodium hydroxide 10 meglumine 12 Cross-linked polyvinylpyrrolidone 5 Amlodipine besylate 5 Dimethicone 5 lactose 80 HPMC 5 Sorbitol 336 magnesium stearate 10

[0095] Preparation process:

[0096] (1) Dissolve the prescribed amounts of telmisartan, sodium hydroxide, meglumine and crospovidone in water in sequence to prepare an aqueous solution for later use;

[0097] (2) The above aqueous solution was spray-dried using a spray dryer. The atomizer frequency was set to 450±10Hz, the inlet air temperature to 190℃, the peristaltic pump speed to 5~15rpm, and the outlet air temperature to be controlled at 80~110℃. The material was discharged after spray drying. The telmisartan spray-dried material was passed through an 80-mesh sieve. After sieving, a sample was taken to measure the particle size. The particle size was D90: 50μm~150μm.

[0098] (3) Amlodipine besylate was slowly added to dimethicone to obtain a suspension;

[0099] (4) Add the above suspension to water to prepare a 10wt% amlodipine besylate suspension, and disperse it fully using a high-shear emulsion disperser for later use.

[0100] (5) Weigh the prescribed amount of lactose into a fluidized bed, and use the drug-containing suspension from step (4) to perform fluidized bed granulation and drying; set the air inlet temperature to 60℃, the material temperature to 55℃, and the fan frequency to 15-25Hz. After the material temperature reaches 55℃, stop heating after drying for 40 minutes.

[0101] (6) Add the prescribed amount of HPMC to water to prepare a 10wt% HPMC aqueous solution;

[0102] (7) After the operation in step (5) is completed, the HPMC aqueous solution in step (6) is then sprayed into the fluidized bed to coat and dry the granules prepared in step (5). The granules are discharged when the moisture content is measured to be 3.0%-5.0%. Amlodipine besylate granules are obtained.

[0103] (8) Add the telmisartan granules prepared in step (2), the amlodipine granules prepared in step (7), sorbitol, and magnesium stearate into a mixer and mix evenly.

[0104] (9) Compress the granules prepared in step (8) into tablets to obtain the compound tablets.

[0105] Example 6

[0106] The prescription composition and dosage for 1000 compound tablets are shown in Table 6:

[0107] Table 6. Prescription composition and dosage for Example 6

[0108] Prescription composition Prescription dosage (g) Telmisartan 80 Sodium hydroxide 10 meglumine 12 Cross-linked polyvinylpyrrolidone 5 Amlodipine besylate 5.0 Dimethicone 5 lactose 80 HPMC 12.5 Sorbitol 336 magnesium stearate 10

[0109] Preparation process:

[0110] (1) Dissolve the prescribed amounts of telmisartan, sodium hydroxide, meglumine and crospovidone in water in sequence to prepare an aqueous solution for later use;

[0111] (2) The above aqueous solution was spray-dried using a spray dryer. The atomizer frequency was set to 450±10Hz, the inlet air temperature to 190℃, the peristaltic pump speed to 5~15rpm, and the outlet air temperature to be controlled at 80~110℃. The material was discharged after spray drying. The telmisartan spray-dried material was passed through an 80-mesh sieve. After sieving, a sample was taken to measure the particle size. The particle size was D90: 50μm~150μm.

[0112] (3) Amlodipine besylate was slowly added to dimethicone to obtain a suspension;

[0113] (4) Add the above suspension to water to prepare a 10wt% amlodipine besylate suspension, and disperse it fully using a high-shear emulsion disperser for later use.

[0114] (5) Weigh the prescribed amount of lactose into a fluidized bed, and use the drug-containing suspension from step (4) to perform fluidized bed granulation and drying; set the air inlet temperature to 60℃, the material temperature to 55℃, and the fan frequency to 15-25Hz. After the material temperature reaches 55℃, stop heating after drying for 40 minutes.

[0115] (6) Add the prescribed amount of HPMC to water to prepare a 10wt% HPMC aqueous solution;

[0116] (7) After the operation in step (5) is completed, the HPMC aqueous solution in step (6) is then sprayed into the fluidized bed to coat and dry the granules prepared in step (5). The granules are discharged when the moisture content is measured to be 3.0%-5.0%. Amlodipine besylate granules are obtained.

[0117] (8) Add the telmisartan granules prepared in step (2), the amlodipine granules prepared in step (7), sorbitol, and magnesium stearate into a mixer and mix evenly.

