Sacubitril valsartan sodium indapamide sustained-release tablets and a preparation method thereof

Abstract

The application provides a sacubitril valsartan sodium indapamide sustained-release tablet and a preparation method thereof. The tablet is a double-layer tablet structure, comprising a first layer of an indapamide sustained-release layer and a second layer of a sacubitril valsartan sodium immediate-release layer. By adjusting the type and amount of the sustained-release material in the indapamide sustained-release layer, the type and amount of the disintegrant in the sacubitril valsartan sodium immediate-release layer and the amount of the binder, the double-layer tablet process is stable, the release behavior is similar to that of single preparation, and the consistency of the drug efficacy is ensured.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and more particularly to a pharmaceutical preparation for treating hypertension comprising an angiotensin receptor-neprilysin inhibitor (ARNI) and a thiazide-like diuretic, especially comprising sacubitril / valsartan sodium and indapamide, and a method for preparing the same. Background Technology

[0002] High blood pressure exerts excessive pressure on the arterial walls, which can damage blood vessels and organs. The higher the blood pressure and the longer it remains uncontrolled, the greater the damage. High blood pressure is closely related to cardiovascular risk and seriously affects patient prognosis. Other complications caused by high blood pressure include atrial fibrillation, heart failure, end-stage renal disease, and dementia.

[0003] There are six main classes of commonly used antihypertensive drugs: calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), thiazide diuretics (divided into thiazide-type diuretics and thiazide-like diuretics; the former includes hydrochlorothiazide and benzylfluorothiazide, while the latter includes indapamide and chlorthalidone), beta-blockers, and angiotensin receptor-neprilysin inhibitors (ARNIs). However, current treatments for hypertension often fail to achieve ideal control with single-drug therapy. For patients with hypertension who do not respond well to single-drug therapy, combination therapy with two or more antihypertensive drugs is recommended. The combination of ARNI and thiazide diuretics has been identified as one of the main recommended optimized combination therapy regimens in the 2024 Chinese Guidelines for the Prevention and Treatment of Hypertension.

[0004] Sacubitril / valsartan sodium is the only marketed ARNI (Antihypertensive Inhibitor) and is a newly added class of commonly used antihypertensive drugs in the 2024 edition of the "Chinese Guidelines for the Prevention and Treatment of Hypertension". Currently marketed sacubitril / valsartan sodium tablets are an immediate-release tablet developed by Novartis, possessing almost all the mechanisms of action of commonly used clinical antihypertensive drugs. While having a strong antihypertensive effect, its target organ protection effect is also very clear. Indapamide extended-release tablets are thiazide-like diuretics that lower blood pressure by regulating calcium influx into vascular smooth muscle cells, thus reducing peripheral vascular resistance. It is generally used to treat mild to moderate hypertension and can also be used to relieve edema caused by heart failure. The combination of these two drugs can synergistically lower blood pressure by inhibiting vasoconstriction and dilating blood vessels, and by promoting diuresis and sodium excretion, thereby reducing blood volume, and can also effectively reduce toxic side effects.

[0005] Chinese patent CN120131641A discloses a compound antihypertensive drug composition in which sacubitril / valsartan sodium, indapamide, and excipients are mixed to form a single-tablet compound. First, sacubitril / valsartan sodium and indapamide are not effectively separated, which can easily cause interaction between the two active ingredients and create stability risks. Second, indapamide is not a sustained-release formulation, which can easily cause fluctuations in blood drug concentration and is not conducive to stable blood pressure reduction.

[0006] In addition to mixing and granulating the two active ingredients to form a single-tablet compound preparation, the two active ingredients can also be granulated separately to form a bilayer tablet. The inventors found that directly formulating the original single-component formulation into a bilayer tablet compound preparation has many formulation problems. The dissolution rates of the two layers, sacubitril / valsartan sodium immediate-release layer and indapamide sustained-release layer, affect each other, resulting in incomplete dissolution of the active ingredients. In addition, there are also problems with brittleness during the preparation of bilayer tablets, and the two layers are not firmly bonded, resulting in delamination.

