Immediate release composition

Abstract

The invention provides a quick-release composition, the quick-release composition contains sacubitril valsartan or a salt thereof and amlodipine or a salt thereof, and the two active components in the quick-release composition can realize quick release. The invention also relates to application of sacubitril valsartan or salt thereof, amlodipine or salt thereof and a quick-release composition thereof in preparation of medicaments for treating cardiovascular diseases.

Description

[0001] This application claims the priority of Chinese Patent Application No. 2024101265395 with the filing date of January 30, 2024, and Chinese Patent Application No. 2024117716775 with the filing date of December 4, 2024. This application incorporates the entire texts of the above-mentioned Chinese patent applications by reference. Technical Field

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

[0003] Sacubitril / valsartan sodium (also known as LCZ696) is a dual inhibitor of angiotensin II receptor and neprilysin, and can be used for treating cardiovascular diseases, including hypertension and heart failure. The marketed preparation is a rapid-release tablet, and the structural formula of sacubitril / valsartan sodium is as follows:

[0004]

[0005] Amlodipine or its salt, such as amlodipine besylate, is a calcium channel blocker (CCB) and can be used for treating hypertension, angina pectoris, etc.

[0006] In the treatment of hypertension, the combined use of an angiotensin receptor inhibitor (ARB) and a calcium channel blocker (CCB) is a conventional regimen. Existing studies have shown that the combination of the two may have certain synergistic effects, and different combinations of the two drugs in different ratios have different synergistic effects. For the same calcium channel antagonist, such as amlodipine, there are also significant differences in the dosage ratios for achieving better synergistic effects when combined with different types of ARBs.

[0007] 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 a specification of 200mg / 5mg.

[0008] Document 2 discloses a pharmacokinetic study on the combined use of LCZ696 and amlodipine, and the combined use regimen is LCZ696 400mg once a day and amlodipine 10mg.

[0009] Document 3 discloses an efficacy analysis of the treatment of hypertension with sacubitril / valsartan combined with amlodipine, wherein the dosing regimen of sacubitril / valsartan includes 200mg / time, 2 times / d, and the dosing regimen of amlodipine is 5mg / time, 1 time / d.

[0010] Although multiple combination regimens of sacubitril / valsartan sodium and amlodipine are disclosed in the prior art, the combination of higher doses of sacubitril / valsartan sodium and amlodipine and the corresponding combination effects have not been reported, nor is there any record of preparing the two drugs into a compound preparation, especially an immediate-release tablet. At the same time, sacubitril / valsartan sodium has a high viscosity, and preparing it into a compound preparation easily causes amlodipine to be unable to be released within the specified time.

[0011] Document 1: CN 116211814 A

[0012] Document 2: HL Hsiao et al.Clin Pharmacol Drug Dev(2015)

[0013] Document 3: "Efficacy Analysis of Sacubitril / Valsartan Combined with Amlodipine and Hydrochlorothiazide in the Treatment of Hypertension", Health World, 2023(13):149-151. Summary of the Invention

[0014] To solve the problems existing in the prior art, a first aspect of the present invention provides an immediate-release composition, and the immediate-release composition contains a first active layer and a second active layer;

[0015] The first active layer contains sacubitril / valsartan or its salt and pharmaceutically acceptable additives;

[0016] The second active layer contains amlodipine or its salt and pharmaceutically acceptable additives.

[0017] The immediate-release composition of the present invention can be a double-layer granule or a double-layer tablet; particularly preferably a double-layer tablet.

[0018] In a preferred embodiment of the present invention, the immediate-release composition is a double-layer 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; the preferred layer weight ratio is 0.2-5:1.

[0019] The immediate-release composition of the present invention further contains a coating layer, and the coating is selected from film coatings, preferably gastric-soluble film coatings. Usually, the coating will slow down the dissolution, but the coating layer of the present invention has no effect on the dissolution of the immediate-release composition.

[0020] In a preferred embodiment of the present invention, the immediate-release composition is a coated double-layer tablet.

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

[0022] In a preferred embodiment of the present invention, when the dissolution rate of the immediate-release composition of the present invention is measured by the basket method in a phosphate buffer solution at pH 6.8 with a rotation speed of 75 rpm, the sacubitril / valsartan has a dissolution rate of not less than 80% within 30 minutes; and / or the amlodipine has a dissolution rate of not less than 80% within 30 minutes.