[0118] (9) Compress the granules prepared in step (8) into tablets to obtain the compound tablets.

[0119] Comparative Example 1

[0120] The prescription composition and dosage for 1000 compound tablets are shown in Table 7:

[0121] Table 7. Prescription composition and dosage for Comparative Example 1

[0122]

[0123]

[0124] Preparation process:

[0125] (1) Dissolve the prescribed amounts of telmisartan, sodium hydroxide, meglumine and crospovidone in water in sequence to prepare an aqueous solution for later use;

[0126] (2) The above aqueous solution was spray-dried using a spray dryer. The atomizer frequency was set to 450±10Hz, the inlet air temperature to 190℃, the peristaltic pump speed to 5~15rpm, and the outlet air temperature to be controlled at 80~110℃. The material was discharged after spray drying. The telmisartan spray-dried material was passed through an 80-mesh sieve. After sieving, a sample was taken to measure the particle size. The particle size was D90: 50μm~150μm.

[0127] (3) Amlodipine besylate was slowly added to dimethicone to obtain a suspension;

[0128] (4) Add the above suspension to water to prepare a 10wt% amlodipine besylate suspension, and disperse it fully using a high-shear emulsion disperser for later use.

[0129] (5) Weigh the prescribed amount of lactose into a fluidized bed, and use the drug-containing suspension from step (4) to perform fluidized bed granulation and drying; set the air inlet temperature to 60℃, the material temperature to 55℃, and the fan frequency to 15-25Hz. After the material temperature reaches 55℃, stop heating after drying for 40 minutes.

[0130] (6) Add the prescribed amount of chitosan to water to prepare a 10wt% chitosan aqueous solution;

[0131] (7) After the operation in step (5) is completed, the chitosan aqueous solution in step (6) is then sprayed into the fluidized bed to coat and dry the granules prepared in step (5). The granules are discharged when the moisture content is measured to be 3.0%-5.0%. Amlodipine besylate granules are obtained.

[0132] (8) Add the telmisartan granules prepared in step (2), the amlodipine granules prepared in step (7), sorbitol, and magnesium stearate into a mixer and mix evenly.

[0133] (9) Compress the granules prepared in step (8) into tablets to obtain the compound tablets.

[0134] Comparative Example 2

[0135] The prescription composition and dosage for 1000 compound tablets are shown in Table 8:

[0136] Table 8. Prescription composition and dosage for Comparative Example 2

[0137]

[0138]

[0139] Preparation process:

[0140] (1) Dissolve the prescribed amounts of telmisartan, sodium hydroxide, meglumine and crospovidone in water in sequence to prepare an aqueous solution for later use;

[0141] (2) The above aqueous solution was spray-dried using a spray dryer. The atomizer frequency was set to 450±10Hz, the inlet air temperature to 190℃, the peristaltic pump speed to 5~15rpm, and the outlet air temperature to be controlled at 80~110℃. The material was discharged after spray drying. The telmisartan spray-dried material was passed through an 80-mesh sieve. After sieving, a sample was taken to measure the particle size. The particle size was D90: 50μm~150μm.

[0142] (3) Amlodipine besylate was slowly added to dimethicone to obtain a suspension;

[0143] (4) Add the above suspension to water to prepare a 10wt% amlodipine besylate suspension, and disperse it fully using a high-shear emulsion disperser for later use.

[0144] (5) Weigh the prescribed amount of lactose into a fluidized bed, and use the drug-containing suspension from step (4) to perform fluidized bed granulation and drying; set the air inlet temperature to 60℃, the material temperature to 55℃, and the fan frequency to 15-25Hz. After the material temperature reaches 55℃, stop heating after drying for 40 minutes.

[0145] (6) Add the prescribed amount of EC to ethanol to prepare a 10 wt% ethanol solution of EC;

[0146] (7) After the operation in step (5) is completed, the ethanol solution of EC in step (6) is then sprayed into the fluidized bed in step (5). At the same time, the air inlet temperature is adjusted to 95°C, the material temperature is 85°C, and the fan frequency is 15-25Hz. After the material temperature reaches 85°C, heating is continued. When the ethanol content is measured to be 3.0%-5.0%, the material is discharged to obtain amlodipine besylate granules.

