Compound composition as well as preparation method and application thereof

Abstract

The invention relates to the field of medicine preparation, in particular to a compound composition and a preparation method and application thereof. The compound composition comprises a sustained-release layer, a blocking layer and a quick-release layer, the sustained-release layer comprises metoprolol and sustained-release layer auxiliary materials, the blocking layer comprises blocking layer auxiliary materials, the quick-release layer comprises amlodipine, metoprolol and quick-release layer auxiliary materials, and the mass ratio of metoprolol of the quick-release layer to metoprolol of the sustained-release layer is (1-3): (6.5-8.5). According to the compound composition, two antihypertensive drugs with complementary action mechanisms are prepared into the long-acting compound composition which is taken once a day, amlodipine and part of metoprolol are rapidly released, the rest metoprolol is slowly released within 24 hours, and rapid antihypertensive and long-acting antihypertensive requirements are met at the same time. The composition is stable in preparation process, convenient to produce and beneficial to industrial production.

Description

Technical Field

[0001] The present invention relates to the field of medicine preparation, and in particular to a compound composition and a preparation method and application thereof. Background Art

[0002] Amlodipine is a calcium channel blocker commonly used to treat hypertension and coronary heart disease. It can control 24-hour blood pressure once a day. Metoprolol is a β-adrenergic receptor blocker, and its therapeutic concentration range is generally considered to be 45-400nmol / L. When the blood concentration is lower than 45nmol / L, metoprolol may not have a sufficient therapeutic effect, and when the blood concentration is higher than 400nmol / L, it may cause excessive β1 receptor blockade and interference with β2 receptors, leading to unnecessary side effects. If the two drugs are used in combination to treat hypertension, the synergistic and complementary effects of the drugs will be well exerted.

[0003] Chinese patent CN103906508A discloses a drug dosage form suitable for once-daily administration for the treatment of cardiovascular diseases, the drug dosage form comprises a fixed dose combination of sustained-release metoprolol and one or more calcium channel blockers and one or more rate-controlling excipients, the channel blocker can be amlodipine, and it has been tested that less than about 6% of metoprolol is released within 1 hour; 25%-50% of metoprolol is released within 6 hours and at least 90% of metoprolol is released after 20 hours. Although the release time of metoprolol in this patent can be maintained for 20 hours, its initial release rate is slow and it cannot cooperate with amlodipine to quickly reduce blood pressure. Its preparation process includes sealing layer I, drug layering, sustained-release coating layer I, sustained-release coating layer II, sealing layer II, PEG coating, tableting, coating, etc., and the preparation process is complicated.

[0004] Chinese patent CN101249083A discloses a sustained-release preparation containing metoprolol and amlodipine, which is composed of a sustained-release part and a quick-release part, wherein metoprolol is the sustained-release part and amlodipine is the quick-release part. In the patent, metoprolol releases 25-45% in the first hour, 45-75% in the fourth hour, and more than 75% in the eighth hour. The quick-release part of amlodipine is characterized in that amlodipine dissolves more than 75% after 30 minutes in an in vitro dissolution test. Although metoprolol is initially released more and achieves a rapid hypotensive effect, it is released in 8 hours and cannot work in a long-term manner, and the sustained-release effect is ordinary and cannot meet the long-term hypotensive effect.

[0005] Chinese patent CN113116851A discloses a gastric retention tablet, comprising a tablet core, a sustained-release layer and an isolation layer, wherein the tablet core comprises a first active pharmaceutical ingredient and the sustained-release layer comprises a second active pharmaceutical ingredient. In this article, metformin hydrochloride is taken as an example, and the second active pharmaceutical ingredient is not added, and the release is completed in 16 hours. Its preparation method includes first granulating the first active pharmaceutical ingredient with the auxiliary material, then tableting with the lubricant, and then coating the isolation layer and the sustained-release layer. The preparation method is relatively complicated and the applicable drug types do not include compound preparations of metoprolol and amlodipine. Summary of the invention

[0006] The present invention aims at the problems existing in the prior art and provides a compound composition and a preparation method and application thereof. By using a specific ratio of metoprolol in a quick-release layer to metoprolol in a sustained-release layer, amlodipine and metoprolol in the quick-release layer are quickly released, and metoprolol in the sustained-release layer is slowly released within 24 hours, thereby achieving the effects of both rapid and long-term blood pressure reduction.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0008] In a first aspect, the present invention provides a composite composition, comprising a sustained-release layer, a barrier layer and a quick-release layer, wherein the sustained-release layer comprises metoprolol and a sustained-release layer excipient; the barrier layer comprises a barrier layer excipient; the quick-release layer comprises amlodipine, quick-release layer metoprolol and a quick-release layer excipient; and the mass ratio of the metoprolol to the sustained-release layer metoprolol is: 1-3:6.5-8.5.

