A bilayer tablet for treating hypertension and a preparation method thereof

Abstract

This application discloses a telmisartan-amlodipine bilayer tablet. The telmisartan layer comprises telmisartan, an alkaline reagent, a binder, a filler, and a lubricant; the amlodipine layer comprises amlodipine besylate, a diluent, a disintegrant, a flow aid, a colorant, and a lubricant. The binder for the telmisartan layer is povidone, with a weight-average molecular weight of 3000–6000 kDa. The diluent for the amlodipine layer is microcrystalline cellulose, specifically a blend of two types. The weight ratio of microcrystalline cellulose PH-102 to PH-302 is 1–4:1–4. The povidone is one or both of povidone K-25 and K-29 / 32. The telmisartan-amlodipine bilayer tablet provided in this application exhibits high stability and dissolution performance similar to the reference tablet.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology, specifically relating to a method for preparing telmisartan amlodipine bilayer tablets (40mg). Background Technology

[0002] Telmisartan is an angiotensin II receptor blocker (ARB) with a potent and long-lasting antihypertensive effect; amlodipine is a dihydropyridine calcium channel blocker (CCB) that also has a significant antihypertensive effect. The combined use of these two drugs is expected to achieve a potent and stable antihypertensive effect for 24 hours. However, due to the poor solubility of telmisartan and the instability of amlodipine in alkaline environments, there are many challenges in preparing the combination formulation.

[0003] The stability of telmisartan and amlodipine, as active ingredients, is a primary concern in drug formulations. It is essential to ensure that these two components do not degrade or interact during storage and use, thereby affecting the efficacy and safety of the drug. Furthermore, the formulation and manufacturing process also significantly impact drug stability; therefore, optimizing the formulation and manufacturing process is necessary to improve the physical and chemical stability of the drug, ensuring stable efficacy and safety throughout its shelf life.

[0004] During the drug development process, the salt formed after telmisartan reacts with an alkaline substance contains a carboxylate ion (-COO-). - Telmisartan combines with cations of basic substances (such as Na+, meglumine cations, etc.) to form soluble ionic compounds. This ionization makes telmisartan molecules, which are normally poorly soluble in water, readily soluble. Its solubility not only affects the bioavailability and therapeutic effect of the drug but is also closely related to its stability and safety. Therefore, the research and quantification of its solubility should be given full attention during drug development and manufacturing.

[0005] Patent document (CN107519144A) discloses a telmisartan-amlodipine bilayer tablet and its preparation method. In this method, amlodipine besylate is mixed with microcrystalline cellulose 101 to obtain amlodipine granules during the preparation of the amlodipine layer particles. Then, telmisartan particles are taken, and meglumine, magnesium stearate, and amlodipine particles are added. The mixture is then compressed into bilayer tablets using a bilayer tablet press to obtain telmisartan-amlodipine bilayer tablets. Although this method can reasonably control the influence of sorbitol particles on the telmisartan content, thereby improving the effective utilization rate of telmisartan, its stability is poor, and there are also problems with dissolution consistency. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing telmisartan-amlodipine bilayer tablets. By optimizing the compounding of different types of excipients, the performance of telmisartan-amlodipine bilayer tablets is improved. Specifically, by examining the selection of excipients in amlodipine, the inventors unexpectedly discovered that by selecting specific excipients and compounding them, the problems of inconsistent dissolution and stability of telmisartan-amlodipine bilayer tablets can be effectively solved, making it suitable for large-scale industrial production.

[0007] This application provides a telmisartan-amlodipine bilayer tablet. The telmisartan layer comprises telmisartan, an alkaline reagent, a binder, a filler, and a lubricant; the amlodipine layer comprises amlodipine besylate, a diluent, a disintegrant, a flow aid, a colorant, and a lubricant. The telmisartan layer's binder is povidone, with a weight-average molecular weight of 3000–6000 kDa. The amlodipine layer's diluent is microcrystalline cellulose, which is a blend of two types of microcrystalline cellulose.

[0008] Preferably, the microcrystalline cellulose is a compound of microcrystalline cellulose PH-102 and microcrystalline cellulose PH-302, and the weight ratio of microcrystalline cellulose PH-102 to microcrystalline cellulose PH-302 is 1-4:1-4.

[0009] Preferably, the polyvinylpyrrolidone is one or both of polyvinylpyrrolidone K-25 and K-29 / 32.

