Compound tablet for treating hypertension and preparation method thereof

Abstract

The present application discloses a compound tablet for treating hypertension, comprising: an azilsartan layer and an amlodipine layer. The raw materials and auxiliary materials for preparing the azilsartan layer include azilsartan, a binder 1, a disintegrant 1, a diluent 1, and a lubricant 1; the binder 1 is a compound of polyethylene glycol, hypromellose, and pregelatinized starch; and based on 100% by weight of the azilsartan layer, the content of azilsartan is 10-20%, the content of the binder 1 is 1-15%, the content of the disintegrant 1 is 5-10%, the content of the diluent 1 is 60-70%, and the content of the lubricant 1 is 0.1-1%; the raw materials and auxiliary materials for preparing the amlodipine layer include amlodipine besylate, a binder 2, a disintegrant 2, a diluent 2, and a lubricant 2. The compound tablet for treating hypertension obtained by the present invention has good dissolution and stability.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical preparations, and in particular to a compound tablet for treating hypertension and a preparation method thereof. Background Art

[0002] Azilsartan and amlodipine are two widely used antihypertensive drugs, belonging to the angiotensin II receptor blockers (ARBs) and calcium channel blockers (CCBs) classes, respectively. Azilsartan lowers blood pressure by blocking the effects of angiotensin II, relaxing blood vessels; while amlodipine reduces cardiac workload and vascular contractility by preventing calcium ions from entering cardiac and vascular smooth muscle cells.

[0003] Although azilsartan and amlodipine have shown significant antihypertensive effects as monotherapy, in some patients, monotherapy cannot achieve the desired blood pressure control target. Therefore, in order to further improve the antihypertensive effect and patient compliance, researchers began to explore the possibility of combining these two drugs into a single-tablet combination preparation.

[0004] In March 2014, azilsartan and amlodipine tablets developed by Takeda Pharmaceutical Company Limited of Japan were approved for marketing in Japan under the trade name Zacras for the treatment of hypertension.

[0005] Furthermore, patent CN102481248A applied for by Takeda Pharmaceutical Company Limited discloses a solid preparation (azilsartan and amlodipine tablets) that uses highly water-soluble sugar alcohols to improve drug dissolution properties.

[0006] Patent CN106668016B discloses a solid preparation of a combination of azilsartan and amlodipine besylate and a preparation method thereof, wherein azilsartan particles are obtained by compounding azilsartan with polyethylene glycol, and amlodipine besylate-containing particles are obtained by compounding amlodipine besylate with starch.

[0007] Patent CN104644632A discloses oral tablets containing azilsartan and amlodipine besylate and a preparation method thereof, wherein azilsartan and amlodipine besylate are encapsulated in lactose and directly compressed with other pharmaceutical excipients to obtain azilsartan and amlodipine besylate tablets.

[0008] The contents described in the above patents are all aimed at solving the dissolution and stability problems of azilsartan and amlodipine, but the effects they can achieve are still limited, and they fail to fully realize the dual excellent performance of the two active ingredients in dissolution and stability. Summary of the Invention

[0009] In order to solve the above problems existing in the prior art, the present invention provides the following technical solutions:

[0010] A compound tablet for treating hypertension, comprising: an azilsartan layer and an amlodipine layer. The raw materials and auxiliary materials for preparing the azilsartan layer include azilsartan, a binder 1, a disintegrant 1, a diluent 1, and a lubricant 1; the binder 1 is a compound of polyethylene glycol, hypromellose, and pregelatinized starch; and based on 100% by weight of the azilsartan layer, the content of azilsartan is 10-20%, the content of the binder 1 is 1-15%, the content of the disintegrant 1 is 5-10%, the content of the diluent 1 is 60-70%, and the content of the lubricant 1 is 0.1-1%.

[0011] The raw and auxiliary materials for preparing the amlodipine layer include amlodipine besylate, a binder 2, a disintegrant 2, a diluent 2 and a lubricant 2. Based on 100% mass of the amlodipine layer, the content of amlodipine besylate is 10-20%, the content of the binder 2 is 1-10%, the content of the disintegrant 2 is 2-10%, the content of the diluent 2 is 60-95%, and the content of the lubricant 2 is 0.1-1%.

