A compound preparation for treating hypertension and its preparation method

Abstract

This application discloses a compound preparation for treating hypertension and its preparation method. The compound preparation comprises: a telmisartan layer and an amlodipine layer. The telmisartan layer is composed of telmisartan, a binder, an alkalizing agent, a filler, and a lubricant. The amlodipine layer is composed of amlodipine besylate, a diluent, a lubricant, a flow aid, and a colorant. The filler of the telmisartan layer is composed of mannitol and sorbitol. The compound preparation obtained by this invention has good dissolution and stability.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparations, and specifically relates to a compound preparation for treating hypertension and its preparation method. Background Technology

[0002] Telmisartan / Amlodipine Tablets were developed by Boehringer Ingelheim Pharmaceuticals, Inc. and approved for marketing by the U.S. Food and Drug Administration (FDA) in October 2009. The brand name is [Brand Name Missing]. This drug is available in four strengths: telmisartan / amlodipine 40mg / 5mg, 40mg / 10mg, 80mg / 5mg, and 80mg / 10mg, designed to provide an effective treatment option for patients with hypertension. It was also approved for marketing in the European Union on October 7, 2010, primarily for the treatment of essential hypertension.

[0003] Telmisartan (international nonproprietary name: Telmisartan), an angiotensin II receptor antagonist (ARB), is used to treat hypertension. Amlodipine, on the other hand, is a calcium channel blocker suitable for treating various types of hypertension (alone or in combination with other drugs) and angina, especially spontaneous angina. While both have their own unique characteristics, their combined use significantly enhances the antihypertensive effect, reduces adverse reactions, and improves patient adherence.

[0004] Telmisartan is a white to pale yellow crystalline powder. When present as a free acid, it has low solubility in the gastrointestinal tract within a pH range of 1–7. Therefore, marketed telmisartan formulations are typically converted to its sodium salt to improve bioavailability and therapeutic efficacy. Amlodipine besylate is a weakly acidic compound that readily dissociates into amlodipine under alkaline conditions and may undergo hydrolysis. Therefore, directly mixing telmisartan sodium (alkaline) with amlodipine may lead to instability in the latter, which is detrimental to the preparation of combination formulations.

[0005] To address the compatibility issues in telmisartan and amlodipine combination formulations, researchers have proposed several technical solutions. For example:

[0006] Patent CN101947219A discloses a compound telmisartan amlodipine besylate pharmaceutical composition and its preparation method. The amlodipine solid dispersion is prepared by solid dispersion technology and then combined with telmisartan, thereby improving the solubility and bioavailability of the active pharmaceutical ingredient.

[0007] Patent CN106822122B discloses an oral pharmaceutical composition of telmisartan and amlodipine and its preparation method, wherein telmisartan exists in the form of solid lipid nanoparticles, ensuring that the stability of amlodipine is not affected even with prolonged contact.

[0008] Patent CN103169701B discloses a telmisartan-amlodipine bilayer tablet and its preparation method. The method uses top-spray fluidized bed technology to prepare telmisartan tablet laminated particles, aiming to improve the stability and bioavailability of the drug.

[0009] Patent CN116898816A discloses a telmisartan amlodipine tablet and its preparation method. By optimizing the formulation of the telmisartan layer, reducing the amount of magnesium stearate and adding an appropriate amount of talc, the problem of inconsistent dissolution rate of telmisartan with the original product is solved.

[0010] While these methods have addressed the compatibility issue of the two active ingredients to some extent, their respective preparation processes are quite complex, and their effectiveness needs further improvement. Therefore, researchers are still exploring simpler and more effective methods to achieve stable coexistence of telmisartan and amlodipine, thereby improving drug efficacy and patient experience. Summary of the Invention

[0011] To address the technical problems existing in the prior art, this application provides a compound preparation for treating hypertension, comprising: a telmisartan layer and an amlodipine layer, wherein the telmisartan layer is composed of telmisartan, a binder, an alkalizing agent, a filler, and a lubricant; the amlodipine layer is composed of amlodipine besylate, a diluent, a lubricant, a flow aid, and a colorant; wherein the filler of the telmisartan layer is composed of mannitol and sorbitol.