[0147] (8) Add the telmisartan granules prepared in step (2), the amlodipine granules prepared in step (7), sorbitol, and magnesium stearate into a mixer and mix evenly.

[0148] (9) Compress the granules prepared in step (8) into tablets to obtain the compound tablets.

[0149] Comparative Example 3

[0150] The prescription composition and dosage for 1000 compound tablets are shown in Table 9:

[0151] Table 9. Prescription composition and dosage for Comparative Example 3

[0152] Prescription composition Prescription dosage (g) Telmisartan 80 Sodium hydroxide 10 meglumine 12 Cross-linked polyvinylpyrrolidone 5 Amlodipine besylate 5 Dimethicone 5 lactose 80 Yuqite L100 7.5 Sorbitol 336 magnesium stearate 10

[0153] Preparation process:

[0154] (1) Dissolve the prescribed amounts of telmisartan, sodium hydroxide, meglumine and crospovidone in water in sequence to prepare an aqueous solution for later use;

[0155] (2) The above aqueous solution was spray-dried using a spray dryer. The atomizer frequency was set to 450±10Hz, the inlet air temperature to 190℃, the peristaltic pump speed to 5~15rpm, and the outlet air temperature to be controlled at 80~110℃. The material was discharged after spray drying. The telmisartan spray-dried material was passed through an 80-mesh sieve. After sieving, a sample was taken to measure the particle size. The particle size was D90: 50μm~150μm.

[0156] (3) Amlodipine besylate was slowly added to dimethicone to obtain a suspension;

[0157] (4) Add the above suspension to water to prepare a 10wt% amlodipine besylate suspension, and disperse it fully using a high-shear emulsion disperser for later use.

[0158] (5) Weigh the prescribed amount of lactose into a fluidized bed, and use the drug-containing suspension from step (4) to perform fluidized bed granulation and drying; set the air inlet temperature to 60℃, the material temperature to 55℃, and the fan frequency to 15-25Hz. After the material temperature reaches 55℃, stop heating after drying for 40 minutes.

[0159] (6) Add the prescribed amount of Euclide L100 to ethanol to prepare a 10wt% ethanol solution of Euclide L100.

[0160] (7) After the operation in step (5) is completed, the ethanol solution of Yuqite L100 in step (6) is then sprayed into the fluidized bed in step (5). At the same time, the air inlet temperature is adjusted to 95°C, the material temperature is 85°C, and the fan frequency is 15-25Hz. After the material temperature reaches 85°C, the heating continues. When the ethanol content is measured to be 3.0%-5.0%, the material is discharged to obtain amlodipine besylate granules.

[0161] (8) Add the telmisartan granules prepared in step (2), the amlodipine granules prepared in step (7), sorbitol, and magnesium stearate into a mixer and mix evenly.

[0162] (9) Compress the granules prepared in step (8) into tablets to obtain the compound tablets.

[0163] Comparative Example 4

[0164] The prescription composition and dosage for 1000 compound tablets are shown in Table 10:

[0165] Table 10: Prescription composition and dosage for Comparative Example 4

[0166] Prescription composition Prescription dosage (g) Telmisartan 80 Sodium hydroxide 10 meglumine 12 Cross-linked polyvinylpyrrolidone 5 Amlodipine besylate 5 Dimethicone 5 lactose 80 Uqite S100 7.5 Sorbitol 336 magnesium stearate 10

[0167] Preparation process:

[0168] (1) Dissolve the prescribed amounts of telmisartan, sodium hydroxide, meglumine and crospovidone in water in sequence to prepare an aqueous solution for later use;

[0169] (2) The above aqueous solution was spray-dried using a spray dryer. The atomizer frequency was set to 450±10Hz, the inlet air temperature to 190℃, the peristaltic pump speed to 5~15rpm, and the outlet air temperature to be controlled at 80~110℃. The material was discharged after spray drying. The telmisartan spray-dried material was passed through an 80-mesh sieve. After sieving, a sample was taken to measure the particle size. The particle size was D90: 50μm~150μm.

[0170] (3) Amlodipine besylate was slowly added to dimethicone to obtain a suspension;

[0171] (4) Add the above suspension to water to prepare a 10wt% amlodipine besylate suspension, and disperse it fully using a high-shear emulsion disperser for later use.