[0023] In a further preferred embodiment of the present invention, when the dissolution rate of the immediate-release composition of the present invention is measured by the basket method in a phosphate buffer solution at pH 6.8 with a rotation speed of 75 rpm, the sacubitril / valsartan has a dissolution rate of not less than 85% within 30 minutes; and / or the amlodipine has a dissolution rate of not less than 85% within 30 minutes.

[0024] In a further preferred embodiment of the present invention, when the dissolution rate of the immediate-release composition of the present invention is measured by the basket method in a phosphate buffer solution at pH 6.8 with a rotation speed of 75 rpm, the amlodipine has a dissolution rate of not less than 75% within 20 minutes.

[0025] In the immediate-release composition of the present invention, in a unit preparation, the amount of amlodipine or its salt contained in the immediate-release composition calculated as the free form is 2.5 mg - 5 mg; and the amount of sacubitril / valsartan or its salt is 200 mg - 400 mg.

[0026] In a preferred embodiment of the present invention, the immediate-release composition contains 5 mg of amlodipine or its salt.

[0027] In a preferred embodiment of the present invention, the amount of sacubitril / valsartan or its salt contained in the immediate-release composition is 200 mg or 400 mg.

[0028] 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.

[0029] 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.

[0030] On the other hand, the present invention provides an immediate-release composition, which contains a first active layer and a second active layer; the first active layer contains sacubitril / valsartan or its salt and a pharmaceutically acceptable additive; the second active layer contains amlodipine or its salt and a pharmaceutically acceptable additive, and optionally contains sacubitril / valsartan or its salt.

[0031] In the second active layer, by controlling the percentage content or proportion of sacubitril / valsartan or its salt, it was unexpectedly found that the effect of sacubitril / valsartan or its salt on the dissolution of amlodipine can be minimized, and the total weight of the immediate-release composition can be effectively reduced, improving the swallowing compliance of patients.

[0032] 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%.

[0033] In a preferred embodiment of the present invention, the proportion of sacubitril / valsartan or its salt in the second active layer, calculated as the free form, relative to the total weight of sacubitril / valsartan or its salt in the immediate-release composition is not higher than 70%.

[0034] In a preferred embodiment of the present invention, the proportion of sacubitril / valsartan or its salt in the second active layer, calculated as the free form, relative to the total weight of sacubitril / valsartan or its salt in the immediate-release composition is not higher than 60%.

[0035] In a preferred embodiment of the present invention, the proportion of sacubitril / valsartan or its salt in the second active layer, calculated as the free form, relative to the total weight of sacubitril / valsartan or its salt in the immediate-release composition is 10% - 80%.

[0036] In a preferred embodiment of the present invention, the proportion of sacubitril / valsartan or its salt in the second active layer, calculated as the free form, relative to the total weight of sacubitril / valsartan or its salt in the immediate-release composition is 10% - 70%.

[0037] In a preferred embodiment of the present invention, the proportion of sacubitril / valsartan or its salt in the second active layer, calculated as the free form, relative to the total weight of sacubitril / valsartan or its salt in the immediate-release composition is 20% - 60%.

[0038] In the immediate-release composition of the present invention, the first active layer contains sacubitril / valsartan or its salt and pharmaceutically acceptable additives; the second active layer contains amlodipine or its salt and pharmaceutically acceptable additives; the additives in the first active layer include fillers, binders, disintegrants, glidants, and lubricants; the additives in the second active layer include fillers, disintegrants, glidants, and lubricants, and optionally contain binders. The additives in the first active layer and the second active layer can be the same or different.

[0039] Suitable fillers for the present invention are optionally selected from one or more combinations of sucrose, lactose, glucose, starch, pregelatinized starch, microcrystalline cellulose, mannitol, sorbitol, 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%.

[0040] In a preferred embodiment of the present invention, the filler in the immediate-release composition is optionally selected from one or more combinations of microcrystalline cellulose, mannitol, and pregelatinized starch.

[0041] In a preferred embodiment of the present invention, the filler in the immediate-release composition is optionally selected from microcrystalline cellulose.

[0042] Suitable disintegrants for the present invention are optionally selected from one or more combinations of starch, cellulose and its derivatives, polysaccharides, guar gum, crospovidone, sodium carboxymethyl starch, sodium cross-linked carboxymethyl cellulose, calcium cross-linked carboxymethyl cellulose, low-substituted hydroxypropyl cellulose; the preferred disintegrants are crospovidone, sodium cross-linked carboxymethyl cellulose, low-substituted hydroxypropyl cellulose; the weight ratio of the disintegrant in the immediate-release composition is 0.1-30%; the preferred weight ratio of the disintegrant is 1-25%; the further preferred weight ratio of the disintegrant is 1-20%.