[0009] Specifically, the mass ratio of the sustained-release layer, the barrier layer and the quick-release layer is 2-4:1-2:1.

[0010] Specifically, the metoprolol in the sustained-release layer and the metoprolol in the immediate-release layer can be independently selected from one of metoprolol free base, metoprolol optical isomers and metoprolol pharmaceutically acceptable salts.

[0011] Specifically, the sustained-release layer excipients include a sustained-release layer sustained-release polymer, a sustained-release layer filler, a sustained-release layer glidant and a sustained-release layer lubricant.

[0012] Specifically, the barrier layer auxiliary materials include a barrier layer sustained-release polymer, a barrier layer filler, a barrier layer glidant and a barrier layer lubricant.

[0013] Specifically, the amlodipine is selected from amlodipine besylate or levamlodipine besylate.

[0014] Specifically, the quick-release layer excipients include a quick-release layer filler, a disintegrant, a quick-release layer glidant and a quick-release layer lubricant.

[0015] Specifically, the slow-release polymer of the barrier layer is at least one of cellulose, Kollidon SR, glyceryl behenate and natural gum.

[0016] Specifically, the sustained-release polymer of the sustained-release layer includes cellulose and natural gum.

[0017] Specifically, the sustained-release layer filler, the barrier layer filler and the immediate-release layer filler can be independently selected from at least one of lactose, microcrystalline cellulose, dextrin, pregelatinized starch, mannitol, starch, calcium sulfate, calcium phosphate and calcium hydrogen phosphate.

[0018] Specifically, the sustained-release layer glidant, the blocking layer glidant and the immediate-release layer glidant can be independently selected from at least one of colloidal silicon dioxide and talc.

[0019] Specifically, the lubricant for the sustained-release layer, the lubricant for the barrier layer and the lubricant for the immediate-release layer can be independently selected from at least one of stearic acid, magnesium stearate, calcium stearate and sodium stearyl fumarate.

[0020] Specifically, the disintegrant is at least one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, cross-linked calcium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxypropyl cellulose and pregelatinized starch.

[0021] Specifically, the cellulose is at least one of methyl cellulose (MC), sodium carboxymethyl cellulose (CMC-Na), hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (HEC) and hydroxypropyl cellulose (HPC).

[0022] The natural gum is at least one of alginate, agar, xanthan gum, tragacanth gum, locust bean gum, pectin, guar gum, gum arabic and carrageenan.

[0023] Preferably, the ratio of cellulose to natural gum in the sustained-release layer is (1-3):1.

[0024] Specifically, the sustained-release layer comprises the following components in percentage by mass: 5.0%-7.5% metoprolol, 50%-73% sustained-release polymer of the sustained-release layer, 20%-40% sustained-release layer filler, 0.5%-5% sustained-release layer glidant and 0.5%-5% sustained-release layer lubricant.

[0025] Specifically, the barrier layer comprises the following components in percentage by mass: 10%-40% of a barrier layer sustained-release polymer, 50%-80% of a barrier layer filler, 0.5%-5% of a barrier layer glidant, and 0.5%-5% of a barrier layer lubricant.

[0026] Specifically, the immediate-release layer comprises the following components in percentage by mass: 2.5%-10% amlodipine, 2.5%-8.75% metoprolol, 70%-90% immediate-release layer filler, 2%-10% disintegrant, 0.5%-5% immediate-release layer glidant and 0.5%-5% immediate-release layer lubricant.

[0027] Preferably, the sustained-release polymer in the sustained-release layer is 54%-65%.

[0028] Preferably, the slow-release polymer in the barrier layer is 19%-30%.