[0007] The original formulation of sacubitril / valsartan sodium tablets was an immediate-release tablet, capable of complete drug release within a short time. The original formulation of indapamide extended-release tablets was a matrix-type extended-release formulation, releasing the drug completely within 24 hours. Sacubitril / valsartan sodium tablets weigh 400 mg per tablet and are produced using 15.1*6.0mm irregularly shaped compression tablets, while indapamide extended-release tablets weigh 200 mg per tablet and are produced using φ8mm round compression tablets. The significant differences in tablet weight and shape between these two single-agent formulations present a considerable challenge in assembling a single-tablet combination formulation that simultaneously achieves release behavior similar to the original single-agent formulations. Summary of the Invention

[0008] In view of the problems in the existing technology of ineffective separation of active ingredients in sacubitril / valsartan sodium and indapamide compound preparations and excessively rapid release of indapamide, as well as the problems of incomplete dissolution, slow dissolution process and layering when the two drugs are made into bilayer tablets, the present invention provides a sacubitril / valsartan sodium and indapamide sustained-release preparation with stable dissolution and intact appearance.

[0009] To achieve the above objectives, the present invention provides a sacubitril / valsartan sodium / indapamide sustained-release tablet, which has a double-layer tablet structure, comprising a first indapamide sustained-release layer and a second sacubitril / valsartan sodium immediate-release layer.

[0010] Furthermore, the bilayer tablet comprises 215-238 mg of sacubitril / valsartan sodium and 1-2 mg of indapamide, preferably 226.2 mg of sacubitril / valsartan sodium and 1.5 mg of indapamide.

[0011] Furthermore, the indapamide sustained-release layer comprises indapamide, lactose, sustained-release material, polyvinylpyrrolidone, magnesium stearate, and colloidal silica.

[0012] Furthermore, the indapamide sustained-release layer comprises 1-2 mg of indapamide, 240-260 mg of lactose, 15-20 mg of polyvinylpyrrolidone, 1.5-2.5 mg of colloidal silica, 125-130 mg of sustained-release material, and 0.3-1.5 mg of magnesium stearate.

[0013] Furthermore, the sustained-release material in the indapamide sustained-release layer includes the pore-forming agent lactose and the backbone material hydroxypropyl methylcellulose, wherein the mass ratio of hydroxypropyl methylcellulose to lactose is 2:1 to 1:1.

[0014] The reference formulation of indapamide sustained-release tablets uses hydroxypropyl methylcellulose as the sustained-release material. During testing, it was found that using the original formulation to create a bilayer tablet resulted in a slower release of the indapamide sustained-release layer, which did not completely dissolve within 24 hours. To address this release issue, this invention selects hydroxypropyl methylcellulose as the matrix material, preferably K4MCR, and lactose as the pore-forming agent, preferably F100. By adjusting the ratio of the matrix material and the pore-forming agent, the release behavior of the indapamide sustained-release layer can be made similar to that of a single-component indapamide sustained-release tablet formulation.

[0015] Furthermore, the sacubitril / valsartan sodium immediate-release layer comprises sacubitril / valsartan sodium, microcrystalline cellulose, hydroxypropyl methylcellulose, disintegrant, magnesium stearate, talc, and silica.

[0016] Furthermore, the sacubitril / valsartan sodium immediate-release layer comprises 215-238 mg of sacubitril / valsartan sodium, 50-80 mg of microcrystalline cellulose, 0.2-0.4 mg of hydroxypropyl methylcellulose, 78-90 mg of disintegrant, 1-3 mg of silica, 8-16 mg of magnesium stearate, and 2-6 mg of talc.

[0017] Furthermore, the immediate-release layer of sacubitril / valsartan sodium uses two disintegrants, one of which is low-substituted hydroxypropyl cellulose, and the other is sodium carboxymethyl starch or crospovidone.

