Quick-release composition

Abstract

A quick-release composition. The quick-release composition comprises sacubitril valsartan or a salt thereof and amlodipine or a salt thereof, wherein both active ingredients in the quick-release composition can realize quick release. The present invention also relates to the use of sacubitril valsartan or a salt thereof and amlodipine or a salt thereof and the quick-release composition thereof in the preparation of a drug for treating cardiovascular diseases.

Description

Immediate-release composition

[0001] This application claims priority to Chinese Patent Application No. 2024101265395 filed on January 30, 2024, and Chinese Patent Application No. 2024117716775 filed on December 4, 2024. This application incorporates the entire contents of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention relates to the field of pharmaceutical preparations, and more particularly to a pharmaceutical composition containing therapeutically effective amounts of sacubitril / valsartan and amlodipine or a salt thereof. The present invention also relates to the use of the pharmaceutical composition in preparing a drug for treating cardiovascular diseases. Background Art

[0003] Sacubitril / valsartan sodium (also known as LCZ696) is a dual inhibitor of angiotensin II receptors and neprilysin, used to treat cardiovascular diseases, including hypertension and heart failure. The marketed formulation is an immediate-release tablet. The structural formula of sacubitril / valsartan sodium is as follows:

[0004] Amlodipine or its salts, such as amlodipine besylate, is a calcium channel blocker (CCB) that can be used to treat hypertension and angina pectoris.

[0005] The combination of angiotensin receptor inhibitors (ARBs) and calcium channel blockers (CCBs) is a common treatment for hypertension. Existing studies have shown that this combination may have a certain degree of synergy, and that different ratios of the two drugs have different synergistic effects. Furthermore, the dosage ratios required to achieve optimal synergistic effects when the same calcium channel blocker, such as amlodipine, is combined with different types of ARBs vary significantly.

[0006] Document 1 discloses a pharmaceutical composition containing sacubitril-valsartan sodium and amlodipine or its salt, wherein the ratio of sacubitril-valsartan sodium to amlodipine or its salt is 10-40:1. The specification examples disclose LCZ696-amlodipine sustained-release tablets with specifications of 200mg / 5mg.

[0007] Reference 2 discloses a pharmacokinetic study of the combined use of LCZ696 and amlodipine, with the combined regimen being LCZ696 400 mg once daily and amlodipine 10 mg.

[0008] Reference 3 discloses an analysis of the efficacy of sacubitril-valsartan combined with amlodipine in the treatment of hypertension, in which the dosage regimen of sacubitril-valsartan includes 200 mg / time, 2 times / day, and the dosage regimen of amlodipine is 5 mg / time, 1 time / day.

[0009] While prior art discloses multiple combinations of sacubitril-valsartan sodium and amlodipine, there are no reports on the combined use of sacubitril-valsartan sodium and amlodipine at higher doses and their efficacy. There is also no documentation of the two drugs being formulated into a combined preparation, particularly an immediate-release tablet. Furthermore, sacubitril-valsartan sodium has a high viscosity, making it difficult to release amlodipine within the prescribed timeframe when formulated into a combined preparation.

[0010] Document 1: CN 116211814 A

[0011] Reference 2: HL Hsiao et al. Clin Pharmacol Drug Dev (2015)

[0012] Reference 3: "Analysis of the efficacy of sacubitril / valsartan combined with amlodipine and hydrochlorothiazide in the treatment of hypertension", Health World, 2023(13):149-151. Summary of the Invention

[0013] In order to solve the problems existing in the prior art, the present invention provides a first aspect of a rapid-release composition, wherein the rapid-release composition comprises a first active layer and a second active layer;

[0014] The first active layer contains sacubitril / valsartan or its salt and pharmaceutically acceptable additives;

[0015] The second active layer contains amlodipine or its salt and pharmaceutically acceptable additives.

[0016] The rapid-release composition of the present invention can be a double-layer granule or a double-layer tablet; a double-layer tablet is particularly preferred.