[0029] In a second aspect, the present invention provides a method for preparing a compound composition, comprising the following steps:

[0030] (1) granulating the raw materials and auxiliary materials of the sustained-release layer to obtain sustained-release granules, granulating the raw materials and auxiliary materials of the barrier layer to obtain barrier granules, and granulating the raw materials and auxiliary materials of the immediate-release layer to obtain immediate-release granules;

[0031] (2) first pre-compressing the sustained-release granules obtained in step (1), then pre-compressing the blocking granules obtained in step (1), and then adding the quick-release granules obtained in step (1) to press into a three-layer tablet; or first pre-compressing the quick-release granules obtained in step (1), then pre-compressing the blocking granules obtained in step (1), and then adding the sustained-release granules obtained in step (1) to press into a three-layer tablet.

[0032] Specifically, the preparation method of the granules in step (1) is selected from any one or more of direct mixing, wet granulation and dry granulation.

[0033] Specifically, the method further comprises the following steps: coating the three-layer tablet.

[0034] In a third aspect, the present invention also provides a use of the compound composition in preparing a drug for preventing or treating hypertension.

[0035] In a fourth aspect, the present invention further provides a compound preparation comprising any of the above compound compositions and pharmaceutically acceptable excipients.

[0036] The technical effects achieved by the present invention are:

[0037] (1) The three-layer tablet design of the present invention prepares two antihypertensive drugs with complementary action mechanisms into a long-acting compound preparation that can be taken once a day.

[0038] (2) The rapid-release layer of the present invention allows amlodipine and part of metoprolol to be rapidly released, quickly reaching the treatment standard and meeting the demand for rapid blood pressure reduction.

[0039] (3) The present invention adjusts the percentage of the sustained-release polymer in the barrier layer and the sustained-release layer to slowly release the remaining metoprolol within 24 hours, thereby meeting the need for long-term blood pressure reduction.

[0040] (4) The preparation method of the present invention is simple, efficient, and convenient to produce, which is conducive to industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 The metoprolol blood concentration within 24 hours of Example 2 and Comparative Example 1;

[0042] Figure 2 The dissolution rate of metoprolol within 24 hours of Example 1, Example 2 and Comparative Example 1;

[0043] Figure 3 The dissolution rate of metoprolol within 24 hours of Example 3, Example 4, Comparative Example 2 and Comparative Example 3;

[0044] Figure 4 The dissolution rate of metoprolol within 24 hours of Example 4, Comparative Example 4 and Comparative Example 5;

[0045] Figure 5 It is the dissolution rate of metoprolol within 24 hours of Example 5 and Example 6. DETAILED DESCRIPTION

[0046] The present invention will be further described in detail below in conjunction with the accompanying drawings and preferred embodiments, but those skilled in the art will appreciate that these are only for the purpose of explaining the preferred embodiments and therefore should not be taken as limiting the scope of the present invention.

[0047] 1. Examples and Comparative Examples

[0048] Example 1

[0049] The raw and auxiliary materials of Example 1 are shown in Table 1.

[0050] Table 1 Raw and auxiliary materials of Example 1

[0051]

[0052]

[0053] Example 1 The preparation method is as follows:

[0054] (1) Preparation of sustained-release granules: premixing the prescribed amount of metoprolol, sustained-release polymer, filler and glidant to obtain sustained-release layer premixed granules, and mixing the sustained-release layer premixed granules with a lubricant to obtain sustained-release layer granules for later use;

[0055] (2) Preparation of blocking granules: Granulate the prescribed amount of sustained-release polymer, filler and glidant to obtain blocking layer premixed granules, and mix the blocking layer premixed granules with a lubricant to obtain blocking layer granules for later use;

[0056] (3) Preparation of immediate-release granules: premix the prescribed amount of amlodipine, metoprolol, filler, disintegrant and immediate-release layer glidant to obtain immediate-release layer premixed granules, and mix the immediate-release layer premixed granules with a lubricant to obtain immediate-release layer granules for later use;

[0057] (4) Compression of three-layer tablets: Place the prescribed amount of sustained-release granules in the tablet press die and pre-compress them; then place the prescribed amount of blocking granules in the tablet press die and pre-compress them; then place the prescribed amount of immediate-release granules in the tablet press die and compress them into three-layer tablets.