[0172] (5) Weigh the prescribed amount of lactose into a fluidized bed, and use the drug-containing suspension from step (4) to perform fluidized bed granulation and drying; set the air inlet temperature to 60℃, the material temperature to 55℃, and the fan frequency to 15-25Hz. After the material temperature reaches 55℃, stop heating after drying for 40 minutes.

[0173] (6) Add the prescribed amount of Euclide S100 to ethanol to prepare a 10wt% ethanol solution of Euclide S100.

[0174] (7) After the operation in step (5) is completed, the ethanol solution of Yuqite S100 in step (6) is then sprayed into the fluidized bed in step (5). At the same time, the air inlet temperature is adjusted to 95°C, the material temperature is 85°C, and the fan frequency is 15-25Hz. After the material temperature reaches 85°C, heating is continued. When the ethanol content is measured to be 3.0%-5.0%, the material is discharged to obtain amlodipine benzylsulfonate granules.

[0175] (8) Add the telmisartan granules prepared in step (2), the amlodipine granules prepared in step (7), sorbitol, and magnesium stearate into a mixer and mix evenly.

[0176] (9) Compress the granules prepared in step (8) into tablets to obtain the compound tablets.

[0177] Comparative Example 5

[0178] The prescription composition and dosage for 1000 compound tablets are shown in Table 11:

[0179] Table 11. Prescription composition and dosage for Comparative Example 5

[0180]

[0181]

[0182] Preparation process:

[0183] (1) Dissolve the prescribed amounts of telmisartan, sodium hydroxide, meglumine and crospovidone in water in sequence to prepare an aqueous solution for later use;

[0184] (2) The above aqueous solution was spray-dried using a spray dryer. The atomizer frequency was set to 450±10Hz, the inlet air temperature to 190℃, the peristaltic pump speed to 5~15rpm, and the outlet air temperature to be controlled at 80~110℃. The material was discharged after spray drying. The telmisartan spray-dried material was passed through an 80-mesh sieve. After sieving, a sample was taken to measure the particle size. The particle size was D90: 50μm~150μm.

[0185] (3) Amlodipine besylate was slowly added to dimethicone to obtain a suspension;

[0186] (4) Add the above suspension to water to prepare a 10wt% amlodipine besylate suspension, and disperse it fully using a high-shear emulsion disperser for later use.

[0187] (5) Weigh the prescribed amount of lactose into a fluidized bed, and use the drug-containing suspension from step (4) to perform fluidized bed granulation and drying; set the air inlet temperature to 60℃, the material temperature to 55℃, and the fan frequency to 15-25Hz. After the material temperature reaches 55℃, stop heating after drying for 40 minutes.

[0188] (6) Add the prescribed amount of HPMC to water to prepare a 10wt% HPMC aqueous solution;

[0189] (7) After the operation in step (5) is completed, the HPMC aqueous solution in step (6) is then sprayed into the fluidized bed to coat and dry the granules prepared in step (5). The granules are discharged when the moisture content is measured to be 3.0%-5.0%. Amlodipine besylate granules are obtained.

[0190] (8) Add the telmisartan granules prepared in step (2), the amlodipine granules prepared in step (7), sorbitol, and magnesium stearate into a mixer and mix evenly.

[0191] (9) Compress the granules prepared in step (8) into tablets to obtain the compound tablets.

[0192] Comparative Example 6

[0193] The prescription composition and dosage for 1000 compound tablets are shown in Table 12:

[0194] Table 12 shows the prescription composition and dosage for Comparative Example 6.

[0195] Prescription composition Prescription dosage (g) Telmisartan 80 Sodium hydroxide 10 meglumine 12 Cross-linked polyvinylpyrrolidone 5 Amlodipine besylate 5 Dimethicone 5 lactose 80 HPMC 13.5 Sorbitol 336 magnesium stearate 10

[0196] Preparation process:

[0197] (1) Dissolve the prescribed amounts of telmisartan, sodium hydroxide, meglumine and crospovidone in water in sequence to prepare an aqueous solution for later use;

[0198] (2) The above aqueous solution was spray-dried using a spray dryer. The atomizer frequency was set to 450±10Hz, the inlet air temperature to 190℃, the peristaltic pump speed to 5~15rpm, and the outlet air temperature to be controlled at 80~110℃. The material was discharged after spray drying. The telmisartan spray-dried material was passed through an 80-mesh sieve. After sieving, a sample was taken to measure the particle size. The particle size was D90: 50μm~150μm.

