A medicament containing amlodipine and azilsartan and a preparation method thereof

Abstract

The present invention relates to the field of medical technology, and in particular to a medicament containing amlodipine and azilsartan and a preparation method. The medicament includes two or more independent mechanisms, and the mechanisms are provided with one of amlodipine drugs and azilsartan drugs; the amlodipine drugs are amlodipine or / and a pharmaceutically acceptable salt thereof; the azilsartan drugs are azilsartan or / and a pharmaceutically acceptable salt thereof. The preparation method is: the amlodipine drugs and the first auxiliary material are made into a first mixed material; the azilsartan drugs and the second auxiliary material are sprayed with the first adhesive in the granulation process to obtain the granules, and then the granules are crushed, and the third auxiliary material containing the second adhesive is added and mixed uniformly to obtain the second mixed material; the second mixed material and the first mixed material are pressed into a medicament. The present invention sets independent mechanisms to reduce the contact area of ​​the two types of drugs and improve the stability. The method of direct compression and fluidized bed granulation makes the preparation process simple and the stability better.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a medicament comprising amlodipine and azilsartan. Background Art

[0002] Hypertension is a disease caused by a variety of complex factors. Its occurrence and persistence are related to blood volume, cardiac function, vascular tension and other factors. The mechanisms of action of antihypertensive drugs currently used in clinical practice are also different. Usually, an antihypertensive drug can only affect part of the mechanism of hypertension, and its antihypertensive effect has certain limitations. In recent years, both international and domestic hypertension guidelines have consistently recommended starting SPC (new single-tablet combination preparation) treatment, because it can easily and efficiently solve the two key problems of combined treatment and compliance faced by hypertension management. The "2018 European Society of Cardiology (ESC) / European Society of Hypertension (ESH) Guidelines" recommend: SPC combined with two drugs is the preferred starting treatment for all patients with hypertension.

[0003] There are many patients with hypertension in my country, but the control rate is low. In order to achieve blood pressure control, most patients need to take combination medications, but compliance is inversely proportional to the number and frequency of medication. The survey found that hypertension drug treatment in my country faces serious problems such as low combination medication rate (only 30%) and poor compliance. Although SPC treatment can bring multiple benefits and is unanimously recommended by many authoritative guidelines, the use rate of SPC in hypertensive patients in my country is less than 10%. Clinicians should pay close attention to this, and the current status of SPC use needs to be improved urgently.

[0004] There are currently several fixed combinations containing a calcium channel blocker ("calcium antagonist") and an angiotensin II receptor antagonist on the market for the treatment of hypertension and angina, such as tablets containing amlodipine and valsartan or amlodipine and azilsartan.

[0005] Azilsartan, whose chemical name is 2-ethoxy-1-[[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid, has the structure shown in Formula I and is an angiotensin II receptor antagonist.

[0006]

[0007] Amlodipine besylate, chemically named: 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate besylate, has the structure shown in formula I1 and is a calcium channel blocker that can selectively inhibit calcium ions from crossing the membrane and entering smooth muscle cells and cardiomyocytes.

[0008]

[0009] In March 2014, Azilsartan Amlodipine Tablets developed by Takeda Pharmaceutical Co., Ltd. of Japan were approved for marketing in Japan under the trade name It is used to treat hypertension. Studies on the compound found that both azilsartan and amlodipine besylate are relatively stable, but the stability of the compound preparation obtained by mixing the two is poor. Summary of the invention

[0010] 1. Technical issues to be resolved

[0011] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a medicament comprising amlodipine and azilsartan, wherein the medicament is provided with two or more independent mechanisms for storing amlodipine and azilsartan respectively, thereby isolating the contact between the two and improving the stability of the medicament;

[0012] Accordingly, the present invention also provides a method for preparing the above-mentioned medicament containing amlodipine and azilsartan, which improves the solubility of amlodipine and azilsartan through direct compression and separate addition of adhesives, reduces the occurrence of impurities, and improves storage stability.