[0012] Furthermore, the mass ratio of the polyethylene glycol, the hypromellose and the pregelatinized starch is 1:(1-4):(1-5).

[0013] Furthermore, the content of the adhesive 1 is 5-10%.

[0014] Furthermore, it is characterized in that the disintegrant 1 is a compound of low-substituted hydroxypropyl cellulose and colloidal silicon dioxide.

[0015] Furthermore, the mass ratio of the low-substituted hydroxypropyl cellulose to the colloidal silicon dioxide is 1:(1-3).

[0016] Furthermore, the content of the disintegrant 1 is 8-10%.

[0017] Furthermore, the diluent 1 is selected from one or more of lactose, corn starch or microcrystalline cellulose PH-101.

[0018] Furthermore, the binder 2 is hydroxypropyl cellulose HPC-SSL, the disintegrant 2 is anhydrous calcium hydrogen phosphate, the diluent 2 is selected from one or both of mannitol RAMRITOL 60 and microcrystalline cellulose PH-101, and the lubricant 2 is magnesium stearate SH-YM-M.

[0019] On the other hand, the present invention also provides a method for preparing the above-mentioned compound tablet for treating hypertension, wherein the disintegrant 1, lubricant 1 and part of the diluent 1 in the azilsartan layer are added externally; and the disintegrant 2 and lubricant 2 in the amlodipine layer are added externally.

[0020] Furthermore, the preparation method of the above-mentioned compound tablet for treating hypertension comprises the following steps:

[0021] (1) Preparation of the azilsartan layer: The azilsartan layer was prepared by a one-step granulation process and the addition of some excipients;

[0022] (2) Preparation of the amlodipine layer: The amlodipine layer was prepared by a one-step granulation process and the addition of some excipients;

[0023] (3) tableting the azilsartan layer obtained in step (1) and the amlodipine layer obtained in step (2) to obtain azilsartan and amlodipine tablets;

[0024] (4) Coating: Coating the plain tablets.

[0025] Compared with the prior art, the compound tablet for treating hypertension of the present invention has the following advantages:

[0026] Improved dissolution characteristics: By controlling the type and ratio of the binder in the azilsartan layer, as well as the type and ratio of the disintegrant, the present invention ensures that the dissolution behavior of azilsartan and amlodipine is highly consistent with that of the original drug. This means that the drug release in the body is more balanced and stable, which helps maintain the ideal blood drug concentration, thereby improving the treatment effect and reducing the potential risk of adverse reactions.

[0027] Enhanced ingredient stability: A major breakthrough of this invention is that it significantly enhances the stability of the active ingredients azilsartan and amlodipine in the preparation, reduces the generation of impurities, ensures the quality reliability of the drug during storage and use cycles, and extends the shelf life of the product.

[0028] Process optimization: The present invention not only simplifies the preparation steps, but also effectively reduces the waste of raw materials, cuts down production costs, improves the overall economic benefits, and is conducive to the sustainable development of the pharmaceutical industry. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 1 and 2 are the dissolution curves of the azilsartan layer of the embodiment and the commercially available product.

[0030] Figure 2 This is the dissolution curve of the comparative example and the commercially available product Azilsartan layer.

[0031] Figure 3 1 is the dissolution curve of the embodiment and the commercially available product amlodipine layer.

[0032] Figure 4 It is the dissolution curve of the comparative example and the commercially available product amlodipine layer. DETAILED DESCRIPTION

[0033] The following will be combined with the accompanying drawings in the embodiments of the present application to clearly describe the technical solutions in the embodiments of the present application. Obviously, the embodiments described are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field fall within the scope of protection of this application.

[0034] The terms "first," "second," and the like in the specification and claims of this application are used to distinguish similar objects, and are not used to describe a specific order or precedence. It should be understood that the terms used in this manner are interchangeable where appropriate, so that the embodiments of this application can be implemented in an order other than that illustrated or described herein, and that the objects distinguished by "first," "second," and the like are generally of the same type, and do not limit the number of objects; for example, the first object can be one or more. In addition, the term "and / or" in the specification and claims refers to at least one of the connected objects, and the character " / " generally indicates that the objects connected are in an "or" relationship.