[0017] In a preferred embodiment of the present invention, the rapid-release composition is a bilayer tablet, and the layer weight ratio of the first active layer to the second active layer is 0.2-6:1; the preferred layer weight ratio is 0.2-5.5:1; and the preferred layer weight ratio is 0.2-5:1.

[0018] The rapid-release composition of the present invention further comprises a coating layer, wherein the coating layer is selected from a film coating, preferably a gastric-soluble film coating. Generally, coating slows down the dissolution, but the coating layer of the present invention does not affect the dissolution of the rapid-release composition.

[0019] In a preferred embodiment of the present invention, the rapid-release composition is a coated double-layer tablet.

[0020] When the dissolution of the rapid-release composition of the present invention is measured in a phosphate buffer solution of pH 6.8 using a basket method at a rotation speed of 75 rpm, the solubility of sacubitril / valsartan is not less than 75% within 30 minutes; and / or the solubility of amlodipine is not less than 75% within 30 minutes.

[0021] In a preferred embodiment of the present invention, when the dissolution of the rapid-release composition of the present invention is measured in a phosphate buffer solution at pH 6.8 using a basket method at a rotation speed of 75 rpm, the sacubitril / valsartan has a solubility of not less than 80% within 30 minutes; and / or the amlodipine has a solubility of not less than 80% within 30 minutes.

[0022] In a further preferred embodiment of the present invention, when the dissolution of the rapid-release composition of the present invention is measured in a phosphate buffer solution at pH 6.8 using a basket method at a rotation speed of 75 rpm, the solubility of sacubitril / valsartan is not less than 85% within 30 minutes; and / or the solubility of amlodipine is not less than 85% within 30 minutes.

[0023] In a further preferred embodiment of the present invention, when the rapid-release composition of the present invention is tested for dissolution in a phosphate buffer solution of pH 6.8 using a basket method at a rotation speed of 75 rpm, the amlodipine has a dissolution rate of not less than 75% within 20 minutes.

[0024] In the rapid-release composition of the present invention, in a unit preparation, the amount of amlodipine or its salt calculated as free form in the rapid-release composition is 2.5 mg-5 mg; the amount of sacubitril-valsartan or its salt is 200 mg-400 mg.

[0025] In a preferred embodiment of the present invention, the immediate-release composition contains 5 mg of amlodipine or its salt.

[0026] In a preferred embodiment of the present invention, the immediate-release composition contains 200 mg or 400 mg of sacubitril / valsartan or a salt thereof.

[0027] In a preferred embodiment of the present invention, the immediate-release composition contains 5 mg of amlodipine or its salt and 200 mg of sacubitril / valsartan or its salt.

[0028] In a preferred embodiment of the present invention, the immediate-release composition contains 5 mg of amlodipine or its salt and 400 mg of sacubitril / valsartan or its salt.

[0029] In another aspect, the present invention provides an immediate-release composition comprising a first active layer and a second active layer; the first active layer comprises sacubitril / valsartan or a salt thereof and a pharmaceutically acceptable additive; the second active layer comprises amlodipine or a salt thereof and a pharmaceutically acceptable additive, and optionally comprises sacubitril / valsartan or a salt thereof.

[0030] In the second active layer, by controlling the percentage or ratio of sacubitril / valsartan or its salt, it was unexpectedly found that the effect of sacubitril / valsartan or its salt on the dissolution of amlodipine could be minimized, and the total weight of the immediate-release composition could be effectively reduced, thereby improving the patient's swallowing compliance.

[0031] In a preferred embodiment of the present invention, when the second active layer contains sacubitril valsartan or its salt, the proportion of sacubitril valsartan or its salt in the second active layer to the total weight of sacubitril valsartan or its salt in the immediate-release composition does not exceed 80%.

[0032] In a preferred embodiment of the present invention, the proportion of sacubitril valsartan or its salt in the second active layer, calculated as free form, relative to the total weight of sacubitril valsartan or its salt in the immediate-release composition is no more than 70%.