[0013] (II) Technical solution

[0014] In order to achieve the above object, the main technical solutions adopted by the present invention include:

[0015] In a first aspect, an embodiment of the present invention provides a medicament comprising amlodipine and azilsartan, characterized in that it comprises two or more mutually independent mechanisms, wherein the mechanisms are provided with one of the amlodipine-type drugs and the azilsartan-type drugs;

[0016] The amlodipine-type drug is amlodipine or / and a pharmaceutically acceptable salt thereof;

[0017] The azilsartan drug is azilsartan and / or a pharmaceutically acceptable salt thereof.

[0018] Optionally, the mechanism is a capsule that can contain the drug, or an integrated structure made of the drug and excipients.

[0019] Optionally, the medicine is a multilayer structure formed by two or more independent structures tightly connected in sequence from the inside to the outside.

[0020] Optionally, the volume ratio of the contact area of ​​the two mechanisms to the medicine is 12-17:100.

[0021] Optionally, the medicine is cylindrical, and has a bottom diameter of 9 mm and a height of 4 to 6 mm.

[0022] Optionally, the volume of the agent is less than 500 mm 3 , preferably less than 450mm 3 , and more preferably less than 420mm 3 .

[0023] Optionally, a partition is provided between the two mechanisms.

[0024] Optionally, the interlayer is mainly prepared from one or a combination of two or more of the following components: hydroxypropyl methylcellulose, polyvinyl alcohol, polyethylene glycol, triacetin, titanium dioxide, and talc.

[0025] In a second aspect, the present invention further provides a method for preparing a medicament comprising amlodipine and azilsartan, comprising the following steps:

[0026] S1 prepares a first mixed material by mixing the amlodipine-type drug and the first auxiliary material;

[0027] S2: spraying the azilsartan drug and the second auxiliary material into the first binder during the fluidized bed granulation process to obtain granules; crushing the obtained granules, adding the third auxiliary material containing the second binder, and mixing them uniformly to obtain a second mixed material;

[0028] S3: preparing a first structure by direct compression of the first mixed material, and passing the second mixed material through a tablet press to coat the outside of the first structure to form a second structure;

[0029] or

[0030] The second mixed material is directly compressed to obtain the second structure, and the first mixed material is passed through a tablet press to cover the outside of the second structure to form the first structure.

[0031] The present invention significantly reduces the amount of the first binder, and the method of adding the second binder after crushing the prepared particles can make the dissolution effect better and give it better storage stability. The amount of the first binder added is 2-5% of the weight of the medicament, and the amount of the second binder added is 5-10% of the weight of the medicament.

[0032] Optionally, the first adhesive is a mixture of highly substituted hydroxypropyl cellulose and polyethylene glycol, and the mass concentration of the highly substituted hydroxypropyl cellulose is 5-12%.

[0033] Optionally, the second binder is highly substituted hydroxypropyl cellulose.

[0034] Optionally, the third auxiliary material is a mixture of low-substituted hydroxypropyl cellulose, high-substituted hydroxypropyl cellulose and microcrystalline cellulose.

[0035] Optionally, the molecular weight of the highly substituted hydroxypropyl cellulose is less than 90,000.

[0036] The molecular weight of the highly substituted hydroxypropyl cellulose is less than 90,000, which can make the prepared medicine have better solubility, reduce the occurrence of impurities and improve storage stability.

[0037] Optionally, in step S2, among the small particles crushed into particles, the amount of small particles with a particle size less than 90 μm is less than 30%, and the amount of small particles with a particle size greater than 250 μm is less than 10%.

[0038] Optionally, the pulverization is performed using a hammer mill, and a 2.0 mm screen is used at a rotation speed of 2500 rpm to pulverize the fluidized bed granules into the above-mentioned particle size range. Within the above-mentioned particle size range, the content of azilsartan in the early, middle and late tablets during the tableting process can reach 98.0%-102.0%.