[0010] Preferably, the telmisartan-amlodipine bilayer tablets comprise the following components: telmisartan, sodium hydroxide, povidone, meglumine, sorbitol, magnesium stearate, talc, amlodipine besylate, microcrystalline cellulose PH-101, pregelatinized starch, corn starch, and colloidal silica; the povidone is povidone K-25 or povidone K-29 / 32; and the microcrystalline cellulose is PH-101 or PH-302.

[0011] Preferably, the telmisartan-amlodipine bilayer tablets comprise, by weight percentage, the following components:

[0012] Telmisartan layer: 16.7% telmisartan, 1.2-1.7% sodium hydroxide, 4-6% povidone, 4-6% meglumine, 65-75% sorbitol, 0-1.8% magnesium stearate, 0-1.0% talc;

[0013] Amlodipine layer: 3.47% amlodipine benzylsulfonate, 60-70% microcrystalline cellulose, 22-28% pregelatinized starch, 2-8% corn starch, 2-8% colloidal silica.

[0014] Preferably, the weight ratio of microcrystalline cellulose PH-102 to microcrystalline cellulose PH-302 is 1-3:1-3.

[0015] Preferably, the weight ratio of microcrystalline cellulose PH-102 to microcrystalline cellulose PH-302 is 1:1.

[0016] This application also provides a method for preparing telmisartan-amlodipine bilayer tablets, including the following steps:

[0017] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0018] (1) Add the prescribed amount of alkaline reagent, telmisartan, and binder to water and stir until dissolved;

[0019] (2) The above solution was spray-dried and granulated to obtain telmisartan complex;

[0020] (3) Mix the telmisartan complex with the filler evenly;

[0021] (4) Add lubricant and continue mixing to obtain telmisartan layer total mixed particles;

[0022] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0023] (1) Mix the gliding agent with a small amount of diluent, crush and sieve, and then rinse with the remaining amount of diluent to obtain the premix;

[0024] (2) Mix the premix, amlodipine besylate, disintegrant and 50% of the prescribed amount of lubricant evenly to obtain a mixture;

[0025] (3) The mixture is dry granulated to obtain drug-containing granules.

[0026] (4) Add the remaining amount of lubricant to the drug-containing granules and continue to mix evenly to obtain amlodipine total mixed granules;

[0027] Step S3: Pressing of the double-layer film.

[0028] Preferably, the method for preparing the telmisartan-amlodipine bilayer tablets includes the following steps:

[0029] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0030] (1) Add the prescribed amounts of sodium hydroxide, telmisartan, povidone K-29 / 32 and meglumine to water in sequence, and stir until dissolved;

[0031] (2) The above solution was spray-dried and granulated to obtain telmisartan complex;

[0032] (3) Mix the telmisartan complex with sorbitol until homogeneous;

[0033] (4) Add the prescribed amount of magnesium stearate and talc powder, continue mixing, and obtain telmisartan total mixed particles;

[0034] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0035] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-302), and pass it through a 0.8mm sieve at high speed using a pulverizer and granulator. Then wash it with the remaining amount of microcrystalline cellulose in the prescription to obtain the pigment premix.

[0036] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture;

[0037] (3) The mixture is granulated by dry method with a feeding speed of 3-7 rpm, a roller pressing speed of 4-6 rpm, a roller pressing pressure of 35-55 bar, and a granulation screen of 18 mesh to obtain drug-containing granules.

[0038] (4) Add the remaining amount of magnesium stearate to the drug-containing granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0039] Step S3: Pressing of the double-layer film.

[0040] Beneficial effects:

[0041] In tablet manufacturing, selecting a suitable thickener is crucial for ensuring the stability and dissolution performance of the tablets. Povidone, in particular, has strong hygroscopic properties, which can cause the tablets to absorb moisture, thus affecting the stability and dissolution performance of the drug. Through extensive experiments, the inventors discovered that using povidone with a weight-average molecular weight of 3000–6000 kDa resulted in telmisartan-amlodipine bilayer tablets with high stability while maintaining good dissolution performance. Furthermore, experimental data showed that changing the type and ratio of microcrystalline cellulose also altered the stability and dissolution performance of the telmisartan-amlodipine bilayer tablets. Therefore, this invention, by optimizing the molecular weight of the povidone in the telmisartan layer and the type and ratio of the microcrystalline cellulose in the amlodipine layer, prepared a telmisartan-amlodipine bilayer tablet with high stability and dissolution performance similar to a reference. Detailed Implementation

[0042] The technical solutions in the embodiments of this application will be 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.

[0043] 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 use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; 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.