[0012] Furthermore, the mass ratio of mannitol to sorbitol is (9-21):1, preferably (10-20):1.

[0013] Furthermore, the telmisartan layer, by weight, comprises 75-85 parts telmisartan, 20-30 parts binder, 25-35 parts alkalizing agent, 300-400 parts filler, and 2-10 parts lubricant.

[0014] Furthermore, the adhesive is polyvinylpyrrolidone, the alkalizing agent is one or both of sodium hydroxide or meglumine, and the lubricant is magnesium stearate.

[0015] Further, the amlodipine layer comprises, by weight, 2-10 parts amlodipine besylate, 150-250 parts diluent, 1-10 parts lubricant, 1-10 parts flow aid, and 0.1-1 parts colorant.

[0016] Furthermore, the diluent is one or more of microcrystalline cellulose, pregelatinized starch, or corn starch, the lubricant is magnesium stearate, the flow aid is silicon dioxide, and the colorant is yellow iron oxide.

[0017] On the other hand, the present invention provides a method for preparing the above-mentioned compound preparation for treating hypertension, comprising the following steps: (1) preparation of telmisartan layer (2) preparation of amlodipine layer (3) pressing of double-layer tablets (4) packaging.

[0018] Further, the preparation of the telmisartan layer includes the following steps: 1) dissolving sodium hydroxide, telmisartan, meglumine, povidone and sorbitol in water; 2) placing mannitol in a fluidized bed, spraying the solution obtained in step 1) into the fluidized bed for granulation, and drying after spraying; 3) sizing the particles obtained in step 2); 4) mixing magnesium stearate and the particles obtained in step 3).

[0019] Furthermore, in step 1), the amount of purified water used is 170% to 250% of the total weight of the solid substances in the solution.

[0020] Furthermore, the temperature of the solution preparation process in step 1) is 45±5℃.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] (1) By optimizing the formulation and preparation process of the telmisartan layer, this invention achieves a high degree of consistency in solubility between telmisartan amlodipine tablets and commercially available products. This feature not only ensures the effectiveness of the drug but also improves the patient's treatment experience.

[0023] (2) Regarding related substances, especially for amlodipine, the impurity content has been effectively reduced and strictly controlled within the safety standard range. This not only enhances the safety and stability of the drug, but also provides patients with more reliable treatment options.

[0024] (3) In addition, the technical solution adopted in this invention is simple and efficient, and is very suitable for large-scale industrial production. Attached Figure Description

[0025] Figure 1 These are dissolution profiles of telmisartan layer examples and commercially available products.

[0026] Figure 2 These are the dissolution curves of telmisartan layer-by-layer and commercially available products.

[0027] Figure 3 These are dissolution curves of amlodipine layer examples and commercially available products.

[0028] Figure 4 This is a comparison of the dissolution curves of amlodipine and commercially available products. Detailed Implementation

[0029] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. 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.

[0030] 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 illustrated or 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.

[0031] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0032] To more easily resolve the compatibility issue between telmisartan and amlodipine, this invention, based on in-depth research on telmisartan-amlodipine tablets, optimizes its formulation design and preparation process. This optimization not only ensures that the dissolution behavior of the two active ingredients is highly consistent with similar products on the market, but also effectively controls the impurity levels in amlodipine, as detailed below:

[0033] Telmisartan-Amlodipine tablets comprise: a telmisartan layer and an amlodipine layer, wherein the telmisartan layer is composed of telmisartan, a binder, an alkalizing agent, a filler, and a lubricant; the amlodipine layer is composed of amlodipine besylate, a diluent, a lubricant, a flow aid, and a colorant; wherein the filler of the telmisartan layer is composed of mannitol and sorbitol.

[0034] In one embodiment of the present invention, the mass ratio of mannitol to sorbitol is (9-21):1, preferably (10-20):1, for example 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1, but is not limited to the listed values; other unlisted values ​​within this range are also applicable. Mannitol and sorbitol are both sugar alcohols, often used as fillers to improve the formability and stability of formulations. However, they differ in structure and certain properties. Although the specific reasons are unclear, when mannitol and sorbitol are mixed in a specific ratio, ideal dissolution and effective control of related substances can be achieved in telmisartan-amlodipine tablets. This specific combination not only optimizes the bioavailability of the drug but also ensures the high quality and stability of the formulation.