[0199] (3) Amlodipine besylate was slowly added to dimethicone to obtain a suspension;

[0200] (4) Add the above suspension to water to prepare a 10wt% amlodipine besylate suspension, and disperse it fully using a high-shear emulsion disperser for later use.

[0201] (5) Weigh the prescribed amount of lactose into a fluidized bed, and use the drug-containing suspension from step (4) to perform fluidized bed granulation and drying; set the air inlet temperature to 60℃, the material temperature to 55℃, and the fan frequency to 15-25Hz. After the material temperature reaches 55℃, stop heating after drying for 40 minutes.

[0202] (6) Add the prescribed amount of HPMC to water to prepare a 10wt% HPMC aqueous solution;

[0203] (7) After the operation in step (5) is completed, the HPMC aqueous solution in step (6) is then sprayed into the fluidized bed to coat and dry the granules prepared in step (5). The granules are discharged when the moisture content is measured to be 3.0%-5.0%. Amlodipine besylate granules are obtained.

[0204] (8) Add the telmisartan granules prepared in step (2), the amlodipine granules prepared in step (7), sorbitol, and magnesium stearate into a mixer and mix evenly.

[0205] (9) Compress the granules prepared in step (8) into tablets to obtain the compound tablets.

[0206] The experimental variables set for each embodiment are shown in Table 13.

[0207] Table 13 Experimental variables set for each embodiment's comparative model

[0208]

[0209] The dissolution performance of the compound tablets prepared in Examples 1-6 and Comparative Examples 1-6 was tested:

[0210] According to the 2020 edition of the Chinese Pharmacopoeia (General Chapter 0931), the dissolution % of telmisartan and amlodipine in the compound tablets of each example and comparative example, as well as the reference preparation (purchased from Boehringer Ingelheim International GmbH, specification 80mg / 5mg) were tested. The specific method is as follows: slurry method at 50 r / min, dissolution medium is 500 mL of 0.01 mol / L HCl solution with a pH of 2.0. The cumulative dissolution of telmisartan and amlodipine was determined at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min, respectively. The test results are shown in Tables 14 and 15.

[0211] Table 14. Dissolution determination of telmisartan in 0.01 mol / L HCl solution at pH 2.0

[0212]

[0213]

[0214] Table 15. Dissolution determination of amlodipine in 0.01 mol / L HCl solution at pH 2.0

[0215]

[0216] Observing Tables 14 and 15, the following conclusions can be drawn:

[0217] As can be seen from Table 14, the dissolution rate of telmisartan in the compound tablets prepared in Examples 1-6 and Comparative Examples 1-6 is similar to that in the reference. Therefore, the type and amount of coating material of amlodipine have little effect on the dissolution rate of telmisartan in the compound tablets.

[0218] As shown in Table 15, the dissolution rate of amlodipine in the compound tablets prepared in Examples 1-4 was similar to that of the reference, while the dissolution rate of amlodipine in the compound tablets prepared in Comparative Examples 1-4 was not similar. The dissolution rate of amlodipine in the compound tablets prepared in Examples 5-6 was similar to that of the reference, while the dissolution rate of amlodipine in the compound tablets prepared in Comparative Examples 5-6 was not similar. Therefore, the type and amount of coating material of amlodipine have a significant impact on the dissolution rate of amlodipine in the compound tablets. When the coating material of amlodipine is a gastric-soluble coating material that is chemically stable under alkaline conditions, and the ratio of the amount of coating material to the amount of amlodipine is (1-2.5):1, the dissolution rate of amlodipine in the prepared compound tablets is better.

[0219] Accelerated stability tests were conducted on the compound tablets of each embodiment and comparative example at 40°C and 75% RH. The contents of telmisartan and amlodipine-related substances were determined at 0 days, 30 days and 60 days, respectively. The test results are shown in Table 17.

[0220] Table 17 Accelerated test results of the compound tablets in each embodiment and comparative example.

[0221]

[0222]

[0223] From observing Table 17, the following conclusions can be drawn:

[0224] The related substances of telmisartan, including single impurities and total impurities, were observed in the compound tablets prepared in Examples 1-6 and Comparative Examples 1-6 after being placed under high temperature and high humidity conditions for 30 days and 60 days. After 60 days of storage, the changes in the related substances of telmisartan in the compound tablets prepared in Examples 1-6 and Comparative Examples 1-6 were still relatively small, indicating that the stability of telmisartan in the compound tablets of the examples and comparative examples was good. Therefore, the choice of coating material for amlodipine in the compound tablets and the amount of coating material have little impact on the stability of telmisartan in the compound tablets.