[0043] In a preferred embodiment of the present invention, in the immediate-release composition, the disintegrant is optionally selected from crospovidone, sodium cross-linked carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0044] Suitable binders for the present invention are optionally 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.; the preferred binders are low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose; the weight ratio of the binder in the immediate-release composition is 0-30%; the preferred binder ratio is 1-25%, and the more preferred binder ratio is 1-20%.

[0045] In a preferred embodiment of the present invention, in the immediate-release composition, the binder is optionally selected from low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and ethyl cellulose.

[0046] In a specific embodiment of the present invention, in the immediate-release composition, the second active layer may not contain a binder.

[0047] The glidant and / or lubricant of the present invention is arbitrarily selected from one or more of colloidal silica, magnesium stearate, calcium stearate, stearic acid, talc powder, calcium phosphate, magnesium carbonate, polyethylene glycol, glyceryl behenate, glyceryl monostearate, sodium stearyl fumarate, etc.; the preferred lubricants are colloidal silica, magnesium stearate or talc powder; the preferred glidants are talc powder, magnesium stearate or colloidal silica. The weight ratio of the glidant or lubricant in the immediate-release composition is 0.1-15%; the preferred 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%.

[0048] Another aspect of the present invention provides the use of sacubitril / valsartan or its salt and amlodipine or its salt in the preparation of a drug for treating cardiovascular diseases. Calculated as the free form, the weight ratio of sacubitril / valsartan to amlodipine is 80:1.

[0049] The cardiovascular diseases described in the present invention include but are not limited to hypertension, heart disease, heart failure, angina pectoris, arrhythmia, cerebrovascular diseases, thrombosis, etc.

[0050] In a further preferred embodiment of the present invention, in the above use, calculated as the free form, it contains 400 mg of sacubitril / valsartan and 5 mg of amlodipine.

[0051] In a further preferred embodiment of the present invention, the present invention provides the use of sacubitril / valsartan or its salt and amlodipine or its salt in the preparation of a drug for treating cardiovascular diseases. In the above use, calculated as the free form, it contains 400 mg of sacubitril / valsartan and 5 mg of amlodipine.

[0052] In a further preferred embodiment of the present invention, the present invention provides the use of an immediate-release composition of sacubitril / valsartan or its salt and amlodipine or its salt in the preparation of a drug for treating cardiovascular diseases. In the above use, calculated as the free form, it contains 400 mg of sacubitril / valsartan and 5 mg of amlodipine. The immediate-release composition is a bilayer tablet.

[0053] Another aspect of the present invention provides a preparation method of a bilayer immediate-release preparation, especially for preparing a bilayer immediate-release tablet containing sacubitril / valsartan or its salt and amlodipine or its salt. The method includes the following steps: Step 1: Mix sacubitril / valsartan or its salt with the required additives and then granulate; Step 2: Mix amlodipine or its salt with the required additives and then granulate; Step 3: Compress the granules obtained in Step 1 and Step 2 into a bilayer tablet.

[0054] In a preferred embodiment of the present invention, the granulation method in the above preparation method is preferably dry granulation.

[0055] In a preferred embodiment of the present invention, in step two, part of sacubitril / valsartan or its salt and amlodipine or its salt and the required additives are mixed and then granulated.

[0056] In a preferred embodiment of the present invention, the preparation method further includes a step of coating the bilayer tablet.

[0057] Another aspect of the present invention provides the use of sacubitril / valsartan or its salt and amlodipine or its salt in the preparation of a drug for treating cardiovascular diseases. Calculated as the free form, the drug contains 400 mg of sacubitril / valsartan; 5 mg of amlodipine.

[0058] In a preferred embodiment of the present invention, the drug is a bilayer tablet.

[0059] When sacubitril / valsartan sodium and amlodipine or its salt are prepared into an immediate-release composition, when the composition is a single-layer tablet, the dissolution of amlodipine or its salt is restricted and the dissolution becomes slower. When preparing the immediate-release composition of the present invention, especially a bilayer tablet, the problem that amlodipine cannot be released within the specified time due to the high viscosity of sacubitril / valsartan or its salt can be effectively avoided.

