Pharmaceutical composition for treating cardiovascular diseases and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition for treating cardiovascular diseases and a preparation method thereof, in particular to a pharmaceutical composition containing levamlodipine besylate and atorvastatin calcium, and the pharmaceutical composition is used for treating mixed hypertension and hyperlipidemia, has a synergistic effect and can effectively reduce blood pressure and blood fat levels. By controlling the granularity and crystal form of levamlodipine besylate and atorvastatin calcium, the dissolution rate and stability of the medicine are optimized. The preparation method adopts a direct powder tabletting process, so that the production process is simplified, the production efficiency is improved, and meanwhile, the uniformity and the stability of the medicine are ensured. In-vitro dissolution experiments show that the dissolution rate of the composition reaches 90% or above within 15 minutes, and the composition has good bioavailability.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to a pharmaceutical composition for treating cardiovascular diseases and a preparation method thereof. Background Art

[0002] Among cardiovascular diseases, high blood pressure and high blood lipids are two important risk factors for atherosclerosis, angina pectoris, myocardial infarction, cerebral infarction, kidney damage, etc. Therefore, it is of great significance to pay attention to high blood pressure and high blood lipids and actively control the occurrence of cardiovascular and cerebrovascular diseases.

[0003] Studies have shown that there is a positive correlation between blood cholesterol levels and blood pressure through a variety of biological mechanisms. The central venous pressure and degree of vascular sclerosis in patients with hyperlipidemia are higher than those in people with well-controlled blood lipids. The central venous pressure of untreated hyperlipidemia patients is significantly higher than that of patients treated with lipid-lowering therapy. Therefore, antihypertensive therapy and lipid-lowering therapy are commonly used combined treatments in clinical practice.

[0004] The combined use of levamlodipine besylate and atorvastatin can treat hypertension and hyperlipidemia at the same time. The two have a synergistic effect, which can not only avoid the side effects such as acroedema, headache, dizziness, etc. caused by racemic amlodipine; but also the small dosage greatly improves the patient's compliance, making the patient's treatment safer and more convenient, and has high social and economic significance.

[0005] CN98808460.0, filed by Pfizer on August 11, 1998, discloses the combined use of amlodipine and atorvastatin for the treatment of angina pectoris, atherosclerosis, hypertension and hyperlipidemia. CN200510065440.6, filed by Shijiazhuang Zhongqi Pharmaceutical Technology Co., Ltd. on April 8, 2005, discloses that the combined use of atorvastatin and levamlodipine can be used synergistically to treat hypertension and hyperlipidemia.

[0006] CN200510012488.0 applied by Shijiazhuang Pharmaceutical Group Ouyi Pharmaceutical Co., Ltd. on April 30, 2005 confirmed that the combined use of atorvastatin and levoamlodipine is superior to that of atorvastatin and racemic amlodipine.

[0007] After searching and analyzing the prior art, it was found that the preparation process of the combination of atorvastatin and levamlodipine protected by most patents is a wet granulation process, which can successfully complete the preparation of tablets, but the operation process is cumbersome and increases the process cost. On September 17, 2014, CN 101288670B applied by Shijiazhuang Zhongqi Pharmaceutical Technology Co., Ltd. of Shijiazhuang Pharmaceutical Group disclosed a preparation method of tablets with atorvastatin calcium and levamlodipine maleate as active ingredients, which is dry granulation tableting, but it did not study the particle size and crystal form of the raw material, and the bioavailability of the drug needs to be considered.

[0008] Therefore, there is a need to provide a composition and a preparation method thereof with simpler process, lower cost and easier industrialization, which can not only ensure the efficacy and stability of various forms of atorvastatin or its pharmaceutically acceptable salts in the preparation of compound combination for treating hypertension and hyperlipidemia, but also increase the solubility of the two active ingredients.