[0035] The inventors of the present application have discovered that by controlling the type and ratio of the binder in the azilsartan layer, as well as the type and ratio of the disintegrant, not only is the release profile of the compound tablet for treating hypertension (i.e., azilsartan and amlodipine tablets) more similar to that of the reference preparation, but the stability of the compound tablet for treating hypertension can also be maintained at a high level. The compound tablet for treating hypertension specifically comprises:

[0036] An azilsartan layer and an amlodipine layer, wherein the raw materials and auxiliary materials for preparing the azilsartan layer include azilsartan, a binder 1, a disintegrant 1, a diluent 1 and a lubricant 1; the binder 1 is a compound of polyethylene glycol, hypromellose and pregelatinized starch; in one embodiment of the present invention, the mass ratio of the polyethylene glycol, the hypromellose and the pregelatinized starch is 1:(1-4):(1-5), for example, 1:1:1, 1:2:1, 1:3:1, 1:4:1, 1:1:2, 1:2:2, 1:3:2, 1:4:2, 1:1:3, 1:2:3, 1:3:3, 1:4:3, 1:1:4, 1:2:4, 1:3:4, 1:4:4, 1:1:5, 1:2:5, 1:3:5 or 1:4:5, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0037] The choice of binder is crucial in tablet production, as it influences the tablet's molding ability, hardness, disintegration time, and drug release characteristics. After screening existing binders, the inventors discovered that the combined use of polyethylene glycol, hypromellose, and pregelatinized starch effectively improves the stability and disintegration rate of azilsartan and amlodipine tablets, ensuring effective drug release. Rapid tablet disintegration facilitates rapid drug dissolution and absorption, improving bioavailability.

[0038] And based on the mass of the azilsartan layer as 100%, the content of azilsartan is 10-20%, the content of binder 1 is 1-15%, the content of disintegrant 1 is 5-10%, the content of diluent 1 is 60-70%, and the content of lubricant 1 is 0.1-1%; in one embodiment of the present invention, the content of the binder 1 is preferably 5-10%, for example, 5%, 6%, 7%, 8%, 9% or 10%, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0039] In one embodiment of the present invention, the disintegrant 1 is a compound of low-substituted hydroxypropyl cellulose and colloidal silicon dioxide.

[0040] In a specific embodiment of the present invention, the mass ratio of the low-substituted hydroxypropyl cellulose to the colloidal silicon dioxide is 1:(1-3), for example 1:1, 1:2 or 1:3, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0041] Colloidal silicon dioxide is a highly porous powder that absorbs water and increases the gaps between powders, promoting water penetration into the interior of the tablet, thereby accelerating the disintegration process. Low-substituted hydroxypropyl cellulose rapidly absorbs water and swells upon contact with water, forming a sponge-like structure, thereby destroying the structure of the tablet and promoting its disintegration. The inventors discovered that the combination of the rapid water absorption and expansion of low-substituted hydroxypropyl cellulose and the water permeability of colloidal silicon dioxide can significantly increase the disintegration rate of the tablet and improve the tablet stability. At the same time, the inventors comprehensively considered factors such as the composition of the compound tablets for treating hypertension, the size of the tablets, the hardness requirements, and the required disintegration time, and explored the optimal usage ratio of low-substituted hydroxypropyl cellulose and colloidal silicon dioxide.

[0042] In one embodiment of the present invention, the content of the disintegrant 1 is 8-10%, for example 8%, 9% or 10%, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0043] In one embodiment of the present invention, the diluent 1 is selected from one or more of lactose, corn starch or microcrystalline cellulose PH-101.

[0044] The raw materials and auxiliary materials for preparing the amlodipine layer include amlodipine besylate, a binder 2, a disintegrant 2, a diluent 2, and a lubricant 2. In one embodiment of the present invention, the binder 2 is hydroxypropyl cellulose HPC-SSL, the disintegrant 2 is anhydrous calcium hydrogen phosphate, the diluent 2 is selected from one or more of mannitol RAMRITOL 60 or microcrystalline cellulose PH-101, and the lubricant 2 is magnesium stearate SH-YM-M.

[0045] The following are specific examples and comparative examples of the present invention, but the present invention is not limited to the following examples.