[0060] Since the common dosage of amlodipine or its salt is 2.5 mg or 5 mg, and the common dosage of sacubitril / valsartan or its salt is 200 mg or 400 mg, the dosage difference between the two is large. When preparing a bilayer preparation, such as a bilayer tablet, there may be difficulties such as large tablet weight difference and poor uniformity of the content of the drug active ingredient. In the present invention, by controlling the bilayer tablet layer weight within a certain ratio, or placing part of sacubitril / valsartan or its salt in the two layers of the bilayer tablet, the above problems can be effectively solved and the problem of difficult swallowing caused by too large tablet weight can be avoided. Detailed Embodiments

[0061] The present invention will be further described in detail below with reference to the embodiments, but the embodiments of the invention are not limited thereto. Unless otherwise specified, the experimental raw materials, reagents, and experimental animals used in the embodiments of the present invention can be obtained by conventional methods in the art.

[0062] The "sacubitril / valsartan or its salt" as used in the present invention includes sacubitril / valsartan sodium salt and its hydrate, sacubitril / valsartan potassium salt and its hydrate.

[0063] The "amlodipine or its salt" as used in the present invention includes p-toluenesulfonate and benzenesulfonate of amlodipine; the amlodipine includes levamlodipine.

[0064] The in vitro dissolution study method of the present invention is as follows:

[0065] Dissolution apparatus: DS-1206

[0066] Dissolution apparatus: Basket

[0067] Volume of dissolution medium: 900 mL

[0068] Temperature: 37 °C ± 0.5; Rotation speed: 75 rpm

[0069] Dissolution medium: Phosphate buffer solution of pH 6.8

[0070] Sampling time points: 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min.

[0071] Effect of Example 1 on blood pressure of rats with hypertension model (SHR)

[0072] Drug preparation: Sacubitril / valsartan sodium and amlodipine tosylate were prepared into a composition according to the following table ratio.

[0073]

[0074] Animal experiment

[0075] Take 16 healthy spontaneously hypertensive SHR rats, 8 males and 8 females, with a body weight of 200 - 240 g. The male and female rats were evenly divided into 2 groups according to blood pressure, with 8 rats in each group.

[0076] Each group was administered according to the following dosing regimen, once a day at 8:00 am; The first group was the blank control group, given the corresponding dose of water. When administering the drug, the composition was suspended in 0.5% CMC-Na. The dosing doses of each group of rats were administered after being converted by the conversion coefficient of human and rat dosing doses.

[0077] Before the start of drug administration, the systolic blood pressure of the caudal artery of each group of rats was measured. After 6 weeks of drug administration, the systolic blood pressure of the caudal artery was measured, and the blood pressure reduction rate (%) of each group was calculated. The blood pressure value was the mean ± standard deviation, and the results are shown in the following table.

[0078]

[0079] It can be seen from the above table results that sacubitril / valsartan sodium has a good antihypertensive effect when used in combination with amlodipine or its salt, especially when sacubitril / valsartan sodium is 400 mg and amlodipine is 5 mg, it has a better antihypertensive effect.

[0080] Example 2 Preparation of monolayer tablets

[0081] Refer to the quality and composition in the following table to prepare monolayer tablets of sacubitril / valsartan sodium and amlodipine tosylate.

[0082]

[0083] Preparation of monolayer tablets:

[0084] Step 1) Preparation of internal granules: Mix sacubitril / valsartan sodium, colloidal silicon dioxide, microcrystalline cellulose, amlodipine besylate, low-substituted hydroxypropyl cellulose, crospovidone, talc, and magnesium stearate; perform dry granulation and set aside.

[0085] Step 2) Preparation of total mixed granules: Total mix the above internal granules with external excipients and set aside.

[0086] Step 3) Compress the total mixed granules into tablets.

[0087] Step 4) Preparation of coating solution: Weigh gastro-resistant film coating premix (Opadry), add it to purified water (amount of purified water = amount of film coating premix * 88 / 12) under stirring conditions, and stir until it is completely dispersed. Stir for more than 45 minutes and set aside.

[0088] Optionally, Step 5) Coating the tablets.

[0089] The dissolution data was measured using the in vitro dissolution study method of the present invention as follows:

[0090]

[0091] From the dissolution data, it can be seen that when directly preparing sacubitril / valsartan sodium and amlodipine besylate into a single-layer tablet, the dissolution of amlodipine is significantly affected. Among the dissolution data of the single-layer tablets, the two specifications of 200 mg / 5 mg and 400 mg / 5 mg cannot achieve the expected rapid dissolution, especially the dissolution in the first 20 minutes is lower than 75%.