[0009] The present invention further studies the prescription and preparation method of levamlodipine besylate atorvastatin calcium tablets, including the study of the crystal form and particle size of levamlodipine besylate, and simultaneously conducts a study on a simulated commercial production batch of 100,000 tablets, aiming to provide levamlodipine besylate atorvastatin calcium tablets with better overall performance and lower process cost. Summary of the invention

[0010] In order to overcome the disadvantages of the above dosage forms, the first object of the present invention is to provide a pharmaceutical composition for treating cardiovascular diseases, which is composed of a pharmaceutically acceptable salt of levamlodipine, atorvastatin or a pharmaceutically acceptable salt thereof, an alkaline excipient, pregelatinized starch, low-substituted hydroxypropyl cellulose, a disintegrant, and a lubricant;

[0011] The second object of the present invention is to provide a method for preparing the composition, which can directly compress the powder into tablets. The powder has good fluidity and is easy to compress into tablets, which not only reduces production time and improves production efficiency, but also improves product stability.

[0012] To achieve the first object of the present invention, the present invention adopts the following technical solution:

[0013] A pharmaceutical composition for treating cardiovascular diseases is composed of the following weights and percentages:

[0014] Table 1: Process recipe weight and percentage

[0015]

[0016] The pharmaceutically acceptable salt of levoamlodipine in the composition uses levoamlodipine besylate, which has stable crystal form and uniform particle size distribution. The addition of atorvastatin or its pharmaceutically acceptable salt can improve the stability of the compound combination for treating hypertension and hyperlipidemia and increase the solubility of the two active ingredients.

[0017] According to the aforementioned pharmaceutical composition, wherein the levoamlodipine besylate crystal form is prepared by the following method:

[0018] 1) Add 40 to 60 parts by volume of purified water (60 to 75° C.) to the levamlodipine besylate solution, stir and react until the solution becomes clear, and filter the reaction solution under reduced pressure while hot into a crystallization tank.

[0019] 2) Stir and cool the reaction solution in the crystallization tank to ≤20°C to precipitate an off-white solid.

[0020] 3) The crystallization liquid is filtered under reduced pressure, and the filter cake is washed with about 6 to 9 times purified water and drained to obtain the wet product of levamlodipine besylate.

[0021] 4) Drying in a vacuum drying oven under reduced pressure of 0.07-0.1 MPa until the moisture content is ≤ 2.0%, and sieving through 80-120 mesh to obtain the levamlodipine besylate bulk drug.

[0022] The obtained levamlodipine besylate raw material medicine, in the XRD powder diffraction patterns of three batches of raw materials (batch numbers: Y181003, Y190805, and Y190905), the X-ray diffraction angles are consistent, indicating that the crystal form is consistent, indicating that the raw material synthesis process is stable, and the crystal form will not change during the storage of the raw material medicine. The characteristic peaks in the diffraction pattern are 6.860°, 10.219°, 12.420°, 13.619°, 14.140°, 15.141°, 20.360°, 21.899°, 23.859°, 25.100°, and 27.220° at 2θ.

[0023] The obtained levoamlodipine besylate crystal size is D 90 30-100um.

[0024] Atorvastatin calcium or its pharmaceutically acceptable salt may be amorphous, crystalline or a mixture of the two or more. The particle size is controlled by D 90 30-100um.

[0025] The alkaline auxiliary material is calcium phosphate, calcium carbonate, calcium oxide or more than two, with a particle size of D 90 20-100um.

[0026] The filler is one of microcrystalline cellulose, starch, pregelatinized starch, lactose, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate or a mixture of two or more thereof, and the particle size is controlled to be D90 20-400um;

[0027] The disintegrant is one of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, or a mixture of two or more thereof. 90 Less than 50um;

[0028] The lubricant is one of magnesium stearate, hydrogenated castor oil, carnauba wax, talcum powder or a mixture of two or more thereof, with a particle size D 90 Less than 50um. ;

[0029] To achieve the second object of the present invention, a method for preparing a pharmaceutical composition for treating cardiovascular diseases is provided:

[0030] The following steps are involved:

[0031] (1) According to the process recipe, take the raw and auxiliary materials with particle size distribution that meets the requirements for use:

[0032] (2) Divide the raw and auxiliary materials in the prescription into 4 equal parts.