[0046] Table 1 Source information of raw materials and auxiliary materials of Examples and Comparative Examples

[0047]

[0048]

[0049] Examples 1 to 8 and Comparative Examples 1 to 10 respectively provide a compound tablet for treating hypertension (i.e., azilsartan and amlodipine tablets), the raw materials and proportions (in parts by weight) of which are shown in Table 2:

[0050] Table 2: Ratio of raw materials and auxiliary materials of Azilsartan and Amlodipine Tablets in Example and Comparative Example

[0051]

[0052]

[0053] The preparation methods of the compound tablets for treating hypertension (i.e., azilsartan and amlodipine tablets) provided in Examples 1 to 8 and Comparative Examples 1 to 10 are as follows:

[0054] (1) Azilsartan layer

[0055] 1) Pass the prescribed amount of lactose through a 60-mesh sieve;

[0056] 2) Adhesive preparation: Add the prescribed amount of adhesive to purified water and stir until completely dissolved to prepare a 10% adhesive solution;

[0057] 3) Premixing

[0058] A. Mix the prescribed amount of corn starch in a laboratory hopper mixer for 5 minutes;

[0059] B. After the mixing in step A is completed, add the prescribed amount of azilsartan and the added amount of microcrystalline cellulose and continue mixing for 5 minutes;

[0060] C. After the mixing in step B is completed, add about 1 / 2 of the prescribed amount of lactose and mix in a hopper mixer for 5 minutes;

[0061] D. After step C, add the remaining 1 / 2 of the lactose and continue mixing for 10 minutes;

[0062] E. After the mixing in step D is completed, the resulting mixture is passed through a granulator with a 1.5 mm round mesh, sieved, and mixed in a laboratory hopper mixer for 8 minutes;

[0063] 4) One-step granulation

[0064] A. Preheating: Add the mixed material obtained in step 3) into the fluidized bed and stop the machine when the material temperature rises to 35°C;

[0065] B. Spraying adhesive: Spray the adhesive into the fluidized bed with the peristaltic pump speed at 7-15 rpm, the atomizing pressure at 0.15 MPa, and the air inlet temperature at 70°C.

[0066] C. Drying: Dry the soft material after spraying the adhesive in a fluidized bed. Set the air inlet temperature to 60°C and control the moisture content below 3%. Stop the machine and remove the material from the oven.

[0067] 5) Granulation: The granules obtained in step 4) were granulated by a 1.5 mm round sieve grinder;

[0068] 6) Total Blending: The excipients low-substituted hydroxypropyl cellulose (if any), colloidal silicon dioxide (if any), and microcrystalline cellulose were mixed with the granules obtained in step 5) in a laboratory hopper mixer at 10 rpm for 10 minutes, and magnesium stearate was added and mixed for 8 minutes;

[0069] (2) Amlodipine layer

[0070] 1) Pass the prescribed amount of mannitol through a 40-mesh sieve;

[0071] 2) Binder preparation: Prepare a 10% solution of hydroxypropyl cellulose; add hydroxypropyl cellulose to purified water and stir until completely dissolved;

[0072] 3) Premixing

[0073] A. Mix amlodipine besylate and approximately 1 / 2 of the prescribed amount of microcrystalline cellulose in a ziplock bag for 5 minutes. Then add the remaining 1 / 2 of the prescribed amount of microcrystalline cellulose and continue mixing for 5 minutes.

[0074] B. Pour about 1 / 2 of the mannitol into a laboratory hopper mixer and mix for 5 minutes at 10 rpm. Add the material obtained in step A and continue mixing for 5 minutes.

[0075] C. After the mixing in step B is completed, add the remaining mannitol and continue mixing for 5 minutes;

[0076] D. After the mixing in step C is completed, the resulting mixture is passed through a granulator and a 1.5 mm round screen, and then further mixed in a laboratory hopper mixer for 8 minutes;

[0077] 4) One-step granulation

[0078] A. Preheating: Add the mixed material obtained in step 3) into the fluidized bed and stop the machine when the material temperature rises to 35°C;

[0079] B. Spraying adhesive: Spray the adhesive into the fluidized bed with the peristaltic pump speed at 7-15 rpm, the atomizing pressure at 0.15 MPa, and the air inlet temperature at 70°C.

[0080] C. Drying: Dry the soft material after spraying the adhesive in a fluidized bed. Set the air inlet temperature to 60°C and control the moisture content below 3%. Stop the machine and remove the material from the oven.