[0044] This application provides a telmisartan-amlodipine bilayer tablet. The telmisartan layer comprises telmisartan, an alkaline reagent, a binder, a filler, and a lubricant; the amlodipine layer comprises amlodipine besylate, a diluent, a disintegrant, a flow aid, a colorant, and a lubricant. The binder for the telmisartan layer is povidone, with a weight-average molecular weight of 3000–6000 kDa. The diluent for the amlodipine layer is microcrystalline cellulose, which is a blend of two types of microcrystalline cellulose. The weight ratio of microcrystalline cellulose PH-102 to microcrystalline cellulose PH-302 is 1–4:1–4, and can be 1:4, 1:1, 2:1, 3:1, or 4:1. The povidone is one or both of povidone K-25 and K-29 / 32.

[0045] In one specific embodiment of the present invention, the telmisartan-amlodipine bilayer tablet comprises the following components: telmisartan, sodium hydroxide, povidone, meglumine, sorbitol, magnesium stearate, talc, amlodipine besylate, microcrystalline cellulose PH-101, pregelatinized starch, corn starch, and colloidal silica; wherein the povidone is povidone K-25 or povidone K-29 / 32; and the microcrystalline cellulose is PH-101 or PH-302.

[0046] Preferably, the telmisartan-amlodipine bilayer tablets comprise, by weight percentage, the following components:

[0047] Telmisartan layer: 16.7% telmisartan, 1.2-1.7% sodium hydroxide, 4-6% povidone, 4-6% meglumine, 65-75% sorbitol, 0-1.8% magnesium stearate, 0-1.0% talc;

[0048] Amlodipine layer: 3.47% amlodipine benzylsulfonate, 60-70% microcrystalline cellulose, 22-28% pregelatinized starch, 2-8% corn starch, 2-8% colloidal silica.

[0049] The telmisartan-amlodipine bilayer tablets comprise, by weight percentage, the following components: telmisartan layer: 16.7% telmisartan, 1.5% sodium hydroxide, 5.0% povidone, 5.0% meglumine, 70.3% sorbitol, 1.2% magnesium stearate, and 0.5% talc.

[0050] Amlodipine layer: 3.47% amlodipine benzylsulfonate, 62.9% microcrystalline cellulose, 26.5% pregelatinized starch, 5.0% corn starch, 1.0% colloidal silica.

[0051] This application also provides a method for preparing telmisartan-amlodipine bilayer tablets, comprising the following steps:

[0052] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0053] (1) Add the prescribed amount of alkaline reagent, telmisartan, and binder to water and stir until dissolved;

[0054] (2) The above solution was spray-dried and granulated to obtain telmisartan complex;

[0055] (3) Mix the telmisartan complex with the filler evenly;

[0056] (4) Add lubricant and continue mixing to obtain telmisartan layer total mixed particles;

[0057] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0058] (1) Mix the gliding agent with a small amount of diluent, crush and sieve, and then rinse with the remaining amount of diluent to obtain the premix;

[0059] (2) Mix the premix, amlodipine besylate, disintegrant and 50% of the prescribed amount of lubricant evenly to obtain a mixture;

[0060] (3) The mixture is dry granulated to obtain drug-containing granules.

[0061] (4) Add the remaining amount of lubricant to the drug-containing granules and continue to mix evenly to obtain amlodipine total mixed granules;

[0062] Step S3: Pressing of the double-layer film.

[0063] Preferably, the method for preparing the telmisartan-amlodipine bilayer tablets includes the following steps:

[0064] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0065] (1) Add the prescribed amounts of sodium hydroxide, telmisartan, povidone K-29 / 32 and meglumine to water in sequence, and stir until dissolved;

[0066] (2) The above solution was spray-dried and granulated to obtain telmisartan complex;

[0067] (3) Mix the telmisartan complex with sorbitol until homogeneous;

[0068] (4) Add the prescribed amount of magnesium stearate and talc powder, continue mixing, and obtain telmisartan total mixed particles;

[0069] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0070] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-302), and pass it through a 0.8mm sieve at high speed using a pulverizer and granulator. Then wash it with the remaining amount of microcrystalline cellulose in the prescription to obtain the pigment premix.

[0071] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture;

[0072] (3) The mixture is granulated by dry method with a feeding speed of 3-7 rpm, a roller pressing speed of 4-6 rpm, a roller pressing pressure of 35-55 bar, and a granulation screen of 18 mesh to obtain drug-containing granules.

[0073] (4) Add the remaining amount of magnesium stearate to the drug-containing granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0074] Step S3: Pressing of the double-layer film.