[0033] (3) Each batch of levoamlodipine besylate is mixed with 1 / 4 of the filler in four equal and increasing portions, and then 1 / 4 of the prescribed amount of atorvastatin calcium and 1 / 4 of the prescribed amount of other excipients are added;

[0034] (4) Each material is first sieved with a large aperture to size the particles, and then sieved with a small aperture to size the particles;

[0035] (5) granulating the four materials and mixing them together;

[0036] (6) Tableting and coating.

[0037] The large aperture sieve is 3-6 mm;

[0038] The small aperture sieve is 1-3 mm;

[0039] The levoamlodipine besylate and atorvastatin calcium particles prepared by the method of the invention are uniform, have good fluidity, are easy to tablet, have a tablet weight difference of ±4%, a uniformity of the central controlled dosage unit (calculated according to levoamlodipine) of RSD≤6%, and a dissolution rate (calculated according to levoamlodipine) of more than 90% in 15 minutes. The production process is simple, which not only reduces the production time and improves the production efficiency, but also improves the dissolution of the drug and the product stability.

[0040] In vitro dissolution experiments show that the release rates of levamlodipine besylate and atorvastatin in the levamlodipine besylate and atorvastatin calcium tablets prepared by the present invention in a dissolution medium, pH 4.5 acetate buffer, exceed 90% within 15 minutes. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Attached Figure 1 These are the X-ray diffraction patterns of three batches of amlodipine besylate raw material.

[0042] Attached Figure 2 This is a sampling diagram for mixing uniformity, illustrating the sampling points for amlodipine besylate.

[0043] Attached Figure 3 This is the dissolution curve of amlodipine in pH 4.5 acetate buffer.

[0044] Attached Figure 4 This is the dissolution curve of atorvastatin calcium in pH 4.5 acetate buffer. DETAILED DESCRIPTION

[0045] The present invention is further illustrated by the following examples, which should not be construed as limiting the present invention.

[0046] Example 1: Preparation of levoamlodipine besylate crystal form

[0047] 1) Add the levamlodipine besylate solution into water, stir and react until the solution becomes clear, and filter the reaction solution under reduced pressure while hot into a crystallization tank.

[0048] 2) Stir and cool the reaction solution in the crystallization tank to ≤20°C to precipitate an off-white solid.

[0049] 3) The crystallization liquid is filtered under reduced pressure, the filter cake is washed with purified water, and then dried to obtain the wet product of levamlodipine besylate.

[0050] 4) Dry in a vacuum drying oven under reduced pressure of 0.07-0.1 MPa until the moisture content is ≤ 2.0%, and sieve to obtain levamlodipine besylate.

[0051] The XRD powder diffraction patterns of the obtained levamlodipine besylate, three batches of raw materials (batch numbers: Y220606, Y220403, Y190301), have consistent X-ray diffraction angles, indicating that the crystal form is consistent, indicating that the raw material synthesis process is stable, and the crystal form will not change during the storage of the raw material. The characteristic peaks in the diffraction pattern obtained by XRD powder diffraction measurement are 6.860°, 10.219°, 12.420°, 13.619°, 14.140°, 15.141°, 20.360°, 21.899°, 23.859°, 25.100°, and 27.220° at 2θ, such as Figure 1 shown.

[0052] The sample sieve was used to screen three groups of levoamlodipine besylate crystal forms with different particle sizes: D90 69um, D90 92um, and D90128um. The air jet mill was used to grind crystal forms with different particle sizes: D90 34um, D90 92um, and D90 128um. 90Two groups of 15um. The crystal form does not change after crushing.

[0053] Example 2: Levoamlodipine besylate atorvastatin calcium tablets, marked as prescription 1.

[0054] Table 2: Prescription 1

[0055]

[0056] Levoamlodipine besylate was prepared using the levoamlodipine besylate prepared in Example 1, and the particle size after crushing was D 90 15um Atorvastatin Calcium Particle Size D 90 It is a 66um raw material drug.