[0081] 5) Granulation: The granules obtained in step 4) were granulated by a 1.5 mm round sieve grinder;

[0082] 6) Total mixing: The additional auxiliary material anhydrous calcium hydrogen phosphate and the granules obtained in step 5) were mixed in a laboratory hopper mixer for 10 minutes at a speed of 10 rpm, and magnesium stearate was added and mixed for 8 minutes;

[0083] (3) Tableting: The granules obtained in (1) and (2) are tableted to produce azilsartan and amlodipine tablets;

[0084] (4) Coating: Use film coating premix to coat the plain tablets.

[0085] Dissolution assay:

[0086] The dissolution rate of the tablets described in Examples 1-8 and Comparative Examples 1-10 was determined by HPLC using the basket method at 100 rpm, 37±0.5°C, and pH 6.8 phosphate buffer. The results are shown in Tables 3 and 4.

[0087] Table 3 Dissolution results of Azilsartan in Examples and Comparative Examples

[0088]

[0089]

[0090] Table 4 Dissolution results of amlodipine in the embodiments and comparative examples

[0091] Dissolution 5min 10min 15min 20min 30min 45min f2 Commercially available products 79.0 92.8 96.1 96.6 97.1 98.1 / Example 1 80.4 93.3 95.4 97.1 98.3 99.4 93 Example 2 83.4 90.5 95.5 96.9 98.8 100.4 78 Example 3 77.4 89.9 93.4 94.9 96.7 99.5 79 Example 4 76.1 88.4 94.2 96.9 98.9 99.3 74 Example 5 75.4 90.3 92.3 94.5 98.4 100.1 73 Example 6 82.4 90.8 94.5 96.7 99.3 100.5 79 Example 7 74.4 88.9 93.2 97.8 98.9 98.4 70 Example 8 78.0 90.4 94.3 95.7 96.8 99.0 84 Comparative Example 1 87.7 96.7 97.5 97.9 98.8 99.9 62 Comparative Example 2 88.8 95.4 97.9 98.3 99.5 99.2 61 Comparative Example 3 86.9 94.6 97.7 99.8 99.5 99.3 66 Comparative Example 4 64.3 80.9 90.4 94.7 96.9 100.0 47 Comparative Example 5 89.0 90.4 94.8 98.7 99.9 100.4 61 Comparative Example 6 86.7 89.9 94.7 97.8 98.9 100.7 65 Comparative Example 7 89.7 90.8 94.3 95.6 97.7 99.8 60 Comparative Example 8 85.9 88.7 90.6 93.4 96.9 98.6 62 Comparative Example 9 89.4 94.3 95.9 97.7 97.9 98.9 61 Comparative Example 10 62.3 81.1 89.4 93.1 95.6 98.5 45

[0092] From Table 3, Table 4 and Figures 1 to 4The dissolution results of azilsartan and amlodipine in Examples 1-6 and Comparative Examples 1-6 show that the binder of the azilsartan layer in Examples 1-6 is a compound of polyethylene glycol, hypromellose, and gelatinized starch, with the three components in a specific ratio (1:(1-3):(1-5)). Compared with the dissolution of commercially available products, the f2 value is used as a judgment indicator. An f2 value greater than 50 is considered similar, and a larger f2 value indicates a better dissolution curve fit. The dissolution similarity of azilsartan and amlodipine in Examples 1-6 is good.

[0093] Comparative Examples 1 to 3 only selected two adhesives. Although the solubility f2 values ​​of azilsartan and amlodipine besylate were around 50, the f2 values ​​of Examples 1 to 6 were larger, and the dissolution curves of Examples 1 to 6 had a better fit with the dissolution curves of commercially available products.

[0094] In Comparative Example 4, the ratio of polyethylene glycol, hypromellose, and gelatinized starch is 1:5:2. From the dissolution data, when the content of hypromellose is too high, the solubility f2 values ​​of azilsartan and amlodipine besylate are both less than 50, failing to achieve a dissolution effect similar to that of commercially available products.