[0033] In a preferred embodiment of the present invention, the proportion of sacubitril valsartan or its salt in the second active layer relative to the total weight of sacubitril valsartan or its salt in the immediate-release composition, calculated as free form, is no more than 60%.

[0034] In a preferred embodiment of the present invention, the proportion of sacubitril valsartan or its salt in the second active layer is 10%-80% relative to the total weight of sacubitril valsartan or its salt in the immediate-release composition, calculated as free form.

[0035] In a preferred embodiment of the present invention, the proportion of sacubitril valsartan or its salt in the second active layer is 10%-70% relative to the total weight of sacubitril valsartan or its salt in the immediate-release composition, calculated as free form.

[0036] In a preferred embodiment of the present invention, the proportion of sacubitril valsartan or its salt in the second active layer is 20%-60% relative to the total weight of sacubitril valsartan or its salt in the immediate-release composition, calculated as free form.

[0037] In the immediate-release composition of the present invention, the first active layer contains sacubitril / valsartan or a salt thereof and pharmaceutically acceptable additives; the second active layer contains amlodipine or a salt thereof and pharmaceutically acceptable additives. The additives in the first active layer include a filler, a binder, a disintegrant, a glidant, and a lubricant; the additives in the second active layer include a filler, a disintegrant, a glidant, a lubricant, and optionally a binder. The additives in the first active layer and the second active layer may be the same or different.

[0038] Suitable fillers of the present invention are selected from one or a combination of two or more of sucrose, lactose, glucose, starch, pregelatinized starch, microcrystalline cellulose, mannitol, sorbitol, and calcium hydrogen phosphate; preferably microcrystalline cellulose and mannitol; the weight ratio of the filler in the immediate-release composition is 1.0%-70%; the preferred filler ratio is 1.0%-50%; the preferred filler ratio is 1.0%-45%, and the more preferred filler ratio is 5.0%-40%.

[0039] In a preferred embodiment of the present invention, the filler in the rapid-release composition is selected from one or a combination of two or more of microcrystalline cellulose, mannitol, and pregelatinized starch.

[0040] In a preferred embodiment of the present invention, the filler in the rapid-release composition is optionally selected from microcrystalline cellulose.

[0041] Suitable disintegrants of the present invention are selected from starch, cellulose and its derivatives, polysaccharides, guar gum, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose, or a combination of two or more thereof; preferred disintegrants are cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; the weight ratio of the disintegrant in the rapid-release composition is 0.1-30%; preferably, the weight ratio of the disintegrant is 1-25%; and more preferably, the weight ratio of the disintegrant is 1-20%.

[0042] In a preferred embodiment of the present invention, in the rapid-release composition, the disintegrant is selected from cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0043] Suitable binders of the present invention are selected from one or more of starch, cellulose and its derivatives, polysaccharides, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, etc.; preferred binders are low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and ethyl cellulose; the weight ratio of the binder in the rapid-release composition is 0-30%; the preferred binder ratio is 1-25%, and the more preferred binder ratio is 1-20%.

[0044] In a preferred embodiment of the present invention, in the rapid-release composition, the binder is selected from low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and ethyl cellulose.

[0045] In a specific embodiment of the present invention, the second active layer of the rapid-release composition may not contain a binder.

[0046] The glidant and / or lubricant of the present invention is arbitrarily selected from one or more of colloidal silicon dioxide, magnesium stearate, calcium stearate, stearic acid, talc, calcium phosphate, magnesium carbonate, polyethylene glycol, glyceryl behenate, glyceryl monostearate, sodium stearyl fumarate, and the like; preferably, the lubricant is colloidal silicon dioxide, magnesium stearate, or talc; preferably, the glidant is talc, magnesium stearate, or colloidal silicon dioxide. The weight ratio of the glidant or lubricant in the immediate-release composition is 0.1-15%; preferably, the weight ratio of the glidant or lubricant is 0.5-10%, and more preferably, the weight ratio of the glidant or lubricant is 0.5-5%.

[0047] In another aspect, the present invention provides a use of sacubitril / valsartan or a salt thereof and amlodipine or a salt thereof in preparing a medicament for treating cardiovascular diseases, wherein the weight ratio of sacubitril / valsartan to amlodipine, calculated as free form, is 80:1.