[0035] In one embodiment of the present invention, the telmisartan layer comprises, by weight, 75-85 parts telmisartan, 20-30 parts binder, 25-35 parts alkalizing agent, 300-400 parts filler, and 2-10 parts lubricant. Preferably, it comprises 80 parts telmisartan, 24 parts binder, 30.72 parts alkalizing agent, 340.48 parts filler, and 4.8 parts lubricant.

[0036] In one embodiment of the present invention, the adhesive is polyvinylpyrrolidone, the alkalizing agent is one or both of sodium hydroxide or meglumine, the lubricant is magnesium stearate, and the polyvinylpyrrolidone is preferably polyvinylpyrrolidone K30.

[0037] In one embodiment of the present invention, the amlodipine layer comprises, by weight, 2-10 parts amlodipine besylate, 150-250 parts diluent, 1-10 parts lubricant, 1-10 parts flow aid, and 0.1-1 parts colorant. Preferably, it comprises 6.935 parts amlodipine besylate (equivalent to 5 parts amlodipine), 188.765 parts diluent, 2 parts lubricant, 5 parts flow aid, and 0.3 parts colorant.

[0038] In one embodiment of the present invention, the diluent is one or more of microcrystalline cellulose, pregelatinized starch or corn starch, the lubricant is magnesium stearate, the flow aid is silicon dioxide, and the colorant is yellow iron oxide.

[0039] In one embodiment of the present invention, the preparation method of telmisartan amlodipine tablets includes the following steps: (1) preparation of telmisartan layer (2) preparation of amlodipine layer (3) pressing of double-layer tablets (4) packaging.

[0040] In one embodiment of the present invention, the preparation of the telmisartan layer includes the following steps: 1) dissolving sodium hydroxide, telmisartan, meglumine, povidone and sorbitol in water; 2) placing mannitol in a fluidized bed, spraying the solution obtained in step 1) into the fluidized bed for granulation, and drying after spraying; 3) sizing the particles obtained in step 2); 4) mixing magnesium stearate and the particles obtained in step 3).

[0041] In one embodiment of the invention, the amount of purified water used in step 1) is 170% to 250% of the total weight of the solids in the solution, for example, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, or 250%, but not limited to the listed values; other unlisted values ​​within this range are also applicable. The amount of purified water used in the pharmaceutical process is crucial. It is used not only to dissolve solid components such as sodium hydroxide, telmisartan, meglumine, povidone, and sorbitol, but also serves as a solvent for the subsequent fluidized bed granulation operation. The appropriate amount of purified water directly affects the characteristics of the granules after granulation, which in turn significantly influences the dissolution performance of telmisartan-amlodipine tablets and the control of related impurities.

[0042] The solid substances are those dissolved in water in step 1), such as sodium hydroxide, telmisartan, meglumine, povidone, and sorbitol.

[0043] The specific embodiments and comparative examples of the present invention are listed below, but the present invention is not limited to the following examples.

[0044] Table 1. Functions and sources of raw materials and auxiliary materials in the examples and comparative examples.

[0045]

[0046]

[0047] Table 2. Information on the main equipment used in the embodiments and comparative examples.

[0048] Equipment Name model factory fluidized bed FLZB-3.0 Chuangzhi Technology (Jiangsu) Co., Ltd. 3D Motion Mixer SHB-500 Tianjin Maoyuan Pharmaceutical Machinery Co., Ltd. oscillating pellet mill YK-60 Taizhou Tiantai Pharmaceutical Machinery Co., Ltd. Rotary tablet press ZP-19 / 2 Beijing Xinlongli Technology Co., Ltd.

[0049] The raw materials and proportions (by weight) of telmisartan amlodipine tablets in Examples 1-5 and Comparative Examples 1-7 are shown in Table 3:

[0050] Table 3. Raw material and excipient ratios (mg / tablet) for the examples and comparative examples of telmisartan-amlodipine tablets.