[0057] Specific preparation method: Divide the raw materials and auxiliary materials in the prescription into 4 materials. Each material of levamlodipine besylate is mixed with 1 / 4 of the amount of pregelatinized starch in four equal and increasing portions, and then 1 / 4 of the amount of atorvastatin calcium and 1 / 4 of the amount of other auxiliary materials are added; each material is first sieved with a large aperture to resize the particles once, and then sieved with a small aperture to resize the particles once;

[0058] The four materials are granulated and mixed together, and the powder is directly compressed into tablets; and film coating is performed by conventional methods.

[0059] Example 3: Levoamlodipine besylate atorvastatin calcium tablets, labeled as prescription 2

[0060] Table 3: Prescription 2

[0061]

[0062] Levoamlodipine besylate was prepared using the levoamlodipine besylate prepared in Example 1, and the particle size after crushing was D 90 34um.

[0063] Atorvastatin calcium particle size D 90 It is a 66um raw material drug.

[0064] Specific preparation method: Divide the raw materials and auxiliary materials in the prescription into 4 materials. Each material of levamlodipine besylate is mixed with 1 / 4 of the amount of pregelatinized starch in four equal and increasing portions, and then 1 / 4 of the amount of atorvastatin calcium and 1 / 4 of the amount of other auxiliary materials are added; each material is first sieved with a large aperture to resize the particles once, and then sieved with a small aperture to resize the particles once;

[0065] The four materials are granulated and mixed together, and the powder is directly compressed into tablets; and film coating is performed by conventional methods.

[0066] Example 4: Levoamlodipine besylate atorvastatin calcium tablets, labeled as prescription 3

[0067] Table 4: Prescription 3

[0068]

[0069] Levoamlodipine besylate was prepared using the levoamlodipine besylate prepared in Example 1, and the screening particle size was D 90 69um. Atorvastatin calcium controlled particle size D 90 66um.

[0070] Specific preparation method: Divide the raw materials and auxiliary materials in the prescription into 4 materials. Each material of levamlodipine besylate is mixed with 1 / 4 of the amount of pregelatinized starch in four equal and increasing portions, and then 1 / 4 of the amount of atorvastatin calcium and 1 / 4 of the amount of other auxiliary materials are added; each material is first sieved with a large aperture to resize the particles once, and then sieved with a small aperture to resize the particles once;

[0071] The four materials are granulated and mixed together, and the powder is directly compressed into tablets; and film coating is performed by conventional methods.

[0072] Example 5: Levoamlodipine besylate atorvastatin calcium tablets, labeled as prescription 4

[0073] Table 5: Prescription 4

[0074]

[0075]

[0076] Levoamlodipine besylate was prepared using the levoamlodipine besylate prepared in Example 1, and the screening particle size was D 90 92um. Atorvastatin calcium particle size D 90 It is a 66um raw material drug.

[0077] Specific preparation method: Divide the raw materials and auxiliary materials in the prescription into 4 materials. Each material of levamlodipine besylate is mixed with 1 / 4 of the amount of pregelatinized starch in four equal and increasing portions, and then 1 / 4 of the amount of atorvastatin calcium and 1 / 4 of the amount of other auxiliary materials are added; each material is first sieved with a large aperture to resize the particles once, and then sieved with a small aperture to resize the particles once;

[0078] The four materials are granulated and mixed together, and the powder is directly compressed into tablets; and film coating is performed by conventional methods.

[0079] Example 6: Levoamlodipine besylate atorvastatin calcium tablets, labeled as prescription 5

[0080] Table 6: Prescription 5

[0081]

[0082] Levoamlodipine besylate was prepared using the levoamlodipine besylate prepared in Example 1, and the screening particle size was D 90 128um.

[0083] Atorvastatin calcium particle size D 90 It is a 66um raw material drug.