[0048] The cardiovascular diseases described in the present invention include but are not limited to hypertension, heart disease, heart failure, angina pectoris, arrhythmia, cerebrovascular disease, thrombosis, etc.

[0049] In a further preferred embodiment of the present invention, the use contains 400 mg of sacubitril / valsartan and 5 mg of amlodipine, calculated as free bodies.

[0050] In a further preferred embodiment of the present invention, the present invention provides a use of sacubitril / valsartan or its salt and amlodipine or its salt in preparing a medicament for treating cardiovascular diseases, wherein the medicament contains 400 mg of sacubitril / valsartan and 5 mg of amlodipine, calculated as a free form.

[0051] In a further preferred embodiment of the present invention, a rapid-release composition of sacubitril / valsartan or a salt thereof and amlodipine or a salt thereof is provided for use in the preparation of a medicament for treating cardiovascular disease. The rapid-release composition, calculated as free form, contains 400 mg of sacubitril / valsartan and 5 mg of amlodipine. The rapid-release composition is a bilayer tablet.

[0052] In another aspect, the present invention provides a method for preparing a bilayer immediate-release formulation, particularly a bilayer immediate-release tablet containing sacubitril / valsartan or its salt and amlodipine or its salt. The method comprises the following steps: Step 1: mixing sacubitril / valsartan or its salt with desired additives and granulating; Step 2: mixing amlodipine or its salt with desired additives and granulating; and Step 3: compressing the granules from Steps 1 and 2 into a bilayer tablet.

[0053] In a preferred embodiment of the present invention, the granulation method of the preparation method is preferably dry granulation.

[0054] In a preferred embodiment of the present invention, in step 2, part of sacubitril / valsartan or its salt and amlodipine or its salt and required additives are mixed and then granulated.

[0055] In a preferred embodiment of the present invention, the preparation method further comprises the step of coating the double-layer tablet.

[0056] In another aspect, the present invention provides a use of sacubitril / valsartan or its salt and amlodipine or its salt in preparing a medicament for treating cardiovascular diseases. The medicament contains 400 mg of sacubitril / valsartan and 5 mg of amlodipine in free form.

[0057] In a preferred embodiment of the present invention, the drug is a bilayer tablet.

[0058] When sacubitril-valsartan sodium and amlodipine or its salt are prepared into an immediate-release composition, the dissolution of amlodipine or its salt is restricted and slowed when the composition is a single-layer tablet. The immediate-release composition of the present invention, particularly a bilayer tablet, effectively avoids the problem of amlodipine not being released within the prescribed time due to the high viscosity of sacubitril-valsartan or its salt.

[0059] Since the common dosage of amlodipine or its salts is 2.5 mg or 5 mg, while the common dosage of sacubitril / valsartan or its salts is 200 mg or 400 mg, the significant difference in dosage between the two can lead to difficulties in preparing bilayer formulations, such as bilayer tablets, such as large differences in tablet weight and poor uniformity of the active pharmaceutical ingredient content. The present invention effectively addresses these issues by controlling the weight of the bilayer tablets within a certain ratio, or by placing a portion of sacubitril / valsartan or its salts in both layers of the bilayer tablets, thereby avoiding swallowing difficulties caused by excessive tablet weight. DETAILED DESCRIPTION

[0060] The present invention is further described in detail below with reference to the examples, but the embodiments of the invention are not limited thereto. Unless otherwise specified, the experimental materials, reagents, and experimental animals used in the examples of the present invention can be obtained by conventional methods in the art.

[0061] The "sacubitril valsartan or its salt" mentioned in the present invention includes sacubitril valsartan sodium salt and its hydrate, sacubitril valsartan potassium salt and its hydrate.

[0062] The "amlodipine or its salt" described in the present invention includes p-toluenesulfonate and benzenesulfonate of amlodipine; the amlodipine described includes levoamlodipine.