[0051]

[0052]

[0053] (Amlodipine besylate 6.935mg / tablet, equivalent to amlodipine 5mg / tablet)

[0054] The preparation methods of telmisartan amlodipine tablets in Examples 1-5 and Comparative Examples 1-7 are as follows: (taking 9000 tablets as an example)

[0055] (1) Preparation of Telmisartan Layer

[0056] 1) Weighing

[0057] Weigh according to the prescription amount.

[0058] 2) Solution preparation

[0059] Weigh the prescribed amount of purified water into a stainless steel container, turn on the agitator, set a suitable speed, and add the prescribed amounts of sodium hydroxide, telmisartan, meglumine, povidone, and sorbitol (if applicable) sequentially while stirring. Continue stirring until fully dissolved. (Maintain a temperature of 45±5℃ during slurry preparation and spraying. When adding materials, wait until each material is completely dissolved before adding the next.)

[0060] 3) Fluidized bed one-step granulation

[0061] Mannitol (or the prescribed amount of sorbitol if mannitol is unavailable) is placed in a fluidized bed. The peristaltic pump is set to a speed of 5.0 rpm and the atomization pressure to 2.0 MPa. The solution obtained in step 2) is sprayed into the fluidized bed for granulation. After spraying, the solution is dried to control the moisture content to <3.5%.

[0062] 4) Whole grains

[0063] The dry granules obtained in step 3) are added to a gyratory pellet mill equipped with a 24-mesh nylon sieve for sieving and granulation.

[0064] 5) Mixing

[0065] Magnesium stearate and the particles obtained in step 4) were added to a three-dimensional mixer for mixing. The mixing parameters were 15 rpm and 20 min.

[0066] (2) Preparation of amlodipine layer

[0067] 1) Weighing and processing of raw and auxiliary materials

[0068] Weigh the amount according to the prescription, and pass the yellow iron oxide through a 100-mesh sieve.

[0069] 2) Premixed

[0070] Microcrystalline cellulose, amlodipine benzyl sulfonate, pregelatinized starch, corn starch and yellow iron oxide were added to a three-dimensional mixer and mixed at 15 rpm for 20 min.

[0071] 3) Sieving

[0072] The silica, magnesium stearate and the premixed material obtained in step 2) are sequentially passed through a gyratory pellet mill (24-mesh nylon screen).

[0073] 4) Total Mix

[0074] Then place the sieved material into a three-dimensional mixer and continue mixing for 5 minutes at a speed of 15 rpm.

[0075] (3) Double-layer film pressing

[0076] A 16.2*7.9 elliptical punch is used for tablet pressing, and the hardness of the first layer is controlled at 40-60N, while the hardness of the double-layer tablet is controlled at 120-180N.

[0077] (4) Packaging

[0078] Pack according to the predetermined specifications.

[0079] The telmisartan amlodipine tablets obtained in Examples 1-5 and Comparative Examples 1-7 and commercially available products were determined. Batch number: 21H2312, Certificate holder: Boehringer Ingelheim International GmbH) solvent Output and related material information :

[0080] Dissolution curves were compared and analyzed using 900 ml of pH 7.5 acetate buffer as the dissolution medium. The dissolution method was performed using a paddle method at 75 rpm, following the "0931 Determination of Dissolution and Release" method in Part IV of the 2020 Chinese Pharmacopoeia. The results are shown in Tables 4 and 5.

[0081] Table 4. Telmisartan layer dissolution results (pH 7.5, 75 rpm)

[0082]

[0083] (f2 is calculated for 5 min, 10 min, and 20 min)

[0084] Table 5. Dissolution results of amlodipine layer (pH 7.5, 75 rpm)

[0085]

[0086]

[0087] (f2 is calculated for 5 min, 10 min, and 20 min)