[0039] Optionally, the added amount of the first adhesive is 2-5% of the content of the medicament, and the added amount of the second adhesive is 5-10% of the content of the medicament.

[0040] Optionally, the second auxiliary material includes lactose, corn starch, microcrystalline cellulose, mannitol, and pregelatinized starch.

[0041] Optionally, the first auxiliary material includes anhydrous calcium hydrogen phosphate, microcrystalline cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, colloidal silicon dioxide, red iron oxide and magnesium stearate.

[0042] Optionally, the third auxiliary material includes high-substituted hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and magnesium stearate.

[0043] (III) Beneficial effects

[0044] The beneficial effects of the present invention are:

[0045] 1. The medicament containing amlodipine and azilsartan of the present invention is provided with mutually independent mechanisms for placing amlodipine-type drugs and azilsartan-type drugs, thereby reducing the contact area between the two types of drugs and improving the stability of the medicament as a compound preparation.

[0046] 2. In the preparation method of the medicament of the present invention, the direct compression and fluidized bed granulation method not only simplifies the preparation process, but also increases stability and has a better in vitro dissolution effect compared with other methods;

[0047] In the present invention, the first binder and the second binder are added in the granulation and overall mixing processes respectively to achieve a better in vitro dissolution effect.

[0048] In addition, the present invention adopts a hammer crushing method during granulation, which not only ensures that the particles have good fluidity, but also perfectly solves the problem that the content of azilsartan in the medicine is less than 98.0%-102.0% due to particle stratification during the tableting process. DETAILED DESCRIPTION

[0049] In order to better explain the present invention and facilitate understanding, the present invention is described in detail below through specific implementation methods.

[0050] The highly substituted hydroxypropyl cellulose in the embodiment of the present invention is a hydroxypropyl ether of cellulose, containing 53.4% ​​to 77.5% of hydroxypropyl, and is a white powder, easily soluble in cold water, soluble in methanol, ethanol, isopropanol and propylene glycol, has good inertness, does not react with drugs, and is an adhesive with excellent performance.

[0051] Low-substituted hydroxypropyl cellulose contains 7% to 9% hydroxypropyl, has a large surface area and porosity, good water absorption speed and water absorption capacity, and its water absorption expansion rate is 500% to 700%. The particles after disintegration are also fine, so it is conducive to the dissolution of drugs. It is mainly used as a tablet disintegrant, and its characteristics are: easy to shape, strong applicability, can increase the hardness and appearance of tablets, can also make tablets disintegrate quickly, and the disintegration degree of tablets is not easily affected by long-term storage.

[0052] Embodiments 1-12 of the present invention provide a medicament containing amlodipine and azilsartan and a preparation method thereof, wherein the medicament is composed of a core layer made of amlodipine and excipients, a shell layer made of azilsartan and excipients coated on the core layer, and a coating layer coated on the outer surface of the shell layer;

[0053] The corresponding weight parts of each component in the core layer, shell layer and coating layer in Examples 1-12 are shown in Table 1;

[0054] The specific preparation method is:

[0055] Preparation of S1 tablet core layer: using a 60-mesh sieve, sieving corresponding weight portions of amlodipine besylate, amlodipine maleate, first microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sodium carboxymethyl starch, calcium carboxymethyl cellulose, colloidal silicon dioxide, and red iron oxide three times by equal amount addition method, adding corresponding weight portions of first magnesium stearate and mixing for 3 minutes to obtain a first mixture, and directly tableting the first mixture into powder to obtain an amlodipine tablet core layer;

[0056] Preparation of S2 shell:

[0057] S21: Using a 60-mesh sieve, sieving and mixing corresponding weight portions of azilsartan, the second microcrystalline cellulose, lactose, and corn starch, placing the mixture in a fluidized bed granulator, spraying corresponding weight portions of a first binder solution obtained by mixing the first highly substituted hydroxypropyl cellulose and the first polyethylene glycol, and performing fluidized bed granulation to obtain fluidized bed granules of an azilsartan layer;