[0063] The in vitro dissolution study method of the present invention is as follows:

[0064] Dissolution apparatus: DS-1206

[0065] Dissolution device: rotating basket

[0066] Dissolution medium volume: 900 mL

[0067] Temperature: 37°C ± 0.5; Speed: 75 rpm

[0068] Dissolution medium: pH 6.8 phosphate buffer

[0069] Sampling time points: 5min, 10min, 15min, 20min, 30min, 45min, 60min.

[0070] Example 1 Effect of blood pressure on hypertensive model (SHR) rats

[0071] Drug preparation: sacubitril valsartan sodium and amlodipine p-toluenesulfonate were prepared into a composition according to the proportions in the table below.

[0072] Animal testing

[0073] Sixteen healthy spontaneously hypertensive SHR rats were collected, half of which were male and half were female, weighing 200-240 g. The male and female rats were evenly divided into two groups according to their blood pressure, with 8 rats in each group.

[0074] Each group received dosing according to the dosing schedule shown in the table below, once daily at 8:00 AM. Group 1 served as a blank control group and received the corresponding dose of water. For dosing, the composition was suspended in 0.5% CMC-Na. The doses administered to each group of rats were converted using the human-to-rat dose conversion factor.

[0075] The tail artery systolic pressure of rats in each group was measured before administration and after 6 weeks of administration, and the blood pressure reduction rate (%) of each group was calculated. The blood pressure values ​​are mean ± standard deviation. The results are shown in the following table.

[0076] As can be seen from the results in the above table, sacubitril valsartan sodium has a good antihypertensive effect when used in combination with amlodipine or its salts, especially when sacubitril valsartan sodium is 400 mg and amlodipine is 5 mg, which has a better antihypertensive effect.

[0077] Example 2 Preparation of single-layer tablets

[0078] Monolayer tablets of sacubitril-valsartan sodium and amlodipine p-toluenesulfonate were prepared according to the mass and composition in the table below.

[0079] Preparation of single-layer tablets:

[0080] Step 1) Preparation of internal granules: sacubitril / valsartan sodium, colloidal silicon dioxide, microcrystalline cellulose, amlodipine besylate, low-substituted hydroxypropyl cellulose, crospovidone, talc, and magnesium stearate are mixed; dry granulation is performed and the mixture is set aside.

[0081] Step 2) Preparation of mixed granules: Mix the above internal granules with the external auxiliary materials and set aside.

[0082] Step 3) compressing the mixed granules into tablets.

[0083] Step 4) Preparation of coating solution: Weigh the gastric soluble film coating premix (Opadry) and add it to purified water (amount of purified water = amount of film coating premix * 88 / 12) under stirring to completely disperse it. Stir for at least 45 minutes and set aside.

[0084] Optionally, step 5) the tablets are coated.

[0085] The dissolution data determined by the in vitro dissolution research method of the present invention are as follows:

[0086] The dissolution data show that directly preparing sacubitril / valsartan sodium and amlodipine besylate into single-layer tablets significantly affects the dissolution of amlodipine. In the dissolution data of single-layer tablets, both the 200mg / 5mg and 400mg / 5mg strengths failed to achieve the expected rapid dissolution, especially with the dissolution in the first 20 minutes being less than 75%.

[0087] Example 3 Preparation of bilayer tablets

[0088] Refer to the following table for the preparation of bilayer tablets of sacubitril valsartan sodium and amlodipine p-toluenesulfonate

[0089] Preparation of bilayer tablets:

[0090] Step 1) Preparation of first layer granules: sacubitril / valsartan sodium, colloidal silicon dioxide, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, talc, and magnesium stearate are mixed; dry granulated, and mixed with external excipients for later use;

[0091] Step 2) Preparation of the second layer of granules: sacubitril / valsartan sodium, colloidal silicon dioxide, microcrystalline cellulose, amlodipine besylate, crospovidone, talc, and magnesium stearate are mixed; dry granulation is performed, and the mixture is mixed with additional excipients and set aside; alternatively, amlodipine besylate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, and talc are mixed and set aside;

[0092] Step 3) performing double-layer tableting on the first layer and the second layer;

[0093] Step 4) Preparation of coating solution: Weigh the gastric soluble film coating premix (Opadry) and add it to purified water (amount of purified water = amount of film coating premix * 88 / 12) under stirring to completely disperse it. Stir for at least 45 minutes and set aside.