[0088] According to Table 4, Table 5 and Appendix Figures 1-4According to the information, in the telmisartan-amlodipine tablets prepared in Examples 1-5 (Example 1: mannitol to sorbitol mass ratio 10:1, Example 2: mannitol to sorbitol mass ratio 13.2:1, Example 3: mannitol to sorbitol mass ratio 20:1, Example 4: purified water amount 250% of solid weight, Example 5: purified water amount 170% of solid weight), the dissolution similarity factor f2 between the telmisartan layer and the amlodipine layer all exceeded 50, indicating that their dissolution is similar to that of commercially available products. However, when sorbitol was used as a filler alone (see Comparative Example 1), when mannitol was used alone (see Comparative Example 5), when the amount of mannitol in the ratio of mannitol to sorbitol was small (see Comparative Example 2: 1:1 and Comparative Example 3: 6.6:1), or when the proportion of mannitol was too high (see Comparative Example 4: 41.5:1), the dissolution similarity factor f2 of the telmisartan-amlodipine tablets obtained did not exceed 50, and the effect was not comparable to that of commercially available products.

[0089] In addition, the amount of purified water used in the solution preparation process of telmisartan amlodipine tablets is also very important. When the amount of purified water is too small (e.g., in Comparative Example 6, the amount of purified water is 150% of the weight of the solid substance) or too large (e.g., in Comparative Example 7, the amount of purified water is 280% of the weight of the solid substance), the dissolution similarity factor f2 of the telmisartan amlodipine layer in the obtained telmisartan amlodipine tablets does not exceed 50, and it fails to achieve the same effect as commercially available products.

[0090] The methods for detecting related substances are as follows:

[0091] Related substances of telmisartan were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0092] Take 0.2g of sodium hydroxide as the solvent, place it in a 1000ml volumetric flask, add 10ml of water, sonicate to dissolve, cool, dilute to the mark with methanol, and shake well to obtain the final product.

[0093] For the test solution, accurately weigh 10 tablets of this product, grind them into a fine powder, accurately weigh an appropriate amount of the fine powder (approximately equivalent to 100 mg of telmisartan), place it in a 100 ml volumetric flask, add approximately 70 ml of solvent, sonicate and shake occasionally for 15 minutes to dissolve the telmisartan, cool to room temperature, dilute to the mark with solvent, shake well, filter through a 0.45 μm filter membrane, accurately measure 5 ml of the filtrate, place it in a 25 ml volumetric flask, dilute to the mark with mobile phase A, and shake well.

[0094] Accurately measure an appropriate amount of the test solution and dilute it with mobile phase A to prepare a solution containing approximately 0.4 μg of telmisartan per 1 ml, which will serve as the control solution.

[0095] For the limit of quantitation solution, accurately measure an appropriate amount of the control solution and dilute it with mobile phase A to prepare a solution containing approximately 0.2 μg of telmisartan per 1 ml, which is used as the limit of quantitation solution (0.1%).

[0096] For system suitability solutions, dissolve and dilute an appropriate amount of amlodipine besylate reference standard with a solvent to prepare a solution containing approximately 0.5 mg of amlodipine per ml, as the amlodipine reference standard stock solution. Separately, dissolve and dilute appropriate amounts of impurity reference standards TM-A, TM-B, TM-F, and TM-G with a solvent to prepare a solution containing 4 μg of each impurity reference standard, as the impurity reference standard stock solution. Accurately weigh approximately 25 mg of telmisartan reference standard, place it in a 25 ml volumetric flask, add approximately 18 ml of solvent, sonicate to dissolve, cool, dilute to the mark with solvent, and mix well, as the telmisartan reference standard stock solution. Accurately measure 2 ml of the telmisartan reference standard stock solution, 0.25 ml of the amlodipine reference standard stock solution, and 1 ml of the impurity reference standard stock solution, place them in the same 10 ml volumetric flask, dilute to the mark with mobile phase A, and mix well.

[0097] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Zorbax SB C18 50×4.6mm, 3.5μm or other equivalent columns); mobile phase A was methanol-phosphate buffer (2.0g ammonium dihydrogen phosphate dissolved in 1000ml water, pH adjusted to 3.0±0.1 with phosphoric acid) (60:40); mobile phase B was methanol-phosphate buffer (80:20); gradient elution was performed according to the table below. Flow rate: 1.2ml / min; column temperature: 35℃; detection wavelength: 298nm; injection volume: 10μl.