[0075] The telmisartan-amlodipine bilayer tablets provided in this application have high stability and dissolution performance similar to the reference.

[0076] The following examples illustrate the proportions further.

[0077] Example 1

[0078] The specific content of raw and auxiliary materials in each layer is as follows:

[0079] Telmisartan layer:

[0080]

[0081] Ammonium chloride leveling:

[0082]

[0083] The preparation process is as follows:

[0084] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0085] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-25 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0086] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0087] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0088] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0089] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0090] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102:PH-302 = 1:1), and use a pulverizer to pass it through a 0.8mm sieve at high speed. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0091] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0092] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0093] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0094] Step S3: Pressing of the double-layer film

[0095] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0096] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0097] Example 2

[0098] The specific content of raw and auxiliary materials in each layer is as follows:

[0099] Telmisartan layer:

[0100]

[0101] Ammonium chloride leveling:

[0102]

[0103]

[0104] The preparation process is as follows:

[0105] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0106] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-25 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0107] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0108] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0109] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0110] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0111] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102:PH-302 = 4:1), and use a pulverizer to pass it through a 0.8mm sieve at high speed. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0112] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0113] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0114] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0115] Step S3: Pressing of the double-layer film

[0116] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0117] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0118] Example 3

[0119] The specific content of raw and auxiliary materials in each layer is as follows:

[0120]

[0121]

[0122] Telmisartan layer:

[0123] Ammonium chloride leveling:

[0124]

[0125] The preparation process is as follows:

[0126] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0127] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-25 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0128] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0129] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0130] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0131] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0132] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102:PH-302=1:4), and use a pulverizer to pass it through a 0.8mm sieve at high speed. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0133] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0134] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0135] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0136] Step S3: Pressing of the double-layer film

[0137] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0138] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0139] Example 4

[0140] The specific content of raw and auxiliary materials in each layer is as follows:

[0141] Telmisartan layer:

[0142]

[0143] Ammonium chloride leveling:

[0144]

[0145] The preparation process is as follows:

[0146] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0147] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-25 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0148] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0149] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0150] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0151] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0152] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102:PH-302 = 1:1), and use a pulverizer to pass it through a 0.8mm sieve at high speed. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0153] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0154] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0155] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0156] Step S3: Pressing of the double-layer film

[0157] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0158] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0159] Example 5

[0160] The specific content of raw and auxiliary materials in each layer is as follows:

[0161] Telmisartan layer:

[0162]

[0163] Ammonium chloride leveling:

[0164]

[0165] The preparation process is as follows:

[0166] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0167] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-25 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0168] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0169] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0170] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0171] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0172] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102:PH-302 = 3:1), and use a pulverizer to pass it through a 0.8mm sieve at high speed. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0173] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0174] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0175] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0176] Step S3: Pressing of the double-layer film

[0177] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0178] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0179] Example 6

[0180] The specific content of raw and auxiliary materials in each layer is as follows:

[0181] Telmisartan layer:

[0182]

[0183] Ammonium chloride leveling:

[0184]

[0185] The preparation process is as follows:

[0186] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0187] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-25 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0188] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0189] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0190] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0191] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0192] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102:PH-302 = 1:3), and use a pulverizer to pass it through a 0.8mm sieve at high speed. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0193] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0194] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0195] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0196] Step S3: Pressing of the double-layer film

[0197] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0198] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0199] Comparative Example 1

[0200] The specific content of raw and auxiliary materials in each layer is as follows:

[0201] Telmisartan layer:

[0202]

[0203] Ammonium chloride leveling:

[0204]

[0205]

[0206] The preparation process is as follows:

[0207] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0208] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-25 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0209] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0210] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0211] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0212] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0213] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102:PH-302 = 5:1), and use a pulverizer to pass it through a 0.8mm sieve at high speed. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0214] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0215] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0216] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0217] Step S3: Pressing of the double-layer film

[0218] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0219] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0220] Comparative Example 2

[0221] The specific content of raw and auxiliary materials in each layer is as follows:

[0222] Telmisartan layer:

[0223]

[0224] Ammonium chloride leveling:

[0225]

[0226] The preparation process is as follows:

[0227] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0228] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-25 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0229] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0230] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0231] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0232] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0233] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102:PH-302 = 1:5), and use a pulverizer to pass it through a 0.8mm sieve at high speed. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0234] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0235] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0236] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0237] Step S3: Pressing of the double-layer film