[0018] Furthermore, in the sacubitril / valsartan sodium immediate-release layer, when the second disintegrant is sodium carboxymethyl starch, the mass ratio of low-substituted hydroxypropyl cellulose to sodium carboxymethyl starch is 2:1-5:3.

[0019] Furthermore, in the sacubitril / valsartan sodium immediate-release layer, when the second disintegrant is crospovidone, the mass ratio of low-substituted hydroxypropyl cellulose to crospovidone is 70:12-70:20.

[0020] Furthermore, the hydroxypropyl methylcellulose is preferably hydroxypropyl methylcellulose E5.

[0021] Furthermore, the disintegrant, talc, and magnesium stearate in the sacubitril / valsartan sodium immediate-release layer comprise both internal and external components.

[0022] Furthermore, the sacubitril / valsartan sodium immediate-release layer contains 66-74 mg of internally added disintegrant, 1-4 mg of internally added talc, and 4-8 mg of internally added magnesium stearate; and 4-20 mg of externally added disintegrant, 1-2 mg of externally added talc, and 4-8 mg of externally added magnesium stearate.

[0023] This invention also provides a method for preparing sacubitril / valsartan sodium indapamide sustained-release tablets, comprising the following steps:

[0024] S1. Preparation of Indapamide Sustained-Release Layer Particle Mix

[0025] Indapamide is thoroughly mixed with 1 / 3 of the prescribed amount of lactose to obtain an indapamide mixture; then half of the remaining lactose, the indapamide mixture, polyvinylpyrrolidone, and the other half of the remaining lactose are added to a wet granulation mixer and mixed evenly; wet granulation and dry granulation are performed; the resulting granules are mixed evenly with silica powder and sustained-release material, and then magnesium stearate is added and mixed thoroughly to obtain the total mixed granules of the indapamide sustained-release layer;

[0026] S2. Preparation of Sacubitril / Valsartan Sodium Immediate-Release Layer Particles

[0027] Premix: Add microcrystalline cellulose, sacubitril / valsartan sodium, and silica in sequence and mix well. This mixture is called premix 1.

[0028] Addition steps and granulation: Add premix 1, a portion of disintegrant, talc, and magnesium stearate to the mixer in sequence and mix thoroughly. This mixture is called premix 2. Premix 2 is then granulated by dry granulation.

[0029] Additional steps: Add the above-obtained granules, the remaining disintegrant, and talc to a mixer and mix evenly. Add hydroxypropyl methylcellulose and the remaining magnesium stearate and mix evenly to obtain the total mixed granules of the immediate-release layer of sacubitril / valsartan sodium.

[0030] S3. Tableting

[0031] The total mixed particles of indapamide sustained-release layer and sacubitril / valsartan sodium immediate-release layer are placed separately in a double-layer tableting device for tableting. The tableting hardness is 100-130N, thus obtaining sacubitril / valsartan sodium indapamide sustained-release tablets.

[0032] Furthermore, in the preparation of the indapamide sustained-release layer mixed particles, the sustained-release materials are hydroxypropyl methylcellulose and lactose, and the mass ratio of hydroxypropyl methylcellulose to lactose is 2:1-1:1.

[0033] Furthermore, in the preparation of the sacubitril / valsartan sodium immediate-release layer total mixed particles, the disintegrant, talc, and magnesium stearate include an internally added portion and an externally added portion, with the portion added first being the internally added portion and the portion added later being the externally added portion.

[0034] Furthermore, the disintegrants used in the preparation of the sacubitril / valsartan sodium immediate-release layer total mixed particles are of two types: one is low-substituted hydroxypropyl cellulose, and the other is sodium carboxymethyl starch or crospovidone.

[0035] Furthermore, in the sacubitril / valsartan sodium immediate-release layer, when the second disintegrant is sodium carboxymethyl starch, the mass ratio of low-substituted hydroxypropyl cellulose to sodium carboxymethyl starch is 2:1-5:3.