[0058] S22: The fluidized bed granules are crushed by a hammer mill at 2500 rpm and a 2.0 mesh, and then a mixture of corresponding weight portions of low-substituted hydroxypropyl cellulose, a second high-substituted hydroxypropyl cellulose (a second binder), and a third microcrystalline cellulose, which are sieved three times with a 60-mesh sieve and mixed, are added again, and mixed for 20 minutes, and then the second magnesium stearate is added and mixed for 3 minutes to obtain a second mixed material;

[0059] S23: passing the second mixed material through a core tablet press to coat the outer side of the amlodipine core tablet to form an azilsartan shell layer;

[0060] S3: coating a mixture of corresponding weight portions of hydroxypropyl methylcellulose, a second polyethylene glycol, titanium dioxide and yellow ferric oxide on the outside of the azilsartan shell layer to form a coating layer, thereby preparing a medicament containing amlodipine and azilsartan.

[0061] The preparation of the coating layer is not necessary.

[0062]

[0063]

[0064] Embodiments 13-15 of the present invention provide a medicament containing amlodipine and azilsartan and a preparation method thereof, wherein the medicament comprises a tablet core layer made of azilsartan and excipients, an isolation layer coated on the outer surface of the tablet core layer, and a shell layer made of amlodipine and excipients coated on the tablet core layer.

[0065] The corresponding weight parts of each component in the core layer, shell layer and isolation layer in Examples 13-15 are shown in Table 2;

[0066] The specific preparation method is:

[0067] Preparation of S1 core layer:

[0068] S11 uses a 60-mesh sieve to sieve and mix corresponding weight portions of azilsartan, the first microcrystalline cellulose, lactose, and corn starch, and then places the mixture in a fluidized bed granulator, sprays corresponding weight portions of a first binder solution obtained by mixing the first highly substituted hydroxypropyl cellulose and the first polyethylene glycol, and performs fluidized bed granulation to obtain fluidized bed granules of the azilsartan layer;

[0069] S12: The fluidized bed granules are crushed by a hammer mill at 2500 rpm and a 2.0 mesh, and then a mixture of corresponding weight portions of low-substituted hydroxypropyl cellulose, a second high-substituted hydroxypropyl cellulose (a second binder), and a second microcrystalline cellulose, which are sieved three times with a 60-mesh sieve and mixed, is added again, and mixed for 20 minutes, and then the first magnesium stearate is added and mixed for 3 minutes to obtain a second mixed material;

[0070] S13 tableting the second mixed material to obtain azilsartan tablet cores;

[0071] S14: coating the outer side of the azilsartan tablet with a mixture of corresponding weight portions of hypromellose and the second polyethylene glycol as an isolation layer;

[0072] Preparation of S2 shell layer: Use a 60-mesh sieve to sieve corresponding weight portions of amlodipine besylate, amlodipine maleate, the third microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sodium carboxymethyl starch, calcium carboxymethyl cellulose, colloidal silicon dioxide, and red iron oxide for 3 times and mix them by equal amount adding method, add corresponding weight portion of the second magnesium stearate and mix for 3 minutes to obtain a first mixture, pass the first mixture through a core tableting machine to coat the outside of the azilsartan tablet core to form an amlodipine shell layer, and prepare a medicament containing amlodipine and azilsartan.

[0073] The preparation of the isolation layer is not necessary.

[0074] Table 2

[0075]

[0076] Comparative Example 1

[0077] The other components and preparation methods are the same as those in Example 1, except that: the shell components and corresponding weight parts of Comparative Example 1 are shown in Table 3, wherein the addition amount of the first highly substituted hydroxypropyl cellulose is 25.7, and the addition amount of the second highly substituted hydroxypropyl cellulose ELF is 0.