[0095] In Comparative Example 5, the ratio of polyethylene glycol, hypromellose, and gelatinized starch is 1:2:6. From the dissolution data, when the content of gelatinized starch in the adhesive is too high, the solubility f2 values ​​of azilsartan and amlodipine besylate just exceed 50. Although the dissolution effect can be similar to that of the commercially available products, the dissolution similarity is poor compared with Examples 1 to 6.

[0096] In Comparative Example 6, the ratio of polyethylene glycol, hypromellose and gelatinized starch is 1:0.5:0.5. From the dissolution data, when the content of hypromellose and gelatinized starch in the adhesive is low, the f2 value of azilsartan is 50 and the f2 value of amlodipine besylate is 65. Although the dissolution effect is similar to that of the commercially available product, the dissolution similarity is poor compared with Examples 1 to 6.

[0097] From Table 3, Table 4 and Figures 1 to 4 The dissolution results of azilsartan and amlodipine in Example 1, Examples 7-8, and Comparative Examples 7-10 show that the disintegrant in the azilsartan layer of Examples 1 and Examples 7-8 is a compound of low-substituted hydroxypropylcellulose and colloidal silicon dioxide, with the two having a specific ratio of 1:(1-3). Compared with the dissolution of commercially available products, the f2 value is used as a judgment indicator. An f2 value greater than 50 is considered similar, and a larger f2 value indicates a better dissolution curve fit. The dissolution similarity of azilsartan and amlodipine in Examples 1 and Examples 7-8 is good.

[0098] Comparative Examples 9-10 selected only one disintegrant, and the dissolution f2 values ​​of azilsartan were all less than 50, failing to achieve a dissolution effect similar to that of the commercially available product.

[0099] In Comparative Example 7, the ratio of low-substituted hydroxypropyl cellulose to colloidal silicon dioxide is 1:4. From the dissolution data, when the colloidal silicon dioxide content is too high, the dissolution f2 value of azilsartan is 47, which is less than 50, and fails to achieve a dissolution effect similar to that of the commercially available product.

[0100] In Comparative Example 8, the ratio of low-substituted hydroxypropyl cellulose to colloidal silicon dioxide is 1:0.5. From the dissolution data, when the content of low-substituted hydroxypropyl cellulose is too high, the dissolution f2 value of azilsartan is 50, which just achieves a dissolution effect similar to that of the commercially available product. However, compared with Examples 1 and Examples 7-8, the dissolution similarity is poor.

[0101] In summary, the selection and proportion of binders and the selection and proportion of disintegrants play a role in the dissolution of the active ingredients in azilsartan and amlodipine tablets.

[0102] Determination of related substances:

[0103] Chromatographic column: Waters C18, 4.6mm×250mm, 5μm or equivalent performance column;

[0104] Mobile phase:

[0105] Mobile phase A: potassium dihydrogen phosphate buffer (take 2.72 g of potassium dihydrogen phosphate, dissolve it in water and dilute it to 1000 ml, and adjust the pH to 3.0 with phosphoric acid);

[0106] Mobile phase B: acetonitrile;

[0107] Column temperature: 30°C; flow rate: 1.0 ml / min; wavelength: 230 nm; injection volume: 10 μl;

[0108] Trapping column: Shimadzu 4.6mm×50mm;

[0109] Gradient program:

[0110] Table 5

[0111]

[0112] Limits: In the chromatogram of the test solution, excluding the benzenesulfonic acid peak with a relative retention time of approximately 0.15, if there are chromatographic peaks with retention times consistent with known impurities, the peak areas of impurities A and B shall not be greater than 2.5 times (0.5%) of the azilsartan peak area in the control solution, the peak area of ​​impurity C shall not be greater than (0.2%) of the azilsartan peak area in the control solution, and the peak area of ​​impurity D shall not be greater than 5 times (1.0%) of the amlodipine peak area in the control solution. The peak area of ​​any other individual impurity shall not be greater than (0.2%) of the main peak area of ​​the azilsartan control solution, and the sum of the peak areas of all impurities (excluding the amlodipine peak) shall not be greater than 15 times (3.0%) of the main peak area of ​​the azilsartan control solution. Peaks in the chromatogram of the test solution that are less than 0.85 times the main peak area of ​​amlodipine in the sensitivity solution shall be ignored (0.05%).