[0084] Specific preparation method: Divide the raw materials and auxiliary materials in the prescription into 4 materials. Each material of levamlodipine besylate is mixed with 1 / 4 of the amount of pregelatinized starch in four equal and increasing portions, and then 1 / 4 of the amount of atorvastatin calcium and 1 / 4 of the amount of other auxiliary materials are added; each material is first sieved with a large aperture to resize the particles once, and then sieved with a small aperture to resize the particles once;

[0085] The four materials are granulated and mixed together, and the powder is directly compressed into tablets; and film coating is performed by conventional methods.

[0086] Example 7: Levoamlodipine besylate atorvastatin calcium tablets, labeled as prescription 6

[0087] Table 7: Prescription 6

[0088]

[0089] Levoamlodipine besylate was prepared using the levoamlodipine besylate prepared in Example 1, and the screening particle size was D 90 69um. Atorvastatin calcium particle size D 90 It is an 18um raw material.

[0090] Specific preparation method: Divide the raw materials and auxiliary materials in the prescription into 4 materials. Each material of levamlodipine besylate is mixed with 1 / 4 of the amount of pregelatinized starch in four equal and increasing portions, and then 1 / 4 of the amount of atorvastatin calcium and 1 / 4 of the amount of other auxiliary materials are added; each material is first sieved with a large aperture to resize the particles once, and then sieved with a small aperture to resize the particles once;

[0091] The four materials are granulated and mixed together, and the powder is directly compressed into tablets; and film coating is performed by conventional methods.

[0092] Example 8: Levoamlodipine besylate atorvastatin calcium tablets, labeled as prescription 7

[0093] Table 8: Prescription 7

[0094]

[0095] Levoamlodipine besylate was prepared using the levoamlodipine besylate prepared in Example 1, and the screening particle size was D 90 69um.

[0096] Atorvastatin calcium particle size D 90 It is a 31um raw material.

[0097] Specific preparation method: Divide the raw materials and auxiliary materials in the prescription into 4 materials. Each material of levamlodipine besylate is mixed with 1 / 4 of the amount of pregelatinized starch in four equal and increasing portions, and then 1 / 4 of the amount of atorvastatin calcium and 1 / 4 of the amount of other auxiliary materials are added; each material is first sieved with a large aperture to resize the particles once, and then sieved with a small aperture to resize the particles once;

[0098] The four materials are granulated and mixed together, and the powder is directly compressed into tablets; and film coating is performed by conventional methods.

[0099] Example 9: Levoamlodipine besylate atorvastatin calcium tablets, labeled as prescription 8

[0100] Table 9: Prescription 8

[0101]

[0102] Levoamlodipine besylate was prepared using the levoamlodipine besylate prepared in Example 1, and the screening particle size was D 90 69um.

[0103] Atorvastatin calcium particle size D 90 It is a 71um raw material drug.

[0104] Specific preparation method: Divide the raw materials and auxiliary materials in the prescription into 4 materials. Each material of levamlodipine besylate is mixed with 1 / 4 of the amount of pregelatinized starch in four equal and increasing portions, and then 1 / 4 of the amount of atorvastatin calcium and 1 / 4 of the amount of other auxiliary materials are added; each material is first sieved with a large aperture to resize the particles once, and then sieved with a small aperture to resize the particles once;

[0105] The four materials are granulated and mixed together, and the powder is directly compressed into tablets; and film coating is performed by conventional methods.

[0106] Example 10: Levoamlodipine besylate atorvastatin calcium tablets, labeled as prescription 9

[0107] Table 10: Prescription 9

[0108]

[0109]

[0110] Levoamlodipine besylate was prepared using the levoamlodipine besylate prepared in Example 1, and the screening particle size was D 90 69um.

[0111] Atorvastatin calcium particle size D 90 It is a 128um raw material.

[0112] Specific preparation method: Divide the raw materials and auxiliary materials in the prescription into 4 materials. Each material of levamlodipine besylate is mixed with 1 / 4 of the amount of pregelatinized starch in four equal and increasing portions, and then 1 / 4 of the amount of atorvastatin calcium and 1 / 4 of the amount of other auxiliary materials are added; each material is first sieved with a large aperture to resize the particles once, and then sieved with a small aperture to resize the particles once;

[0113] The four materials are granulated and mixed together, and the powder is directly compressed into tablets; and film coating is performed by conventional methods.