[0098] Table 6

[0099]

[0100] For the assay, accurately measure the test solution and the control solution, inject them separately into the liquid chromatograph, and record the chromatograms.

[0101] If the chromatogram of the test solution shows a known impurity peak, the area of ​​any peak shall not exceed 0.5 times (0.1%) of the main peak area of ​​the control solution; if other impurity peaks show a peak, the area of ​​any peak shall not exceed 0.2% of the main peak area of ​​the control solution, and the total amount of other impurities shall not exceed 0.2% of the main peak area of ​​the control solution; any impurity peak in the chromatogram of the test solution that is less than 0.5 times (0.05%) of the main peak area of ​​the limit of quantitation solution shall be ignored.

[0102] Related substances of amlodipine besylate were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0103] Solvent A is taken from mobile phase A, and the pH value is adjusted to 2.9±0.1 with phosphoric acid.

[0104] Solvent B is taken from mobile phase A, and the pH value is adjusted to 2.7±0.1 with phosphoric acid.

[0105] For the test solution, accurately weigh 10 tablets of this product, grind them into a fine powder, accurately weigh an appropriate amount of the fine powder (approximately equivalent to 10 mg of amlodipine), place it in a 20 ml brown volumetric flask, accurately add 10 ml of solvent B, sonicate for 15 minutes while shaking occasionally to dissolve, cool, dilute to the mark with solvent B, shake well, centrifuge, take the supernatant and filter it through a 0.45 μm filter membrane, and take the filtrate as the test solution.

[0106] Accurately measure an appropriate amount of the test sample and dilute it with solvent A to prepare a solution containing 2 μg of amlodipine per 1 ml, which will serve as the control solution.

[0107] Accurately measure an appropriate amount of the control solution and dilute it with solvent A to prepare a solution containing 0.5 μg of amlodipine per 1 ml, which is used as the limit of quantitation solution (0.1%).

[0108] For the system suitability solution, take an appropriate amount of impurity AL-I reference standard and dilute it with solvent A to prepare a solution containing approximately 30 μg per 1 ml, which is used as the impurity AL-I stock solution; separately, accurately weigh approximately 14 mg of amlodipine besylate reference standard, place it in a 20 ml volumetric flask, add 1 ml of impurity AL-I stock solution, add solvent A, sonicate to dissolve and dilute to the mark, shake well, and use this as the system suitability solution.

[0109] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Waters Symmetry C18 150×4.6 mm, 5 μm or other equivalent columns); mobile phase A was triethylamine buffer (7.0 mL triethylamine diluted with water to 1000 mL, pH adjusted to 3.0 ± 0.1 with phosphoric acid)-methanol-acetonitrile (55:30:15); mobile phase B was triethylamine buffer-methanol-acetonitrile (30:60:10), with gradient elution according to the table below. The flow rate was 1.2 mL / min; the column temperature was 25 °C; impurity AL-I was detected at 237 nm, and other non-specific degradation products of amlodipine were detected at 360 nm; the injection volume was 25 μl.

[0110] Table 7

[0111]

[0112]

[0113] For the assay, accurately measure the control solution and the test solution, inject them separately into the liquid chromatograph, and record the chromatograms.

[0114] If AL-I is present in the chromatogram of the test solution (detected at 237 nm), the peak area (multiplied by a correction factor of 2.0) shall not exceed 0.75 times (0.3%) the area of ​​the main peak in the control solution; if other impurities are present (detected at 360 nm), the peak area shall not exceed 0.5 times (0.2%) the area of ​​the main peak in the control solution; the total impurities of amlodipine shall not exceed 2.5 times (1.0%) the area of ​​the main peak in the control solution. Any impurity peaks in the chromatogram of the test solution smaller than 0.5 times (0.05%) the area of ​​the main peak in the limit of quantitation solution, and peaks with relative retention times before 0.15, shall be disregarded.