[0113] Table 6 Impurity information in Azilsartan and Amlodipine Tablets is as follows:

[0114]

[0115]

[0116] The results of related substance detection of the tablets described in Examples 1 to 8 and Comparative Examples 1 to 10 are shown in Table 7.

[0117] Table 7 Test results of related substances in Examples and Comparative Examples

[0118]

[0119]

[0120]

[0121]

[0122] From the related substance test results of azilsartan and amlodipine besylate in Examples 1 to 6 and Comparative Examples 1 to 6 in Table 7, it can be seen that the contents of related substances in the azilsartan and amlodipine besylate tablets obtained in Examples 1 to 6 met the limit requirements at day 0 and after being stored under high temperature (40°C and 60°C), high humidity (90% humidity) and light (4500±500 Lux) for 30 days, and the contents increased slowly.

[0123] Comparative Examples 1 to 3 used only two adhesives. The total impurity content of the azilsartan and amlodipine tablets obtained in Comparative Example 1 reached 1.197% after 30 days of exposure to light (4500±500 Lux), a rapid increase compared to 0.314% on day 0. The total impurity content of the azilsartan and amlodipine tablets obtained in Comparative Example 2 reached 1.187% after 30 days of exposure to light (4500±500 Lux), a rapid increase compared to 0.372% on day 0. Furthermore, the content of impurity D reached 0.931% after 30 days of exposure, a rapid increase. The impurity D content (0.999%) and total impurities (1.199%) of the azilsartan and amlodipine tablets obtained in Comparative Example 3 also increased rapidly after 30 days of exposure to light (4500±500 Lux).

[0124] In Comparative Example 4, the ratio of pre-polyethylene glycol, hypromellose, and gelatinized starch was 1:5:2. According to the relevant material data, when the hypromellose content was too high, the impurity D (0.94%) and total impurities (1.133%) also increased rapidly after being placed under light (4500±500 Lux) for 30 days.

[0125] In Comparative Example 5, the ratio of pre-polyethylene glycol, hydropropyl methylcellulose, and gelatinized starch is 1:2:6. According to the relevant material data, when the gelatinized starch content in the adhesive is too high, the total impurity content reaches 1.209% after 30 days of exposure to light (4500±500Lux), which is 0.351% on the 0th day. The total impurity content increases too fast. At the same time, the content of impurity D reaches 0.976% after 30 days of exposure to light, which is 0.084% on the 0th day. The growth rate is too fast.

[0126] In Comparative Example 6, the ratio of pre-polyethylene glycol, hypromellose, and gelatinized starch is 1:0.5:0.5. According to the relevant material data, when the content of hypromellose and gelatinized starch in the adhesive is low, the total impurity content reaches 1.298% after 30 days of exposure to light (4500±500Lux), which is 0.312% on the 0th day, indicating that the total impurity content increases too quickly.

[0127] As can be seen from the results of related substances in Table 7 for Example 1, Examples 7-8, and Comparative Examples 7-10, the disintegrant in the azilsartan layer of Examples 1 and Examples 7-8 is a compound of low-substituted hydroxypropylcellulose and colloidal silicon dioxide in a specific ratio (1:(1-3)). The contents of related substances in the azilsartan and amlodipine tablets obtained in Examples 1 and Examples 7-8 met the limit requirements at day 0 and after being stored under high temperature (40°C and 60°C), high humidity (90% humidity), and light (4500±500 Lux) for 30 days, and the contents increased slowly.

[0128] Comparative Example 9 selected only low-substituted hydroxypropyl cellulose as a disintegrant. After being placed under light (4500±500 Lux) for 30 days, the total impurity content reached 1.198%, compared with 0.295% on the 0th day, indicating that the total impurity content increased too quickly.

[0129] In Comparative Example 10, only colloidal silicon dioxide was selected as the disintegrant. After 30 days of exposure to light (4500±500 Lux), the total impurity content reached 1.256%, which was 0.309% on day 0, indicating an excessively rapid increase in total impurities. Furthermore, the content of impurity D reached 0.994% after 30 days of exposure to light, which was 0.103% on day 0, indicating an excessively rapid increase.