[0058] Example 2

[0059] The difference from Example 1 is that 3 mg of metoprolol succinate is used in the immediate-release layer, and 20.75 mg of metoprolol succinate is used in the sustained-release layer. Only the amount of filler in each layer is adjusted so that the total weight of each layer remains consistent with that in Example 1. The preparation method is the same as that in Example 1.

[0060] Example 3

[0061] The difference from Example 1 is that the type of sustained-release polymer in the sustained-release layer is different. The sustained-release polymer in the sustained-release layer is replaced with 120 mg of HPMC K200M and 60 mg of locust bean gum, and the preparation method is the same as that in Example 1.

[0062] Example 4

[0063] The raw and auxiliary materials of Example 4 are shown in Table 2, and the preparation method is the same as that of Example 1.

[0064] Table 2 Raw and auxiliary materials of Example 4

[0065]

[0066] Example 5

[0067] The difference from Example 1 is that the slow-release polymer of the barrier layer uses 45 mg of HPMC K100M, accounting for 30% of the total weight of the barrier layer, and the slow-release polymer of the slow-release layer uses 120 mg of HPMC K100M and 45 mg of xanthan gum. The preparation method is the same as that of Example 1.

[0068] Example 6

[0069] The difference from Example 1 is that the slow-release polymer of the barrier layer uses 15 mg of Kollidon SR and 15 mg of HPMCK4M, which together account for 20% of the total weight of the barrier layer. The preparation method is the same as that of Example 1.

[0070] Comparative Example 1

[0071] The difference from Example 1 is that the mass ratio of metoprolol in the immediate-release layer and metoprolol in the sustained-release layer is different. 9.5 mg of metoprolol succinate is used in the immediate-release layer, and 14.25 mg of metoprolol succinate is used in the sustained-release layer. Only the amount of filler in each layer is adjusted so that the total weight of each layer is consistent with that in Example 1. The preparation method is the same as that in Example 1.

[0072] Comparative Example 2

[0073] The difference from Example 3 is that the type of sustained-release polymer in the sustained-release layer is different. The sustained-release polymer in the sustained-release layer is replaced with 180 mg of HPMC K100M, and the preparation method is the same as that in Example 3.

[0074] Comparative Example 3

[0075] The difference from Example 3 is that the sustained-release polymer in the sustained-release layer is different in type. The sustained-release polymer in the sustained-release layer is replaced with 120 mg of HPMC K4M and 60 mg of HPMC K100LV, and the preparation method is the same as that in Example 3.

[0076] Comparative Example 4

[0077] The raw and auxiliary materials of Comparative Example 4 are shown in Table 3, and the preparation method is the same as that of Example 4.

[0078] Table 3 Comparative Example 4 Raw and Auxiliary Materials

[0079]

[0080] Comparative Example 5

[0081] The raw and auxiliary materials of Comparative Example 5 are shown in Table 4, and the preparation method is the same as that of Example 4.

[0082] Table 4 Comparative Example 5 Raw and Auxiliary Materials

[0083]

[0084] 2. Test Experiment

[0085] (1) Blood drug concentration test

[0086] Two tablets of the test preparation were administered to the subjects on an empty stomach at 8:00 in the morning, and upper limb venous blood was collected before administration (0h) and 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 7h, 8h, 9h, 10h, 12h, 14h, and 24h after administration to detect the blood concentration of metoprolol.

[0087] According to the above method, the blood concentration of metoprolol in Example 1, Example 2 and Comparative Example 1 within 24 hours of taking the medicine was detected, as shown in Table 5.

[0088] Table 5 Blood drug concentrations of Example 2 and Comparative Example 1 within 24 hours

[0089]

[0090]

[0091] (2) Dissolution test

[0092] Chinese Pharmacopoeia 2015 Edition Part IV General Chapter 0931 Method 2, paddle method 50 rpm, 37°C, 500 mL of pH 6.8 medium.

[0093] According to the method described above, the dissolution of amlodipine in Examples 1-6 and Comparative Examples 1-5 was tested. Amlodipine was the immediate release part, and the dissolution was greater than 75% after 30 minutes.

[0094] According to the method described above, the dissolution of metoprolol in Examples 1-6 and Comparative Examples 1-5 was tested, as shown in Table 6.