[0238] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0239] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0240] Comparative Example 3

[0241] The specific content of raw and auxiliary materials in each layer is as follows:

[0242] Telmisartan layer:

[0243]

[0244] Ammonium chloride leveling:

[0245]

[0246] The preparation process is as follows:

[0247] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0248] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-29 / 32 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0249] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0250] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0251] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0252] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0253] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102:PH-302 = 5:1), and use a pulverizer to pass it through a 0.8mm sieve at high speed. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0254] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0255] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0256] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0257] Step S3: Pressing of the double-layer film

[0258] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0259] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0260] Comparative Example 4

[0261] The specific content of raw and auxiliary materials in each layer is as follows:

[0262] Telmisartan layer:

[0263]

[0264] Ammonium chloride leveling:

[0265]

[0266] The preparation process is as follows:

[0267] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0268] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-29 / 32 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0269] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0270] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0271] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0272] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0273] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102:PH-302 = 1:5), and use a pulverizer to pass it through a 0.8mm sieve at high speed. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0274] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0275] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0276] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0277] Step S3: Pressing of the double-layer film

[0278] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0279] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0280] Comparative Example 5

[0281] The specific content of raw and auxiliary materials in each layer is as follows:

[0282] Telmisartan layer:

[0283]

[0284] Ammonium chloride leveling:

[0285]

[0286] The preparation process is as follows:

[0287] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0288] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-25 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0289] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0290] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0291] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0292] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0293] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102:PH-101 = 1:1), use a pulverizer and granulator to pass it through a 0.8mm sieve at high speed, and then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0294] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0295] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0296] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0297] Step S3: Pressing of the double-layer film

[0298] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0299] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0300] Comparative Example 6

[0301] The specific content of raw and auxiliary materials in each layer is as follows:

[0302] Telmisartan layer:

[0303]

[0304] Ammonium chloride leveling:

[0305]

[0306]

[0307] The preparation process is as follows:

[0308] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0309] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-25 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0310] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0311] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0312] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0313] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0314] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102:PH-101 = 1:1), use a pulverizer and granulator to pass it through a 0.8mm sieve at high speed, and then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0315] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0316] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0317] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0318] Step S3: Pressing of the double-layer film

[0319] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0320] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0321] Comparative Example 7

[0322] The specific content of raw and auxiliary materials in each layer is as follows:

[0323] Telmisartan layer:

[0324]

[0325] Ammonium chloride leveling:

[0326]

[0327]

[0328] The preparation process is as follows:

[0329] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0330] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-25 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0331] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0332] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0333] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0334] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0335] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-101), and pass it through a 0.8mm sieve at high speed using a pulverizer and granulator. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0336] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0337] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0338] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0339] Step S3: Pressing of the double-layer film

[0340] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0341] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0342] Comparative Example 8

[0343] The specific content of raw and auxiliary materials in each layer is as follows:

[0344] Telmisartan layer:

[0345]

[0346]

[0347] Ammonium chloride leveling:

[0348]

[0349] The preparation process is as follows:

[0350] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0351] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-25 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0352] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0353] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0354] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0355] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0356] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-102), and pass it through a 0.8mm sieve at high speed using a pulverizer and granulator. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0357] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0358] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0359] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0360] Step S3: Pressing of the double-layer film

[0361] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0362] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0363] Comparative Example 9

[0364] The specific content of raw and auxiliary materials in each layer is as follows:

[0365] Telmisartan layer:

[0366]

[0367] Ammonium chloride leveling:

[0368]

[0369] The preparation process is as follows:

[0370] Step S1: Preparation of Telmisartan Layered Total Mixture Particles

[0371] (1) Heat water to 35-50°C, and add sodium hydroxide, telmisartan, povidone K-29 / 32 and meglumine in the prescribed amounts in sequence, and stir until dissolved.

[0372] (2) The above solution was spray-dried and granulated to obtain telmisartan complex.

[0373] (3) After sieving the telmisartan complex and sorbitol, place them in a hopper mixer and mix them evenly.

[0374] (4) Add the prescribed amount of magnesium stearate and talc, and continue mixing to obtain telmisartan total mixed particles.

[0375] Step S2: Preparation of total mixed particles of ammonium chloride solution

[0376] (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-302), and pass it through a 0.8mm sieve at high speed using a pulverizer and granulator. Then wash it with the remaining amount of microcrystalline cellulose to obtain the pigment premix.

[0377] (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture.