[0114] Example 11: Levoamlodipine besylate atorvastatin calcium tablets, labeled as prescription 10

[0115] Table 11: Prescription 10

[0116]

[0117] Levoamlodipine besylate uses commercially available raw materials, and the detected crystal forms are shown in Table 12:

[0118] Table 12: Crystalline characteristics of commercially available amlodipine besylate API in prescription 10:

[0119]

[0120] Atorvastatin calcium particle size D 90 It is a 71um raw material drug.

[0121] Specific preparation method: Divide the raw materials and auxiliary materials in the prescription into 4 materials. Each material of levamlodipine besylate is mixed with 1 / 4 of the amount of pregelatinized starch in four equal and increasing portions, and then 1 / 4 of the amount of atorvastatin calcium and 1 / 4 of the amount of other auxiliary materials are added; each material is first sieved with a large aperture to resize the particles once, and then sieved with a small aperture to resize the particles once;

[0122] The four materials are granulated and mixed together, and the powder is directly compressed into tablets; and film coating is performed by conventional methods.

[0123] Effect evaluation:

[0124] Detection method:

[0125] 1. Appearance

[0126] Take 100 tablets of the test sample and spread them flat on a plastic sieve plate or a white porcelain plate. Inspect them for half a minute at a distance of 30 cm from the tablets in natural light, looking at only one side.

[0127] 3. Hardness

[0128] The tablet hardness was tested using a tablet hardness tester with direct reading.

[0129] 4. Friability

[0130] Take 40 tablets onto weighing paper and use a hair dryer to blow away the powder on the surface of the tablets, place them in a weighing bottle, and weigh them accurately (W1). Place the weighed sample in a cylinder and start the motor to rotate 100 times (25 rpm). After the test, take out the sample for inspection. The sample should not be broken, cracked, or crushed. Take the sample after the test, blow away the powder with a hair dryer, place it in a weighing bottle, and weigh it accurately (W2). The difference between the two weighings is the weight of the sample after the test.

[0131] 4. Dissolution: Take this product and follow the dissolution method (Appendix 1 of Part IV of the 2020 edition of the Chinese Pharmacopoeia) with phosphate buffer as the solvent and a speed of 75 revolutions per minute. After 30 minutes, take 5 ml of the solution, filter it, and take the filtrate as the test solution; determine it according to the content determination method, and calculate the dissolution amount of levamlodipine tablets and atorvastatin calcium in each tablet, respectively. The limit is 75% of the labeled amount, which should meet the requirements.

[0132] 5. Content determination: Take 10 tablets of this product, accurately weigh, grind, accurately weigh an appropriate amount, add mobile phase to dilute to the scale, shake well, filter, take 20ul of the filtrate and inject it into the liquid chromatograph, record the chromatogram and calculate the contents of levamlodipine and atorvastatin calcium in the test sample by the external standard method based on the peak area.

[0133] 6. Related substances: Take the fine powder under the content determination item, accurately weigh an appropriate amount, add the mobile phase to dilute to the scale, shake well, and use it as the reference solution. Accurately measure the reference solution and inject it into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component of atorvastatin calcium is about 20% to 25% of the full scale, then accurately measure the above two solutions and inject them into the liquid chromatograph, record the chromatogram to twice the retention time of the atorvastatin calcium peak, and the sum of the peak areas of each impurity shall not be greater than twice the peak area of ​​atorvastatin calcium in the reference solution.

[0134] 7. Crystal form: According to the general chapter 0451 X-ray diffraction method on page 55 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, grind an appropriate amount of this product through a 100-mesh sieve and use XRD powder diffraction measurement to obtain the characteristic peak at 2θ in the diffraction pattern.