[0130] In Comparative Example 7, the ratio of low-substituted hydroxypropyl cellulose to colloidal silicon dioxide is 1:4. According to the relevant material data, when the colloidal silicon dioxide content is too high, the total impurity content reaches 1.283% after 30 days of exposure to light (4500±500 Lux), which is a significant increase compared to 0.35% on the 0th day. At the same time, the content of impurity D reaches 0.999% after 30 days of exposure to light, which is an excessively rapid increase compared to 0.089% on the 0th day.

[0131] In Comparative Example 8, the ratio of low-substituted hydroxypropyl cellulose to colloidal silicon dioxide is 1:0.5. According to the relevant material data, when the content of low-substituted hydroxypropyl cellulose is too high, the total impurity content reaches 1.322% after 30 days of exposure to light (4500±500Lux), which is significantly higher than 0.333% on the 0th day. At the same time, the content of impurity D reaches 1.012% after 30 days of exposure to light, which is too fast compared with 0.099% on the 0th day.

[0132] In conclusion, the selection and proportion of binders and the selection and proportion of disintegrants jointly affect the stability of azilsartan and amlodipine tablets.

[0133] The embodiments of the present application are described above in conjunction with the accompanying drawings, but the present application is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are merely illustrative and not restrictive. Under the guidance of this application, ordinary technicians in this field can also make many forms without departing from the purpose of this application and the scope of protection of the claims, all of which are within the protection of this application.

Claims

1. A compound tablet for treating hypertension, comprising: The azilsartan layer and the amlodipine layer are characterized in that the raw materials for preparing the azilsartan layer include azilsartan, a binder 1, a disintegrant 1, a diluent 1 and a lubricant 1; the binder 1 is a compound of polyethylene glycol, hypromellose and pregelatinized starch; and based on 100% by mass of the azilsartan layer, the content of azilsartan is 10-20%, the content of the binder 1 is 1-15%, the content of the disintegrant 1 is 5-10%, the content of the diluent 1 is 60-70%, and the content of the lubricant 1 is 0.1-1%; The raw materials and auxiliary materials for preparing the amlodipine layer include amlodipine besylate, a binder 2, a disintegrant 2, a diluent 2 and a lubricant 2; and based on 100% by mass of the amlodipine layer, the content of amlodipine besylate is 10-20%, the content of the binder 2 is 1-10%, the content of the disintegrant 2 is 2-10%, the content of the diluent 2 is 60-95%, and the content of the lubricant 2 is 0.1-1%. The mass ratio of the polyethylene glycol, the hypromellose and the pregelatinized starch is 1:(1-4):(1-5), The disintegrant 1 is a compound of low-substituted hydroxypropyl cellulose and colloidal silicon dioxide. The mass ratio of the low-substituted hydroxypropyl cellulose to the colloidal silicon dioxide is 1:(1-3).

2. The compound tablet for treating hypertension according to claim 1, characterized in that The content of the adhesive 1 is 5-10%.

3. The compound tablet for treating hypertension according to claim 2, characterized in that: The content of the disintegrant 1 is 8-10%.

4. The compound tablet for treating hypertension according to claim 3, characterized in that: The diluent 1 is selected from one or more of lactose, corn starch or microcrystalline cellulose PH-101.

5. The compound tablet for treating hypertension according to claim 4, characterized in that: The binder 2 is hydroxypropyl cellulose HPC-SSL, the disintegrant 2 is anhydrous calcium hydrogen phosphate, the diluent 2 is selected from one or both of mannitol RAMRITOL 60 and microcrystalline cellulose PH-101, and the lubricant 2 is magnesium stearate SH-YM-M.

6. The method for preparing the compound tablet for treating hypertension according to claims 1 to 5, characterized in that: The disintegrant 1, the lubricant 1 and part of the diluent 1 in the azilsartan layer are added externally; the disintegrant 2 and the lubricant 2 in the amlodipine layer are added externally.

7. The method for preparing the compound tablet for treating hypertension according to claim 6, characterized in that: The steps include: (1) Preparation of azilsartan layer: The azilsartan layer was prepared by a one-step granulation process and the addition of some excipients; (2) Preparation of the amlodipine layer: The amlodipine layer was obtained by a one-step granulation process and the addition of some excipients; (3) tableting the azilsartan layer obtained in step (1) and the amlodipine layer obtained in step (2) to obtain azilsartan and amlodipine tablets; (4) Coating: Coating the plain tablets.

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