[0378] (3) The mixture is granulated by dry method. The feeding speed is 3-7 rpm, the roller pressing speed is 4-6 rpm, the roller pressing pressure is 35-55 bar, the granulation screen is 18 mesh, and the granules containing the drug are obtained by sieving.

[0379] (4) Add the remaining amount of magnesium stearate to the medicated granules and continue to mix evenly to obtain amlodipine total mixed granules.

[0380] Step S3: Pressing of the double-layer film

[0381] (1) Compress the total mixture of telmisartan particles into tablets to obtain telmisartan tablets.

[0382] (2) Press the amlodipine layer total mixed particles onto telmisartan tablets to obtain telmisartan-amlodipine bilayer tablets.

[0383] Dissolution Determination

[0384] Following the guidelines for "Dissolution and Release Assay Method 0931" in the General Chapters of the Chinese Pharmacopoeia (2020 Edition), the dissolution rate of telmisartan-amlodipine bilayer tablets was determined (medium: 0.1 mol / L hydrochloric acid, pH 4.5 acetate solution, pH 6.8 phosphate solution, pH 7.5 phosphate solution). A reference formulation (trade name: Batch number: 21K1507), the results are shown in Tables 1 to 8 below:

[0385] Referring to the "Technical Guidelines for Dissolution Testing of Common Oral Solid Dosage Forms" issued by the Center for Drug Evaluation of the National Medical Products Administration, the similarity factor (f2) in the non-model-dependent method is calculated using the following formula:

[0386]

[0387] Where n is the number of sampling time points, R t T represents the dissolution value of the reference sample (or the sample before the change) at time t. t This represents the dissolution rate of the test batch (the modified sample) at time t. An f2 value higher than 50 indicates that the two curves are similar.

[0388] When the dissolution rate of the test formulation and the reference formulation is ≥85% within 15 minutes, their dissolution behavior can be considered similar, and there is no need to compare f2.

[0389] Table 1. Dissolution determination of telmisartan in 0.1 mol / L hydrochloric acid solution

[0390]

[0391]

[0392] Table 2. Dissolution determination of telmisartan in acetate solution at pH 4.5

[0393]

[0394] Table 3. Dissolution determination of telmisartan in phosphate solution at pH 6.8

[0395]

[0396]

[0397] Table 4. Dissolution determination of telmisartan in phosphate solution at pH 7.5

[0398]

[0399] Table 5. Determination of dissolution rate of amlodipine in 0.1 mol / L hydrochloric acid solution

[0400]

[0401]

[0402] Table 6. Dissolution determination of amlodipine in acetate solution at pH 4.5

[0403]

[0404] Table 7. Dissolution determination of amlodipine in phosphate solution at pH 6.8

[0405]

[0406]

[0407] Table 8. Dissolution determination of amlodipine in phosphate solution at pH 7.5

[0408]

[0409] The following conclusions can be drawn from observing Tables 1 to 8:

[0410] (a) Observation of the dissolution of telmisartan in different media in telmisartan-amlodipine bilayer tablets:

[0411] In different media, the telmisartan-amlodipine bilayer tablets prepared in Examples 1-6 all had a dissolution factor f2 greater than 50 or a dissolution amount ≥85% within 15 minutes that was similar to the reference formulation. That is, the dissolution curves of the telmisartan-amlodipine bilayer tablets prepared in Examples 1-6 were similar to those of the reference formulation in different media.

[0412] Compared with the reference formulation, the telmisartan-amlodipine bilayer tablets prepared in Comparative Examples 1-9 showed a dissolution factor f2 greater than 50 in pH 4.5 acetate solution, indicating that the dissolution curves of telmisartan prepared in Comparative Examples 1-9 were similar to those of the reference formulation in pH 4.5 acetate solution. However, in pH 6.8 phosphate solution and pH 7.5 phosphate solution, the dissolution factor f2 of telmisartan was less than 50, indicating that the dissolution curves of telmisartan prepared in Comparative Examples 1-9 were similar to those of the reference formulation in pH 4.5 acetate solution. The dissolution profiles of the prepared telmisartan-amlodipine bilayer tablets were dissimilar to those of the reference formulation in pH 6.8 phosphate and pH 7.5 phosphate solutions. In 0.1 mol / L hydrochloric acid solution, the dissolution factor f2 of telmisartan fluctuated around 50. Therefore, the dissolution profiles of the telmisartan-amlodipine bilayer tablets prepared in Comparative Examples 1–9 were partially similar to, but partially dissimilar to, the reference formulation in 0.1 mol / L hydrochloric acid solution. Thus, when the weight-average molecular weight of povidone is 3000–6000 kDa, the amlodipine diluent is a blend of two microcrystalline celluloses, and the weight ratio of microcrystalline cellulose PH-102 to PH-302 is 1–4:1–4, the dissolution performance of telmisartan in the prepared telmisartan-amlodipine bilayer tablets is similar to that of the reference formulation.