[0115] Table 8 Impurity Information

[0116]

[0117]

[0118] Table 9. Data on related substances

[0119]

[0120] According to the information on related substances in Table 9, the contents of related substances in the telmisartan-amlodipine tablets prepared in Examples 1-5 were low and met the limit requirements. However, when only sorbitol was used as a filler (see Comparative Example 1), the AL-I impurity in the amlodipine layer reached the limit value of 0.3%; when only mannitol was used (see Comparative Example 5), the AL-I impurity in the amlodipine layer reached 0.45%, exceeding the limit value of 0.3%; and when the amount of mannitol in the ratio of mannitol to sorbitol was small (see Comparative Example 2: 1:1 and Comparative Example 3: 6.6:1), not only did the AL-I impurity in the amlodipine layer exceed the limit value, but the types and contents of impurities in the telmisartan layer were also high; when the proportion of mannitol was too high (see Comparative Example 4: 41.5:1), similarly, the AL-I impurity in the amlodipine layer exceeded the limit value, and the types and contents of impurities in the telmisartan layer were also high.

[0121] In addition, during the preparation of telmisartan amlodipine tablets, if the amount of purified water used in the solution preparation is too small (e.g., in Comparative Example 6, the amount of purified water is 150% of the weight of the solid substance) or too large (e.g., in Comparative Example 7, the amount of purified water is 280% of the weight of the solid substance), the types of impurities in the amlodipine layer of the obtained telmisartan amlodipine tablets will increase, and the impurity AL-I will exceed the limit value.

[0122] In summary, the telmisartan-amlodipine tablets obtained by this invention have both good dissolution rates of telmisartan and amlodipine tablets and low content of related substances.

[0123] The embodiments of this application have been described above with reference to the accompanying drawings. However, 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 compound preparation for treating hypertension, characterized in that, include: The telmisartan layer and the amlodipine layer are provided. The telmisartan layer is composed of telmisartan, binder, alkalizing agent, filler and lubricant. The amlodipine layer is composed of amlodipine besylate, diluent, lubricant, flow aid and colorant. The filler of the telmisartan layer is composed of mannitol and sorbitol.

2. The compound preparation for treating hypertension according to claim 1, characterized in that, The mass ratio of mannitol to sorbitol is (9-21):1, preferably (10-20):

1.

3. The compound preparation for treating hypertension according to claim 2, characterized in that, The telmisartan layer, by weight, comprises 75-85 parts telmisartan, 20-30 parts binder, 25-35 parts alkalizing agent, 300-400 parts filler, and 2-10 parts lubricant.

4. The compound preparation for treating hypertension according to claim 3, characterized in that, The adhesive is polyvinylpyrrolidone, the alkalizing agent is one or both of sodium hydroxide or meglumine, and the lubricant is magnesium stearate.

5. The compound preparation for treating hypertension according to claim 4, characterized in that, The amlodipine layer, by weight, comprises 2-10 parts amlodipine besylate, 150-250 parts diluent, 1-10 parts lubricant, 1-10 parts flow aid, and 0.1-1 parts colorant.

6. The compound preparation for treating hypertension according to claim 5, characterized in that, The diluent is one or more of microcrystalline cellulose, pregelatinized starch or corn starch, the lubricant is magnesium stearate, the flow aid is silicon dioxide, and the colorant is yellow iron oxide.

7. The method for preparing the compound preparation for treating hypertension according to any one of claims 1 to 6, characterized in that, The process includes the following steps: (1) preparation of telmisartan layer, (2) preparation of amlodipine layer, (3) pressing of double-layer tablets, and (4) packaging.

8. The preparation method according to claim 7, characterized in that, The preparation of the telmisartan layer includes the following steps: 1) dissolving sodium hydroxide, telmisartan, meglumine, povidone and sorbitol in water; 2) placing mannitol in a fluidized bed, spraying the solution obtained in step 1) into the fluidized bed for granulation, and drying after spraying; 3) sizing the particles obtained in step 2); 4) mixing magnesium stearate and the particles obtained in step 3).

9. The preparation method according to claim 8, characterized in that, In step 1), the amount of purified water used is 170% to 250% of the total weight of the solid substances in the solution.

10. The preparation method according to claim 9, characterized in that, The temperature of the solution preparation process in step 1) is 45±5℃.

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