[0095] Table 6 Dissolution of Examples 1-6 and Comparative Examples 1-5

[0096] Time (h) 0.5 1 2 4 6 8 12 16 20 24 Example 1 13.6 18.4 27.6 39.1 47.2 56.2 69 81.8 89.3 95.9 Example 2 14.1 20.2 29.1 40.2 49 58.2 70.3 81.4 88.4 95.2 Example 3 13.2 19.1 27.8 39 47.6 58.1 72.5 83.6 90.2 96.8 Example 4 12.9 19.6 24.2 30.9 38.2 45.9 62.4 75.9 88.8 94.6 Example 5 13 19.9 24.5 31.3 38.6 46.4 63 76.7 89.7 95.5 Example 6 14.2 22.7 27.3 34.2 41.6 50.4 68.4 80.1 93.2 99.1 Comparative Example 1 47.8 53.1 62.2 72.1 79.9 85.2 93.1 99.4 100.9 101.7 Comparative Example 2 13.8 19.6 26.1 35.4 43.9 49.2 58.6 68.0 77.4 84.1 Comparative Example 3 15.6 22.6 30.4 48.2 60.4 72.4 85.6 93.4 100.9 101.7 Comparative Example 4 12.0 15.0 19.3 27.4 34.5 44.4 57.4 66.8 77.2 82.0 Comparative Example 5 9.68 12.6 16.5 23.1 31.5 39.3 48.4 58.5 66.6 72.33

[0097] By comparing Examples 1-2 and Comparative Example 1, it can be seen that the mass ratio of the immediate-release layer metoprolol to the sustained-release layer metoprolol in Examples 1-2 is within the protection scope of the present application, and the metoprolol can be sustained-released for 24 hours; when the mass ratio of the immediate-release layer metoprolol to the sustained-release layer metoprolol in Comparative Example 1 is 2:3 (not within the protection scope of the present application), the metoprolol in the sustained-release portion cannot achieve 24 hours of sustained release, and the metoprolol blood concentration in the early stage is too high, which is prone to adverse reactions.

[0098] By comparing Examples 3-4 and Comparative Examples 2-3, it can be seen that the sustained-release polymer in the sustained-release layer of Example 3-4 is a combination of cellulose and natural gum, and the metoprolol can be evenly released within 24 hours; the sustained-release polymer in the sustained-release layer of Comparative Example 2-3 only uses cellulose, and the sustained-release effect of metoprolol is not good, and the sustained release for 24 hours cannot be achieved or the release is incomplete. For example, in Comparative Example 2, the dissolution endpoint is only 84%, and the active drug cannot be completely released; as in Comparative Example 3, the sustained-release effect is poor and can only be maintained for 16 hours.

[0099] The type of sustained-release polymer in Example 4 and Comparative Examples 4-5 is the same, and the total sustained-release polymer content of the three-layer tablet is the same. The metoprolol in Example 4 (the content of the sustained-release polymer in the sustained-release layer and the barrier layer is within the protection scope of the present invention) can be uniformly released within 24 hours; when the sustained-release polymer in the sustained-release layer (based on the tablet layer) is too low (40% in Comparative Example 4) or too high (76% in Comparative Example 5), or the sustained-release polymer in the barrier layer is too low (6.7% in Comparative Example 5) or too high (78.7% in Comparative Example 4), the active substance cannot be completely released, affecting the final blood concentration of the active substance in the body, thereby affecting the efficacy.

[0100] The present invention is described in detail above. The present invention uses specific examples to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the present invention and its core ideas. It should be pointed out that for ordinary technicians in this technical field, without departing from the principles of the present invention, the present invention can also be improved and modified in a number of ways, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound composition comprising a sustained-release layer, a barrier layer and a quick-release layer, characterized in that: The sustained-release layer comprises metoprolol and sustained-release layer excipients; The blocking layer includes a blocking layer auxiliary material; The immediate-release layer comprises amlodipine, metoprolol and immediate-release layer excipients; The mass ratio of the metoprolol in the immediate-release layer to the metoprolol in the sustained-release layer is: 1-3:6.5-8.

5.

2. The compound composition according to claim 1, characterized in that The mass ratio of the sustained-release layer, the barrier layer and the quick-release layer is 2-4:1-2:

1.