[0413] (II) Observation of the dissolution of amlodipine in telmisartan-amlodipine bilayer tablets in different media:

[0414] In different media, the telmisartan-amlodipine bilayer tablets prepared in Examples 1-6 showed similar dissolution rates of amlodipine within 15 minutes compared to the reference formulation. In other words, the dissolution curves of amlodipine in the telmisartan-amlodipine bilayer tablets prepared in Examples 1-6 and the reference formulation were similar in different media.

[0415] Compared with the reference formulation, the dissolution profiles of amlodipine in the telmisartan-amlodipine bilayer tablets prepared in Comparative Examples 1–9 were similar to those in the reference formulation in 0.1 mol / L hydrochloric acid solution, pH 4.5 acetate solution, and pH 7.5 phosphate solution. In pH 6.8 phosphate solution, the dissolution factor f2 of amlodipine in the telmisartan-amlodipine bilayer tablets prepared in Comparative Examples 1–9 fluctuated around 50. The dissolution profiles of amlodipine in the telmisartan-amlodipine bilayer tablets prepared in Comparative Examples 1, 3, and 4 were similar to those of the reference formulation, while the dissolution profiles of amlodipine in the telmisartan-amlodipine bilayer tablets prepared in Comparative Examples 2, 5, 6, 7, 8, and 9 were not similar to those of the reference formulation.

[0416] Therefore, when the weight-average molecular weight of povidone is 3000-6000 kDa, the amlodipine diluent is a combination of two microcrystalline celluloses, and the weight ratio of microcrystalline cellulose PH-102 to microcrystalline cellulose PH-302 is 1-4:1-4, the dissolution performance of amlodipine in the prepared telmisartan-amlodipine bilayer tablets is similar to that of the reference formulation.

[0417] High-performance liquid chromatography (HPLC) was used to determine the content and related substances of telmisartan and amlodipine to ensure that the product quality met the pharmacopoeia standards. Simultaneously, degradation tests under different conditions were conducted to evaluate the product's stability; the results are shown in Table 9.

[0418] Table 9 Accelerated test data of telmisartan and amlodipine tablets prepared in Examples 1 and 5 and Comparative Examples 1 and 9

[0419]

[0420]

[0421] The following conclusions can be drawn from observing Table 9:

[0422] In Examples 1 and 5, the telmisartan-amlodipine bilayer tablets prepared under light (4500 Lx ± 500 Lx), high temperature (60℃ ± 2℃), and high humidity (90% ± 5% relative humidity) conditions showed changes in impurities (including single and total impurities) related to telmisartan and amlodipine after 0, 10, and 30 days of storage, but the changes were minor. In contrast, the telmisartan-amlodipine bilayer tablets prepared in Comparative Examples 1 and 9 showed larger changes in impurities (including single and total impurities) related to telmisartan and amlodipine after 0, 10, and 30 days of storage under light (4500 Lx ± 500 Lx), high temperature (60℃ ± 2℃), and high humidity (90% ± 5% relative humidity) conditions, and the content of related substances exceeded the standard limits after 10 or 30 days of storage. Therefore, it can be seen that the telmisartan-amlodipine bilayer tablets prepared in Examples 1 and 5 have significantly higher stability after being placed in an environment of (4500Lx±500Lx), high temperature (60℃±2℃), and high humidity (relative humidity of 90%±5%) for 10 and 30 days than the telmisartan-amlodipine bilayer tablets prepared in Comparative Examples 1 and 9. That is, the telmisartan-amlodipine bilayer tablets provided in this application have significant stability.

[0423] 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.

Claims

1. A bilayer tablet for treating hypertension, the bilayer tablet comprising a telmisartan layer and an amlodipine layer, wherein, The telmisartan layer comprises: telmisartan, an alkaline reagent, a binder, a filler, and a lubricant; the amlodipine layer comprises amlodipine besylate, a diluent, a disintegrant, a flow aid, a colorant, and a lubricant. The characteristic feature is that the binder of the telmisartan layer is povidone, the weight-average molecular weight of which is 3000–6000 kDa; and the diluent of the amlodipine layer is microcrystalline cellulose, which is a blend of two types of microcrystalline cellulose.