[0225] The related substances of amlodipine, including single impurities and total impurities, were observed after the compound tablets prepared in Examples 1-6 and Comparative Examples 1-6 were placed under high temperature and high humidity conditions for 30 days and 60 days. The changes in related substances of amlodipine in the compound tablets prepared in Examples 1-4 were relatively small after 60 days of placement under high temperature and high humidity conditions; however, the changes in related substances of amlodipine in the compound tablets prepared in Comparative Examples 1-4 were larger after 60 days of placement under high temperature and high humidity conditions, and at 60 days, the related substances of amlodipine in the compound tablets all exceeded the standard limits. This indicates that the choice of coating material for amlodipine in the compound tablets has a significant impact on the stability of amlodipine. Compound tablets prepared using a gastric-soluble coating material that is stable under alkaline conditions exhibit better stability of amlodipine. After being placed under high temperature and high humidity conditions for 60 days, the compound tablets prepared in Examples 5 and 6 showed relatively small changes in the amount of amlodipine-related substances. However, after being placed under high temperature and high humidity conditions for 60 days, the compound tablets prepared in Comparative Examples 5 and 6 showed larger changes in the amount of amlodipine-related substances. Moreover, after 60 days, the amount of amlodipine-related substances in the compound tablets exceeded the standard limits. It can be seen that the amount of coating material used for amlodipine has a significant impact on the stability of amlodipine in the compound tablets. When the ratio of the amount of amlodipine coating material to the amount of amlodipine is (1-2.5):1, the stability of amlodipine in the prepared compound tablets is better.

[0226] It is understood that the above embodiments are merely exemplary implementations used to illustrate the principles of this application, and this application is not limited thereto. For those skilled in the art, various modifications and improvements can be made without departing from the spirit and substance of this application, and these modifications and improvements are also considered to be within the scope of protection of this invention.

Claims

1. A compound tablet for treating hypertension, comprising telmisartan, amlodipine besylate, an alkalizing agent, a binder, a filler, a lubricant, and a flow aid, characterized in that, include: The amlodipine besylate is coated with a film, and the coating material of the film is a gastric-soluble coating material that is stable under alkaline conditions. The weight ratio of the coating material to amlodipine besylate is (1-2.5):

1.

2. The compound tablet for treating hypertension according to claim 1, characterized in that, The coating material is one or more of hydroxypropyl methylcellulose, E-series hydroxypropylcellulose, and hydroxypropyl methylcellulose.

3. The compound tablet for treating hypertension according to claim 1, characterized in that, The coating material is one or more of Euclidean E100 and Euclidean EPO.

4. The compound tablet for treating hypertension according to claim 1, characterized in that, The weight ratio of the coating material to amlodipine besylate is (1.5-2):

1.

5. A compound tablet for treating hypertension according to claim 1, characterized in that, The weight ratio of the coating material to amlodipine besylate is 1.5:

1.

6. A compound tablet for treating hypertension according to claim 1, characterized in that, The compound tablets include telmisartan, sodium hydroxide, meglumine, crospovidone, amlodipine besylate tablets, dimethicone, lactose, coating material, sorbitol, and magnesium stearate.

7. A compound tablet for treating hypertension according to claim 1, characterized in that, The compound tablets are single-layer tablets.

8. A compound tablet for treating hypertension according to any one of claims 1 to 7, wherein the preparation method comprises the following steps: The preparation method of the telmisartan amlodipine monolayer tablets includes the following steps: 1) Preparation of telmisartan granules: Telmisartan, alkalizing agent, and binder are dissolved in water to prepare an aqueous solution, which is then spray-dried. 2) Preparation of amlodipine besylate granules: Amlodipine besylate was dissolved in a gliding agent, mixed with water, emulsified, and then granulated with a filler to obtain granules. The granules were coated with a coating material solution and dried for later use. 3) After mixing telmisartan granules and amlodipine besylate granules, compress them into tablets. In the emulsification step, use a high-shear emulsifier or an ultrasonic mixer for emulsification and dispersion.

9. The method for preparing a compound tablet for treating hypertension according to claim 8, characterized in that, The coating material solution is either an aqueous coating solution or an organic coating solution.

Images