[0078] Table 3

[0079] Shell components Weight Azilsartan 20 Second microcrystalline cellulose 8 lactose 119.95 Corn starch 35 The first highly substituted hydroxypropyl cellulose ELF 25.7 First Polyethylene Glycol 7.7 Low substituted hydroxypropyl cellulose 13 The second most highly substituted hydroxypropyl cellulose ELF 0 Microcrystalline cellulose 19.4 Second magnesium stearate 1.25

[0080] Comparative Example 2

[0081] Other components and preparation methods are the same as those in Example 1, except that in Comparative Example 2, the first highly substituted hydroxypropyl cellulose and the second highly substituted hydroxypropyl cellulose are both of JXF type.

[0082] Among them, the molecular weight of the highly substituted hydroxypropyl cellulose JXF used in Comparative Example 2 is greater than 90,000, and the molecular weight of the highly substituted ELF hydroxypropyl cellulose used in Example 1 is less than 90,000.

[0083] Test 1: A comparative dissolution test was performed on the medicaments containing amlodipine and azilsartan obtained in Examples 1-15 of the present invention and Comparative Examples 1 and 2, and the dissolution curves of azilsartan under the paddle method at 75 rpm in different pH media (pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 5.8 phosphate buffer, pH 6.8 phosphate buffer) were measured, and the results are shown in Tables 4-7 (wherein the values ​​are dissolution percentages); the solubility of amlodipine in each medium at 75 rpm for 15 minutes was measured by the paddle method, and the results are shown in Table 8.

[0084] Among them, the control drug is azilsartan and amlodipine tablets produced by Takeda of Japan.

[0085] Table 4 Azilsartan dissolution results (pH 5.8 phosphate buffer)

[0086] Dissolution time (min) 0 5 10 15 30 60 Comparator drugs 0 6.4 32.6 58.7 87.9 98.0 Example 1 0 7.2 33.1 59.6 89.8 99.5 Example 2 0 16.7 47.2 65.4 90.2 100.5 Example 3 0 36.2 75.3 90.7 98.2 98.9 Example 4 0 18.2 50.3 70.9 92.3 99.7 Example 5 0 4.4 28.4 52.3 85.4 99.1 Example 6 0 8.7 37.7 64.3 92.7 99.8 Example 7 0 8.5 36.7 63.3 91.7 100.2 Example 8 0 5.1 17.8 43.3 78.7 97.6 Example 9 0 8.1 33.7 60.2 89.7 99.8 Example 10 0 6.5 31.7 57.2 85.1 100.7 Embodiment 11 0 4.5 19.7 45.2 79.9 98.2 Example 12 0 7.3 34.1 60.4 91.1 100.8 Example 13 0 12.4 54.7 85.4 99.7 98.9 Embodiment 14 0 12.7 55.6 87.4 100.3 99.8 Embodiment 15 0 32.6 67.8 93.5 100.6 100.7 Comparative Example 1 0 29.2 52.8 72.4 93.7 99.7 Comparative Example 2 0 3.1 21.2 48.5 81.3 99.5

[0087] Table 5 Azilsartan dissolution results (pH 6.8 phosphate buffer)

[0088] Dissolution time (min) 0 5 10 15 30 60 Comparator drugs 0 13.3 64.0 92.5 98.7 99.8 Example 1 0 14.2 65.7 92.1 98.4 99.5 Example 5 0 10.2 56.7 84.7 94.3 99.5 Example 6 0 15.7 71.3 94.7 98.7 99.8 Example 7 0 15.6 71.7 94.3 99.1 100.2 Example 9 0 15.1 70.9 94.5 98.3 99.4 Example 10 0 13.7 62.2 87.1 95.4 100.1 Example 12 0 14.4 65.7 93.1 98.2 99.7 Comparative Example 1 0 43.9 84.7 93.7 98.7 100.1 Comparative Example 2 0 5.6 44.5 88.5 97.8 99.8