2. The double-layer tablet for treating hypertension according to claim 1, characterized in that, The microcrystalline cellulose is a compound of microcrystalline cellulose PH-102 and microcrystalline cellulose PH-302, and the weight ratio of microcrystalline cellulose PH-102 to microcrystalline cellulose PH-302 is 1-4:1-4.

3. A double-layer tablet for treating hypertension according to claim 1, characterized in that, The povidone is one or both of povidone K-25 and K-29 / 32.

4. A double-layered tablet for treating hypertension according to claim 1, characterized in that, It comprises the following components: telmisartan, sodium hydroxide, povidone, meglumine, sorbitol, magnesium stearate, talc, amlodipine besylate, microcrystalline cellulose PH-101, pregelatinized starch, corn starch, and colloidal silica; wherein the povidone is povidone K-25 or povidone K-29 / 32; and the microcrystalline cellulose is PH-101 or PH-302.

5. A double-layer tablet for treating hypertension according to claim 4, characterized in that, By weight percentage, it includes the following components: Telmisartan layer: 16.7% telmisartan, 1.2-1.7% sodium hydroxide, 4-6% povidone, 4-6% meglumine, 65-75% sorbitol, 0-1.8% magnesium stearate, 0-1.0% talc; Amlodipine layer: 3.47% amlodipine benzylsulfonate, 60-70% microcrystalline cellulose, 22-28% pregelatinized starch, 2-8% corn starch, 2-8% colloidal silica.

6. A double-layer tablet for treating hypertension according to claim 2, characterized in that, The weight ratio of microcrystalline cellulose PH-102 to microcrystalline cellulose PH-302 is 1-3:1-3.

7. A double-layer tablet for treating hypertension according to claim 2, characterized in that, The weight ratio of microcrystalline cellulose PH-102 to microcrystalline cellulose PH-302 is 1:

1.

8. A bilayer tablet for treating hypertension according to any one of claims 1 to 7, wherein the preparation method comprises the following steps: Step S1: Preparation of Telmisartan Layered Total Mixture Particles (1) Add the prescribed amount of alkaline reagent, telmisartan, and binder to water and stir until dissolved; (2) The above solution was spray-dried and granulated to obtain telmisartan complex; (3) Mix the telmisartan complex with the filler evenly; (4) Add lubricant and continue mixing to obtain telmisartan layer total mixed particles; Step S2: Preparation of total mixed particles of ammonium chloride solution (1) Mix the gliding agent with a small amount of diluent, crush and sieve, and then rinse with the remaining amount of diluent to obtain the premix; (2) Mix the premix, amlodipine besylate, disintegrant and 50% of the prescribed amount of lubricant evenly to obtain a mixture; (3) The mixture is dry granulated to obtain drug-containing granules. (4) Add the remaining amount of lubricant to the drug-containing granules and continue to mix evenly to obtain amlodipine total mixed granules; Step S3: Pressing of the double-layer film.

9. A bilayer tablet for treating hypertension according to claim 8, comprising the following steps: Step S1: Preparation of Telmisartan Layered Total Mixture Particles (1) Add the prescribed amounts of sodium hydroxide, telmisartan, povidone K-29 / 32 and meglumine to water in sequence, and stir until dissolved; (2) The above solution was spray-dried and granulated to obtain telmisartan complex; (3) Mix the telmisartan complex with sorbitol until homogeneous; (4) Add the prescribed amount of magnesium stearate and talc powder, continue mixing, and obtain telmisartan total mixed particles; Step S2: Preparation of total mixed particles of ammonium chloride solution (1) Mix the colorant (brilliant blue, black iron oxide), colloidal silica and a small amount of microcrystalline cellulose mixture (PH-302), and pass it through a 0.8mm sieve at high speed using a pulverizer and granulator. Then wash it with the remaining amount of microcrystalline cellulose in the prescription to obtain the pigment premix. (2) Mix the pigment premix, amlodipine besylate, pregelatinized starch, corn starch and 50% of the prescribed amount of magnesium stearate evenly to obtain a mixture; (3) The mixture is granulated by dry method with a feeding speed of 3-7 rpm, a roller pressing speed of 4-6 rpm, a roller pressing pressure of 35-55 bar, and a granulation screen of 18 mesh to obtain drug-containing granules. (4) Add the remaining amount of magnesium stearate to the drug-containing granules and continue to mix evenly to obtain amlodipine total mixed granules. Step S3: Pressing of the double-layer film.

Images