[0036] Furthermore, in the sacubitril / valsartan sodium immediate-release layer, when the second disintegrant is crospovidone, the mass ratio of low-substituted hydroxypropyl cellulose to crospovidone is 70:12-70:20.

[0037] In this invention, lactose is used as the main filler material in the indapamide sustained-release layer, accounting for a large proportion of the formulation, while other materials account for a small proportion. This invention divides the lactose filler into three parts for feeding. First, 1 / 3 of the lactose is mixed with indapamide to form an indapamide mixture. The remaining 2 / 3 of the lactose is added in a hamburger-like manner, with half of the remaining lactose added first as a base (in contact with the equipment). Considering that lactose has a higher density than other materials, the other half of the remaining lactose is placed on top. This feeding order helps reduce the adhesion of materials to the equipment, thereby reducing formulation errors.

[0038] In summary, the beneficial effects of the present invention are as follows:

[0039] Based on the research and development of indapamide sustained-release tablets and sacubitril / valsartan sodium tablets, this invention uses a double-layer tablet structure to create a single-tablet compound formulation, which can effectively isolate the two active ingredients, reduce the interaction between the active ingredients, and ensure the stability of the formulation.

[0040] The dissolution rates of the indapamide sustained-release layer and the sacubitril / valsartan sodium immediate-release layer influence each other, resulting in incomplete dissolution and slow dissolution processes. This invention optimizes the type and amount of sustained-release material in the indapamide sustained-release layer by adding porogen lactose and adjusting the mass ratio of the backbone material hydroxypropyl methylcellulose and porogen lactose, enabling the indapamide sustained-release layer in the bilayer tablet to be completely and stably released within 24 hours. Similarly, by optimizing the type and amount of disintegrant in the sacubitril / valsartan sodium immediate-release layer, the immediate-release layer in the bilayer tablet can be rapidly and stably released. The release behavior of the bilayer tablet of this invention is similar to that of the monotherapy formulation, ensuring consistency in the clinical efficacy of the drug.

[0041] By adding a small amount of hydroxypropyl methylcellulose to the immediate-release layer of sacubitril / valsartan sodium, the delamination problem that occurred after compression of bilayer tablets was successfully solved without affecting drug dissolution. Detailed Implementation

[0042] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0043] Examples 1-10

[0044] According to the formulation in Table 1, indapamide was mixed with about 1 / 3 lactose and passed through a 60-mesh sieve to obtain an indapamide mixture. The obtained indapamide mixture, along with half of the remaining lactose, polyvinylpyrrolidone, and the other half of the remaining lactose, was added to a wet granulator and mixed for 10 minutes. Granulation was carried out using water as a wetting agent, and the mixture was dried in a fluidized bed at 60°C to below 1%. Dry granulation was performed using a 1.2 mm sieve. The granules were then mixed with colloidal silica, hydroxypropyl methylcellulose (the skeleton material), and lactose (the pore-forming agent) for 30 minutes. Magnesium stearate was then added and mixed evenly to obtain indapamide granules A1, A2, and A4-A7.

[0045] According to the prescription in Table 2, premixing is performed first: add sacubitril / valsartan sodium, microcrystalline cellulose, and silica to a mixer, mix for 10 minutes, and pass through a 30-mesh sieve twice to obtain premix 1;

[0046] Next, perform the internal addition step and granulation: Add the premix 1, disintegrant internal addition, talc internal addition, and magnesium stearate internal addition to the mixer in sequence, mix for 10 minutes, pass through a 30-mesh sieve twice, continue mixing, and mix evenly; after mixing, perform dry granulation and granulate using a 1.0 mm sieve.

[0047] Finally, the following steps are performed: the granules obtained above are added to a mixer along with the disintegrant and talc additives, and mixed for 30 minutes. Then, hydroxypropyl methylcellulose and magnesium stearate additives are added and mixed for 5 minutes. This mixture is called sacubitril / valsartan granules B3-B10.