[0089] Table 6 Azilsartan dissolution results (pH 1.2 hydrochloric acid solution)

[0090]

[0091]

[0092] Table 7 Azilsartan dissolution results (pH 4.5 acetate buffer)

[0093] Dissolution time (min) 0 5 10 15 30 60 Comparator drugs 0 0.8 6.1 10.2 14.3 16.4 Example 1 0 0.7 5.9 10.3 14.2 16.3 Example 5 0 0.7 5.4 9.7 13.6 15.9 Example 6 0 1.0 6.7 10.9 14.9 16.7 Example 7 0 0.8 6.3 10.4 14.3 16.2 Example 9 0 0.9 6.5 10.9 15.1 16.9 Example 10 0 1.0 6.5 10.7 14.6 16.2 Example 12 0 1.2 6.9 10.6 14.9 16.5 Comparative Example 1 0 5.7 10.2 11.5 14.3 16.1 Comparative Example 2 0 0.8 6.3 10.3 14.1 16.6

[0094] Table 8 15-minute dissolution results of amlodipine in various media

[0095]

[0096] The dissolution rate of the control drug can represent the dissolution rate that has been clinically proven to have less side effects on the human body and better efficacy. The dissolution rate that deviates from the control drug is considered to have a greater potential safety risk to the human body or has poorer efficacy.

[0097] It can be seen from Tables 4 and 5 that under the conditions of pH 5.8 and pH 6.8, the dissolution of azilsartan at each time point in Examples 1, 5, 6, 7, 9, 10, and 12 is similar to that of the control drug, while the dissolution of Comparative Example 1 and Comparative Example 2 at each time point is quite different from that of the control drug;

[0098] It can be seen from this that: in Example 1, the adhesive highly substituted hydroxypropyl cellulose ELF was added in a separate manner (internal granulation and external mixing), and its solubility at each time point was consistent with that of the control drug, while the all-in-one addition of highly substituted hydroxypropyl cellulose ELF in Comparative Example 1 significantly affected the solubility, which was greatly different from that of the control drug; the preparation of the drug with highly substituted hydroxypropyl cellulose JXF also failed to improve the dissolution.

[0099] Tables 6 and 7 show that under pH 1.2 and pH 4.5 conditions, the dissolution rate of azilsartan within 60 min is relatively low, which is related to the obvious influence of pH on the solubility of the drug itself and the in vivo pK characteristics of the drug. The dissolution rates of the example and the control drug under these two pH conditions are also highly consistent.

[0100] As can be seen from Table 8, in multiple media of pH 5.8, pH 6.8, pH 4.5, and pH 1.2, the dissolution of amlodipine in each embodiment and the control drug meets the requirement that the cumulative dissolution rate within 15 minutes is greater than 85%, which can ensure in vivo absorption and efficacy.

[0101] Experiment 2: The pharmaceutical preparations containing amlodipine and azilsartan obtained in Examples 1-15 of the present invention and Comparative Examples 1 and 2 were placed under strict inspection conditions (without packaging, bare wafers placed, 40°C ± 2°C, relative humidity 75% ± 5%) to inspect the stability, and the results are shown in Table 9.

[0102] Among them, the control drug is azilsartan and amlodipine tablets produced by Takeda of Japan.

[0103] Table 9 Impurity results of control drugs, examples and comparative examples

[0104]

[0105]

[0106] As shown in Table 9, it can be obtained that the impurities of azilsartan and amlodipine in Examples 1-15 of the present invention can be controlled at a relatively low level. Under the harsh inspection conditions (without packaging, bare wafer placement, 40°C ± 2°C, relative humidity 75% ± 5%), the impurities of the examples are still maintained at a relatively low level, without significant growth, and the stability is significantly improved compared with the control drug.