[0135] The present invention uses a commercial production batch of 100,000 pieces for screening, which more truly reflects its operability in commercial production than laboratory batches.

[0136] Table 13-1: Commercial production batch prescriptions for 100,000 tablets 1-5

[0137]

[0138] Table 13-2: Commercial production batch prescription of 100,000 tablets 6-9

[0139]

[0140] Table 14: Comparison of 100,000-piece commercial production batches

[0141]

[0142] Table 15: Test results of appearance, hardness and friability of prescription tablets

[0143]

[0144] Table 16: Stability test results of prescriptions 1-10, AM stands for amlodipine besylate, AT stands for atorvastatin calcium

[0145]

[0146] Table 17: Comparison of XDR crystal form detection at 0 days

[0147]

[0148] Table 18: Comparison of XDR crystal form detection after 6 months of acceleration

[0149]

[0150] Implementation: Example 12: Select the prescription 8 with better performance and continue to scale up the batch by 10 times, see prescription 11, and continue to study the performance of this prescription in commercial large-scale production.

[0151] Table 19: Prescription 11

[0152]

[0153] Levoamlodipine besylate was prepared by the process of Example 1, and the screening particle size was D 90 62um.

[0154] Atorvastatin calcium particle size D 90 It is a raw material of 80um.

[0155] Specific preparation method: Divide the raw materials and auxiliary materials in the prescription into 4 materials. Each material of levamlodipine besylate is mixed with 1 / 4 of the amount of pregelatinized starch in four equal and increasing portions, and then 1 / 4 of the amount of atorvastatin calcium and 1 / 4 of the amount of other auxiliary materials are added; each material is first sieved with a large aperture to resize the particles once, and then sieved with a small aperture to resize the particles once;

[0156] After the four materials are granulated, put them all into the square cone mixing barrel and mix them for 30 minutes using a square cone mixer. Figure 2 Take samples for mixing uniformity and check the content of levamlodipine besylate. The sampling points are shown in Figure 2 , contents are shown in Table 20.

[0157] Table 20: Mixing uniformity of levamlodipine besylate and atorvastatin calcium (calculated as levamlodipine)

[0158] Sampling point Content (calculated as levoamlodipine) % 1 2.026 2 2.027 3 1.988 4 2.008 5 1.871 6 1.968 7 2.007 8 1.967 9 1.934 10 1.985 11 1.934 RSD 2.39

[0159] The total mixed powder of prescription 11 of preparation example 12 was directly compressed into powder tablets; film coating was performed by conventional methods, aluminum-plastic packaging was performed, and outer packaging was simulated. According to the requirements of the stability guidelines of the 2020 edition of the Chinese Pharmacopoeia, a stability study under accelerated intermediate conditions (30°C ± 2°C / RH 65% ± 5%) was carried out, mainly focusing on the content of the product and the related substances. The test results were good in 6 months and met the requirements. The results are shown in Table 21:

[0160] Table 21: Accelerated stability study results of Formulation Example 12 (Formulation 11).

[0161]

[0162] The in vitro dissolution curves of the amlodipine atorvastatin calcium tablets obtained in Preparation Example 12 and the amlodipine atorvastatin calcium tablets (specification: each tablet contains 5 mg amlodipine and 10 mg atorvastatin calcium, batch number: 20230601) produced by Pfizer, a listed control preparation, were compared in pH 4.5 acetate buffer (volume 900 ml, basket method 100 revolutions). The results showed that the dissolution of the amlodipine atorvastatin calcium tablets was similar to that of the control preparation, and both were rapidly dissolved (more than 90% dissolved in 15 minutes). The results are shown in Tables 1 and 2. Figure 3 and Figure 4 The dissolution of atorvastatin calcium can also be consistent with that of the control preparation.