[0048] Table 1: Indapamide granules

[0049]

[0050] Table 2: Sacubitril / Valsartan Sodium Granules

[0051]

[0052] Indapamide granules and sacubitril / valsartan sodium granules were compressed into tablets according to the combinations in Table 3, with a tablet hardness of 100-130N. Specifically, A1, A2, and B3 were compressed into single-component, single-layer tablets, while A4 and B4, A5 and B5, A6 and B6, A7 and B7, A4 and B8, A4 and B9, and A4 and B10 were compressed into compound, double-layer tablets.

[0053] Table 3: Tablet Preparation

[0054]

[0055] Comparative Examples 1-9:

[0056] Indapamide particles A8 and sacubitril / valsartan sodium particles B11-B15 in Tables 4 and 5 were prepared according to the preparation method in the examples.

[0057] Table 4: Indapamide granules

[0058]

[0059] Table 5: Sacubitril / Valsartan Sodium Granules

[0060]

[0061] According to the combinations in Table 6, indapamide granules, coxacubitril, and valsartan sodium granules were respectively compressed into double-layer tablets with a tablet hardness of 100-130N.

[0062] Table 6: Tablet Preparation

[0063]

[0064] Release behavior measurement:

[0065] (1) Determination of indapamide release behavior: The dissolution and release rate determination method (General Rule 0931 Method II) was used. 0.01 mol / L hydrochloric acid solution was used as the dissolution medium and the rotation speed was 50 revolutions per minute. The operation was carried out according to the method. Samples were taken after 1 hour, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours and 24 hours. The results were measured.

[0066] (2) Sacubitril / valsartan release behavior determination: The determination was carried out in accordance with the method of dissolution and release determination (General Rule 0931 Method II), using pH 4.5 acetate buffer as the dissolution medium, rotating at 50 revolutions per minute, and the procedure was followed. Samples were taken at 5 min, 10 min, 15 min, 30 min, 45 min, and 60 min, and the results were determined.

[0067] Release behavior results and appearance observations in Examples 1-10

[0068]

[0069] Results of release behavior and appearance observations of Comparative Examples 1-9:

[0070]

[0071] Example 1 is the original reference formulation, and Example 2 is a scaled-up version of the original formulation. The dissolution results show that indapamide sustained-release tablets with a tablet weight of 400mg can still achieve 24-hour sustained-release characteristics.

[0072] Example 3 is the original reference formulation of sacubitril / valsartan immediate-release tablets, which can achieve immediate-release characteristics.

[0073] A comparison of the dissolution results of Examples 4-10 with those of Examples 1 and 3 shows that the release characteristics of the immediate-release layer of sacubitril / valsartan sodium and the sustained-release layer of indapamide in the bilayer tablets of the present invention are similar to the release characteristics of the single-drug formulation of the reference formulation, thus ensuring the consistency of drug efficacy.

[0074] Comparative Example 1 was a bilayer tablet prepared by combining the reference formulations of indapamide extended-release tablets and sacubitril / valsartan sodium immediate-release tablets. The dissolution results showed that the dissolution of the indapamide extended-release layer and the sacubitril / valsartan sodium immediate-release layer affected each other, resulting in incomplete dissolution of either. Therefore, directly preparing bilayer tablets using the original formulations cannot simultaneously meet the release rate requirements of both formulations.

[0075] In Comparative Example 2, the amount of low-substituted hydroxypropyl cellulose was reduced and the amount of cross-linked povidone was increased in the immediate-release layer of sacubitril / valsartan sodium, while the amount of overall disintegrant remained unchanged. It was found that the immediate-release layer of the bilayer sacubitril / valsartan sodium tablets did not release completely at 60 min and could not achieve the release effect of the original single-agent sacubitril / valsartan sodium tablets.

[0076] In Comparative Example 3, the amount of disintegrant in the immediate-release layer of sacubitril / valsartan sodium remained unchanged, and only cross-linked povidone was used as the disintegrant. The dissolution test results showed that the dissolution rate of the immediate-release layer of sacubitril / valsartan sodium was low at 10 min and 15 min, and the release was slow in the middle process. The dissolution rate increased rapidly at 30 min, indicating that the immediate-release layer could not release steadily.