[0107] Test 3: The fluidized bed granules in step S22 of Example 1 of the present invention were sized with a hammer mill, sieved with different speeds and screens of different specifications, and the content of azilsartan during tableting and the fluidity of the material during tableting were determined; and the fluidized bed granules were sized with a hammer mill instead of a granulator, and screens of different specifications were used to determine the content of azilsartan during tableting in step S23 and the fluidity of the material during tableting; the results are shown in Table 10.

[0108] Table 10 Particle size distribution and effects of different crushing and granulation methods in Example 1

[0109]

[0110] As shown in Table 10, in the embodiments of the present invention, the azilsartan shell fluidized bed granules are crushed on a 2.0 mm screen at 2500 rpm to obtain granules, and the content of azilsartan in the obtained medicament can reach 98.0-102.0%, and the fluidity of the material during tableting can be ensured.

[0111] This shows that in step S2, the pulverization is performed using a hammer mill, using a 2.0 mm screen and a rotation speed of 2500 rpm, and the fluidized bed particles are pulverized into the following particle size distribution: no more than 30% of particles below 90 μm, and no more than 10% of particles above 250 μm. Within this particle size range, the content of azilsartan in the early, middle and late stages of the tableting process can reach 98.0%-102.0%.

[0112] Among them, the calculation method of the content of Azilsartan is as follows:

[0113] The content of azilsartan in the medicine = (the mass of azilsartan in the actual test / the actual mass of the medicine) / (theoretical mass of the medicine / theoretical mass of the medicine) * 100%. For example: the theoretical weight of the medicine is 300 mg, and the theoretical azilsartan is 20 mg. However, during the actual tableting, due to deviations in the equipment, the weight of the tablets produced may range from 290 to 310 mg, which will cause the content of azilsartan to be between 97% and 103%. In theory, when the content reaches more than 98.0%, it can be said that its loss rate is almost zero.

[0114] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A medicament comprising amlodipine and azilsartan, characterized in that: It includes two or more independent institutions, wherein the institutions have one of the drugs of the amlodipine class and the azilsartan class; The amlodipine-type drug is amlodipine or / and a pharmaceutically acceptable salt thereof; The azilsartan drug is azilsartan or / and a pharmaceutically acceptable salt thereof; The preparation method of the medicament containing amlodipine and azilsartan comprises the following steps: S1 prepares a first mixed material by mixing the amlodipine-type drug and the first auxiliary material; S2: spraying the azilsartan drug and the second auxiliary material into the first binder during the fluidized bed granulation process to obtain granules; crushing the obtained granules, adding the third auxiliary material containing the second binder, and mixing them uniformly to obtain a second mixed material; S3: preparing a first structure by direct compression of the first mixed material, and passing the second mixed material through a tablet press to coat the outside of the first structure to form a second structure; or The second mixed material is directly compressed to obtain a second structure, and the first mixed material is passed through a tablet press to cover the outside of the second structure to form the first structure; The first adhesive is a mixture of highly substituted hydroxypropyl cellulose and polyethylene glycol, and the mass concentration of the highly substituted hydroxypropyl cellulose is 5-12%; The second binder is highly substituted hydroxypropyl cellulose; The molecular weight of the highly substituted hydroxypropyl cellulose is less than 90,000.

2. The medicament comprising amlodipine and azilsartan as claimed in claim 1, characterized in that: In step S2, among the small particles crushed into particles, the amount of small particles with a particle size less than 90 μm is less than 30%, and the amount of small particles with a particle size greater than 250 μm is less than 10%.

3. The method for preparing the medicament comprising amlodipine and azilsartan as claimed in claim 1, characterized in that: The added amount of the first adhesive is 2-5% of the weight of the medicament, and the added amount of the second adhesive is 5-10% of the weight of the medicament.

4. The method for preparing the medicament comprising amlodipine and azilsartan as claimed in claim 1, characterized in that: The volume ratio of the contact area of ​​the two mechanisms to the medicine is 12~17:100.

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