[0094] Step 5) coating the tablets.

[0095] Dissolution test

[0096] The tablets of Examples 3-1 and 3-2 were subjected to dissolution tests, with 8 tablets in each group. The average value was taken to determine the dissolution of amlodipine and sacubitril / valsartan in each tablet. The original tablets were used for comparison. The results are as follows.

[0097] Sacubitril-valsartan dissolution

[0098] Amlodipine dissolution

[0099] The dissolution data show that when sacubitril / valsartan sodium and amlodipine or its salt are prepared into a bilayer tablet, the dissolution of amlodipine within 20 minutes can be significantly improved.

[0100] Example 4 Preparation of double-layer tablets

[0101] The following double-layer tablets were prepared by referring to the preparation method of Example 3.

[0102] Content uniformity determination:

[0103] Take 10 test samples and determine the relative content x1, x2, ..., xn of each single dose based on the labeled amount as 100 according to the method specified under each variety. Calculate the content mean and standard deviation S. The absolute value of the difference between the labeled amount and 100 is A. Judgment standard: A + 2.2S ≤ 15.

[0104] Judging from the content uniformity data, when the sacubitril-valsartan sodium content is 400mg or 200mg and the amlodipine content is 5mg, the weights of the two active pharmaceutical ingredients are relatively large. When the proportion of sacubitril-valsartan sodium in the layer remains unchanged, the layer weight ratio of the sacubitril-valsartan sodium layer to the amlodipine layer reaches 8:1. During tablet preparation, large layer weight differences will significantly affect the tablet's process stability, especially the content uniformity of the amlodipine layer will not meet requirements and will adversely affect dissolution. When the double-layer weight ratio is controlled within 5:1 (sacubitril-valsartan sodium layer:amlodipine layer), satisfactory content uniformity (A+2.2S no greater than 15) can be achieved.

[0105] Example 5

[0106] The formulation of Tablet 3-1 was used to investigate the effects of different excipients, especially different disintegrants, on dissolution.

[0107] The in vitro dissolution rate of the tablets was determined by referring to the dissolution test method of the present invention. The results are as follows:

[0108] The dissolution data showed that among the different disintegrants of the present invention, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose as disintegrants can achieve good dissolution, while sodium carboxymethyl starch disintegrant cannot achieve the expected dissolution rate in the bilayer tablet.

[0109] Example 6

[0110] The following double-layer tablets were further prepared according to the method of Example 3:

[0111] The dissolution rates of different tablets were determined using the dissolution test method of the present invention. The results are as follows:

[0112] Example 7

[0113] LCZ696 was placed in two layers at different ratios, and double-layer tablets with the following formulation were prepared according to the method of Example 3.

[0114] Dissolution test

[0115] The dissolution of tablets 7-1 and 7-2 was measured according to the dissolution test method.

[0116] Example 8

[0117] The following tablets were further prepared by referring to the same method:

[0118] Example 9

[0119] The following tablets were further prepared by referring to the same method:

[0120] According to the dissolution test method, Tablets 8 and 9 had similar dissolution characteristics to Example 3-1.

[0121] Example 10

[0122] The following tablets were further prepared by referring to the same method:

[0123] The dissolution data determined by the in vitro dissolution research method of the present invention are as follows:

[0124] Example 11

[0125] Sacubitril, valsartan and amlodipine tablets human pre-test: adopt the sacubitril, valsartan and amlodipine tablets (specification: 400mg / 5mg) of embodiment, single oral test drug or control drug on an empty stomach, with 240mL warm water delivery. After administration 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 14h, 24h, 36h, 48h, 72h, 96h (total 19 times) venous blood was drawn 4mL for detection. Cmax and AUC data are as follows:

Claims

1. A rapid-release composition, characterized in that The rapid-release composition comprises a first active layer and a second active layer, wherein the first active layer comprises sacubitril / valsartan or a salt thereof and a pharmaceutically acceptable additive, and the second active layer comprises amlodipine or a salt thereof and a pharmaceutically acceptable additive.