[0077] In Comparative Example 4, the mass ratio of the backbone material hydroxypropyl methylcellulose and the pore-forming agent lactose in the sustained-release material of the indapamide sustained-release layer was adjusted to 3:1. The dissolution results showed that the indapamide sustained-release layer could not be completely dissolved after 24 hours, and could not achieve the release effect of the original single-component indapamide sustained-release tablets.

[0078] In Comparative Example 5, the immediate-release layer of sacubitril / valsartan sodium was the original reference formulation, and in Comparative Example 6, the sustained-release layer of indapamide was the original reference formulation. The dissolution test results show that optimizing only one layer of the formulation does not result in good dissolution of the bilayer tablets, and it still cannot achieve a release effect similar to that of the original single-component formulation.

[0079] In Comparative Examples 1, 5, 7, and 8, the immediate-release layer of sacubitril / valsartan sodium, with or without the addition of hydroxypropyl methylcellulose or with a small amount of hydroxypropyl methylcellulose, showed poor adhesion of the double-layer tablets, resulting in delamination and affecting the quality of the drug.

[0080] In Comparative Example 9, the excessive amount of hydroxypropyl methylcellulose added to the immediate-release layer of sacubitril / valsartan sodium affected the dissolution of the immediate-release layer of sacubitril / valsartan sodium, resulting in incomplete dissolution and affecting the efficacy.

[0081] As can be seen from the dissolution test results of the above examples and comparative examples, the present invention, by optimizing the formulation and preparing bilayer tablets, solves the problems of mutual influence of dissolution and stratification that occur when single ingredients are directly made into bilayer tablets. Outside the dosage range of the present invention, good formulation effects cannot be achieved.

[0082] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A sacubitril / valsartan sodium / indapamide sustained-release tablet, characterized in that, It has a double-layer structure, comprising a first layer of indapamide sustained-release layer, which contains 1-2 mg of indapamide, 240-260 mg of lactose, 15-20 mg of polyvinylpyrrolidone, 1.5-2.5 mg of colloidal silica, 125-130 mg of sustained-release material, and 0.3-1.5 mg of magnesium stearate; and a second layer of sacubitril / valsartan sodium immediate-release layer, which contains 215-238 mg of sacubitril / valsartan sodium, 50-80 mg of microcrystalline cellulose, 0.2-0.4 mg of hydroxypropyl methylcellulose E5, 78-90 mg of disintegrant, 1-3 mg of silica, 8-16 mg of magnesium stearate, and 2-6 mg of talc. The sustained-release material in the indapamide sustained-release layer includes the pore-forming agent lactose and the backbone material hydroxypropyl methylcellulose K4MCR, wherein the mass ratio of hydroxypropyl methylcellulose K4MCR to lactose is 2:1-1:

1. The immediate-release layer of sacubitril / valsartan sodium uses two disintegrants, one of which is low-substituted hydroxypropyl cellulose and the other is sodium carboxymethyl starch, with a mass ratio of low-substituted hydroxypropyl cellulose to sodium carboxymethyl starch of 2:1-5:

3. Or the disintegrant in the immediate-release layer of sacubitril / valsartan sodium, one of which is low-substituted hydroxypropyl cellulose and the other is crospovidone, wherein the mass ratio of low-substituted hydroxypropyl cellulose to crospovidone is 70:12-70:

20.