3. The compound composition according to claim 1, characterized in that The metoprolol in the sustained-release layer and the metoprolol in the immediate-release layer can be independently selected from one of metoprolol free base, metoprolol optical isomers and metoprolol pharmaceutically acceptable salts; and / or The sustained-release layer excipients include a sustained-release layer sustained-release polymer, a sustained-release layer filler, a sustained-release layer glidant and a sustained-release layer lubricant; and / or The barrier layer auxiliary materials include a barrier layer sustained-release polymer, a barrier layer filler, a barrier layer glidant and a barrier layer lubricant; The amlodipine is selected from amlodipine besylate or levamlodipine besylate; and / or The quick-release layer auxiliary materials include a quick-release layer filler, a disintegrant, a quick-release layer glidant and a quick-release layer lubricant.

4. The compound composition according to claim 2, characterized in that: The sustained-release polymer of the sustained-release layer comprises cellulose and natural gum; and / or The slow-release polymer of the barrier layer is at least one of cellulose, Kollidon SR, glyceryl behenate and natural gum; and / or The sustained-release layer filler, the retardation layer filler and the immediate-release layer filler can be independently selected from at least one of lactose, microcrystalline cellulose, dextrin, pregelatinized starch, mannitol, starch, calcium sulfate, calcium phosphate and calcium hydrogen phosphate; and / or The sustained-release layer glidant, the blocking layer glidant and the immediate-release layer glidant can be independently selected from at least one of colloidal silicon dioxide and talc; and / or The sustained-release layer lubricant, the barrier layer lubricant and the immediate-release layer lubricant can be independently selected from at least one of stearic acid, magnesium stearate, calcium stearate and sodium stearyl fumarate; and / or The disintegrant is at least one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, cross-linked calcium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxypropyl cellulose and pregelatinized starch.

5. The compound composition according to claim 4, characterized in that: The cellulose is at least one of methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose and hydroxypropyl cellulose; The natural gum is at least one of alginate, agar, xanthan gum, tragacanth gum, locust bean gum, pectin, guar gum, gum arabic and carrageenan.

6. The compound composition according to claim 4, characterized in that: The sustained-release layer comprises the following components by weight percentage: 5.0%-7.5% of metoprolol, 50%-73% of sustained-release polymer in the sustained-release layer, 20%-40% of a sustained-release filler, 0.5%-5% of a sustained-release glidant, and 0.5%-5% of a sustained-release lubricant in the sustained-release layer; and / or The barrier layer comprises the following components in percentage by weight: 10%-40% of a barrier layer sustained-release polymer, 50%-80% of a barrier layer filler, 0.5%-5% of a barrier layer glidant, and 0.5%-5% of a barrier layer lubricant; and / or The immediate release layer comprises the following components in percentage by mass: 2.5%-10% of amlodipine, 2.5%-8.75% of metoprolol, 70%-90% of immediate release layer filler, 2%-10% of disintegrant, 0.5%-5% of immediate release layer glidant and 0.5%-5% of immediate release layer lubricant.

7. A method for preparing the compound composition according to any one of claims 1 to 6, characterized in that: The following steps are involved: (1) granulating the metoprolol in the sustained-release layer and the excipients in the sustained-release layer to obtain sustained-release granules, granulating the excipients in the blocking layer to obtain blocking granules, and granulating the amlodipine, metoprolol and excipients in the immediate-release layer to obtain immediate-release granules; (2) first pre-compressing the sustained-release granules obtained in step (1), then pre-compressing the blocking granules obtained in step (1), and then adding the quick-release granules obtained in step (1) to press into a three-layer tablet; or first pre-compressing the quick-release granules obtained in step (1), then pre-compressing the blocking granules obtained in step (1), and then adding the sustained-release granules obtained in step (1) to press into a three-layer tablet.

8. The preparation method according to claim 7, characterized in that: The preparation method of the granules in step (1) is selected from any one or more of direct mixing, wet granulation and dry granulation.

9. Use of the compound composition according to any one of claims 1 to 6 or the compound composition prepared by the preparation method according to any one of claims 7 to 8 in preparing drugs for preventing or treating hypertension.

10. A compound preparation, characterized in that: The invention comprises the compound composition according to any one of claims 1 to 6 or the compound composition prepared by the preparation method according to any one of claims 7 to 8 and pharmaceutically acceptable excipients.

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