2. The immediate-release composition according to claim 1, having at least one of the following dissolution characteristics: When the dissolution rate of the sacubitril / valsartan or its salt is measured in a phosphate buffer solution at pH 6.8 using a basket method at a rotation speed of 75 rpm, the sacubitril / valsartan or its salt has a dissolution rate of not less than 75% within 30 minutes; and / or, when the dissolution rate is measured in a phosphate buffer solution having a pH of 6.8 using a basket method at a rotation speed of 75 rpm, the amlodipine or a salt thereof has a solubility of not less than 75% within 30 minutes; And / or, when the dissolution is measured in a phosphate buffer solution of pH 6.8 using a basket method at a rotation speed of 75 rpm, the amlodipine or its salt has a solubility of not less than 75% within 20 minutes.

3. The rapid-release composition according to claim 1, wherein the weight ratio of the first active layer to the second active layer is 0.2-6:1; preferably, the weight ratio of the first active layer to the second active layer is 0.2-5.5:

1. The immediate-release composition according to claim 1 , further comprising a coating layer. The immediate-release composition according to claim 1 , comprising 200 mg or 400 mg of sacubitril / valsartan or a salt thereof. The immediate-release composition according to claim 1 , comprising 2.5 mg or 5 mg of amlodipine or a salt thereof. 7 . The rapid-release composition according to claim 1 , wherein the second active layer further contains sacubitril / valsartan or a salt thereof.

8. The immediate-release composition according to claim 7, wherein the weight of sacubitril-valsartan or its salt in the second active layer accounts for no more than 80% of the total weight of sacubitril-valsartan or its salt in the immediate-release composition.

9. A rapid-release composition, characterized in that The immediate-release composition comprises a first active layer and a second active layer, wherein the first active layer comprises sacubitril valsartan or a salt thereof and a pharmaceutically acceptable additive, and the second active layer comprises amlodipine or a salt thereof and a pharmaceutically acceptable additive; and when the second active layer comprises sacubitril valsartan or a salt thereof, the proportion of the sacubitril valsartan or a salt thereof in the second active layer to the total weight of the sacubitril valsartan or a salt thereof in the immediate-release composition does not exceed 80%.

10. The immediate-release composition according to claim 9, wherein the proportion of sacubitril-valsartan or its salt in the second active layer to the total weight of sacubitril-valsartan or its salt in the immediate-release composition is no more than 70%.

11. The rapid-release composition according to any one of claims 1 or 9, wherein the pharmaceutically acceptable additives include a filler, a binder, a disintegrant, a glidant and a lubricant.

12. The rapid-release composition according to any one of claims 1 or 9, comprising: Filler 1.0%-70%; Disintegrant 0.1-30%; Adhesive 0-30%; Glidant and / or lubricant 0.1-15%; or contain: Filler 1.0%-50%; Disintegrant 0.1-30%; Adhesive 0-30%; Glidants and / or lubricants 0.1-15%.

13. The rapid-release composition according to any one of claims 1 or 9, wherein the filler is selected from sucrose, lactose, glucose, starch, pregelatinized starch, microcrystalline cellulose, and mannitol.

14. The rapid-release composition according to any one of claims 1 or 9, wherein the disintegrant is selected from starch, cellulose and its derivatives, polysaccharides, guar gum, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and cross-linked calcium carboxymethyl cellulose.

15. The rapid-release composition according to any one of claims 1 or 9, wherein the binder is selected from low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and ethyl cellulose.

16. Use of sacubitril / valsartan or its salt and amlodipine or its salt in the preparation of a medicament for treating cardiovascular diseases, wherein the medicament contains 400 mg of sacubitril / valsartan and 5 mg of amlodipine in free form.

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