2. The sacubitril / valsartan sodium / indapamide sustained-release tablet according to claim 1, characterized in that, The indapamide sustained-release layer comprises 1.5 mg indapamide, 249 mg lactose, 17.2 mg polyvinylpyrrolidone, 2 mg colloidal silica, 128 mg sustained-release material, and 0.8 mg magnesium stearate; and the sacubitril / valsartan sodium immediate-release layer comprises 226.2 mg sacubitril / valsartan sodium, 69.8 mg microcrystalline cellulose, 0.2 mg hydroxypropyl methylcellulose E5, 78 mg disintegrant, 2 mg silica, 12 mg magnesium stearate, and 4 mg talc. The sustained-release material in the indapamide sustained-release layer includes the pore-forming agent lactose and the backbone material hydroxypropyl methylcellulose K4MCR, wherein the mass ratio of hydroxypropyl methylcellulose K4MCR to lactose is 2:

1. The immediate-release layer of sacubitril / valsartan sodium uses two disintegrants, one of which is low-substituted hydroxypropyl cellulose and the other is sodium carboxymethyl starch; the mass ratio of low-substituted hydroxypropyl cellulose to sodium carboxymethyl starch is 50:

28.

3. The sacubitril / valsartan sodium / indapamide sustained-release tablet according to claim 1, characterized in that, The indapamide sustained-release layer comprises 1.5 mg indapamide, 249 mg lactose, 17.2 mg polyvinylpyrrolidone, 2 mg colloidal silica, 128 mg sustained-release material, and 0.8 mg magnesium stearate; and the sacubitril / valsartan sodium immediate-release layer comprises 226.2 mg sacubitril / valsartan sodium, 69.8 mg microcrystalline cellulose, 0.2 mg hydroxypropyl methylcellulose E5, 86 mg disintegrant, 2 mg silica, 12 mg magnesium stearate, and 4 mg talc. The sustained-release material in the indapamide sustained-release layer includes the pore-forming agent lactose and the backbone material hydroxypropyl methylcellulose K4MCR, wherein the mass ratio of hydroxypropyl methylcellulose K4MCR to lactose is 2:

1. The immediate-release layer of sacubitril / valsartan sodium uses two disintegrants, one of which is low-substituted hydroxypropyl cellulose and the other is crospovidone, with a mass ratio of low-substituted hydroxypropyl cellulose to crospovidone of 70:

16.

4. The sacubitril / valsartan sodium indapamide sustained-release tablet according to claim 1, characterized in that, The sacubitril / valsartan sodium immediate-release layer contains both internal and external components for the disintegrant, talc, and magnesium stearate. The mixture contains 66-74 mg of disintegrant, 1-4 mg of talc, and 4-8 mg of magnesium stearate; and 4-20 mg of disintegrant, 1-2 mg of talc, and 4-8 mg of magnesium stearate.

5. A method for preparing sacubitril / valsartan sodium indapamide sustained-release tablets as described in any one of claims 1-4, characterized in that, Includes the following steps: S1. Preparation of Indapamide Sustained-Release Layer Particle Mix Indapamide is thoroughly mixed with 1 / 3 of the prescribed amount of lactose to obtain an indapamide mixture; then half of the remaining lactose, the indapamide mixture, polyvinylpyrrolidone, and the other half of the remaining lactose are added to a wet granulation mixer and mixed evenly; wet granulation and dry granulation are performed; the resulting granules are mixed evenly with silica powder and sustained-release material, and then magnesium stearate is added and mixed thoroughly to obtain the total mixed granules of the indapamide sustained-release layer; S2. Preparation of Sacubitril / Valsartan Sodium Immediate-Release Layer Particles Premix: Add microcrystalline cellulose, sacubitril / valsartan sodium, and silica in sequence and mix well. This mixture is called premix 1. Internal addition steps and granulation: Add premix 1, disintegrant internal addition portion, talc internal addition portion, and magnesium stearate internal addition portion to the mixer in sequence, mix thoroughly and evenly, and record as premix 2; perform dry granulation on premix 2; Additional steps: Add the above-obtained granules, disintegrant additive, and talc additive to a mixer and mix evenly. Add hydroxypropyl methylcellulose E5 and magnesium stearate additive and mix evenly to obtain the total mixed granules of sacubitril / valsartan sodium immediate-release layer. S3. Tableting The total mixed particles of indapamide sustained-release layer and sacubitril sodium immediate-release layer are placed separately in a double-layer tableting device and compressed into tablets with a tablet hardness of 100-130 N.

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