[0163] Table 22: Table of dissolution results of amlodipine and control preparations in Example 12

[0164]

[0165] Table 23: Dissolution results of atorvastatin calcium and control preparations in Example 12

[0166]

[0167] The present invention provides a pharmaceutical composition for treating cardiovascular diseases and a preparation method thereof. The composition comprises levamlodipine besylate and atorvastatin calcium, and is mainly used for treating mixed hypertension and hyperlipidemia, and has a significant synergistic effect. The particle size and crystal form of levamlodipine besylate and atorvastatin calcium are strictly controlled to ensure the stability and dissolution of the drug. The particle size of levamlodipine besylate is controlled at 30-100 μm in D90, and the particle size of atorvastatin calcium is controlled at 30-100 μm in D90, ensuring the uniformity and bioavailability of the drug. The preparation method adopts a powder direct tableting process, simplifies the traditional wet granulation process, reduces the production steps, reduces the production cost, and improves the production efficiency, which is suitable for large-scale commercial production. The selection and optimization of excipients (such as microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose, magnesium stearate, etc.) ensure the fluidity, compressibility and stability of the drug. In vitro dissolution experiments show that the dissolution rate of the composition within 15 minutes reaches more than 90%, has excellent bioavailability, can quickly release drugs, and exert therapeutic effects. Through accelerated stability experiments (6 months under 40°C / 75% RH conditions), the composition showed good stability, and the content, solubility and related substances of amlodipine besylate and atorvastatin calcium met the requirements of the pharmacopoeia, and no obvious degradation or crystal changes occurred. The study of 100,000 tablets of commercial production batches verified the feasibility and stability of the preparation method in large-scale production, with good repeatability and consistency. Further verification through 1 million tablets of commercial production scale-up showed that the process remained efficient and stable in large-scale production, the uniformity of drug content (RSD≤2.39%), tablet hardness, friability and other physical indicators in the production process met the requirements, and there was no significant change in dissolution and stability, indicating that the preparation method has strong potential for industrial production. The present invention solves the problem of low drug bioavailability in traditional preparation processes by controlling crystal form and particle size, simplifying the process and optimizing excipients, and has high economic and social benefits. The pharmaceutical composition is suitable for patients with mixed hypertension and hyperlipidemia, has a small dosage and few side effects, significantly improves the patient's treatment compliance, and has broad clinical application prospects. In general, the present invention provides a pharmaceutical composition and a preparation method thereof with simple process, low cost, and easy industrialization, which has important clinical application value and economic significance.

Claims

1. A pharmaceutical composition for treating cardiovascular diseases is used in treating combined hypertension and hyperlipidemia, characterized in that The invention is composed of a pharmaceutically acceptable salt of levamlodipine, atorvastatin or a pharmaceutically acceptable salt thereof, an alkaline excipient, pregelatinized starch, low-substituted hydroxypropyl cellulose, a disintegrant and a lubricant; The pharmaceutically acceptable salt of levoamlodipine is levoamlodipine besylate; The particle size control of the levamlodipine besylate D 90 30-100um; The levamlodipine besylate raw material drug is a stable crystalline form, and the characteristic peaks 2θ in the diffraction pattern measured by XRD powder diffraction are 6.860°, 10.219°, 12.420°, 13.619°, 14.140°, 15.141°, 20.360°, 21.899°, 23.859°, 25.100°, and 27.220°; The atorvastatin or its pharmaceutically acceptable salt is atorvastatin calcium; The atorvastatin calcium particle size control D 90 30-100um.

2. The filler is one of microcrystalline cellulose, starch, pregelatinized starch, lactose, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate or a mixture of two or more thereof; The disintegrant is one of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, or a mixture of two or more thereof; The lubricant is one of magnesium stearate, hydrogenated castor oil, carnauba wax, talcum powder or a mixture of two or more thereof; The preparation method of the pharmaceutical composition for treating cardiovascular diseases comprises the following steps: mixing levamlodipine besylate and a filler in equal and increasing amounts, and then mixing and grinding with atorvastatin calcium and the remaining auxiliary materials, mixing, tableting, and coating to obtain coated tablets.

3. The composition of atorvastatin and levamlodipine according to claim 1, characterized in that It is composed of the following ingredients and their weight percentages:

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