[0092] Preparation of double-layer tablets in Example 3

[0093] Refer to the following prescription to prepare double-layer tablets of sacubitril / valsartan sodium and amlodipine p-toluenesulfonate

[0094]

[0095]

[0096] Preparation of double-layer tablets:

[0097] Step 1) Preparation of the first-layer granules: Mix sacubitril / valsartan sodium, colloidal silicon dioxide, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, talc, and magnesium stearate; perform dry granulation, total mix with external excipients, and set aside;

[0098] Step 2) Preparation of the second layer of granules: Mix sacubitril / valsartan sodium, colloidal silicon dioxide, microcrystalline cellulose, amlodipine besylate, crospovidone, talc, and magnesium stearate; perform dry granulation, and then perform total mixing with the externally added excipients for standby; alternatively, mix amlodipine besylate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, and talc for standby.

[0099] Step 3) Perform double-layer tabletting on the first layer and the second layer.

[0100] Step 4) Preparation of the coating solution: Weigh the gastric-soluble film coating premix (Opadry), and add it to purified water (the amount of purified water = the amount of the film coating premix * 88 / 12) under stirring conditions and stir to make it completely dispersed. Stir for more than 45 minutes for standby.

[0101] Step 5) Coat the tablets.

[0102] Dissolution test

[0103] Take the tablets of Examples 3-1 and 3-2 for dissolution test, with 8 tablets in each group. Take the average value, determine the dissolution of amlodipine and sacubitril / valsartan in each tablet, and take the reference listed drug tablets for comparison. The results are as follows.

[0104] Dissolution of sacubitril / valsartan

[0105]

[0106] Dissolution of amlodipine

[0107]

[0108] It can be seen from the dissolution data that when sacubitril / valsartan sodium and amlodipine or its salt are prepared into double-layer tablets, the dissolution of amlodipine within 20 minutes can be significantly improved.

[0109] Preparation of the double-layer tablet in Example 4

[0110] Prepare the following double-layer tablets with reference to the preparation method of Example 3.

[0111]

[0112]

[0113] Determination of content uniformity:

[0114] Take 10 test samples, and according to the method specified in each variety item, respectively determine the relative content x1, x2,..., xn of each single dose with the labeled amount as 100, calculate the content mean value and the standard deviation S, and the absolute value of the difference between the labeled amount 100 and the calculated value is A. Judgment criterion: A + 2.2S ≤ 15.

[0115] A + 2.2S Sacubitril and valsartan sodium Amlodipine besylate Tablet 4-1 5.5 18.2 Tablet 4-2 6.0 14.1 Tablet 4-3 5.8 9.5 Tablet 4-4 5.6 14.8

[0116] Judging from the content uniformity data, when the content of sacubitril / valsartan sodium is 400 mg or 200 mg and the content of amlodipine is 5 mg, the weights of the two drug active ingredients are relatively large. With the proportion of sacubitril / valsartan sodium in this layer remaining unchanged, the layer weight ratio of the sacubitril / valsartan sodium layer to the amlodipine layer reaches 8:1. During the tablet preparation process, such a large layer weight difference will significantly affect the process stability of the tablets. In particular, the content uniformity of the amlodipine layer cannot meet the requirements, and it has an adverse effect on dissolution. When the double-layer weight ratio is controlled within 5:1 (sacubitril / valsartan sodium layer: amlodipine layer), satisfactory content uniformity (A + 2.2S not higher than 15) can be obtained.

[0117] Example 5

[0118] Using the prescription composition of Tablet 3-1, the effects of different excipients, especially different disintegrants, on dissolution were investigated.

[0119]

[0120] Referring to the dissolution test method of the present invention, the in vitro dissolution of the tablets was determined, and the results are as follows:

[0121]

[0122] The dissolution data indicate that among the different disintegrants of the present invention, crospovidone and croscarmellose sodium can achieve good dissolution as disintegrants. However, sodium carboxymethyl starch cannot achieve the expected dissolution rate in the double-layer tablets.

[0123] Example 6

[0124] Following the method of Example 3, the following double-layer tablets were further prepared

[0125]

[0126]

[0127] Referring to the dissolution test method of the present invention, the dissolution of different tablets was determined, and the results are as follows:

[0128]

[0129] Example 7

[0130] LCZ696 was placed in two layers in different proportions, and double-layer tablets with the following prescriptions were prepared following the method of Example 3.

[0131]

[0132]

[0133] Dissolution test

[0134] Determine the dissolution of tablets 7-1 and 7-2 with reference to the method of the dissolution test.

[0135]

[0136] Example 8

[0137] Further prepare the following tablets with reference to the same method:

[0138]

[0139]

[0140] Example 9

[0141] Further prepare the following tablets with reference to the same method:

[0142]

[0143]

[0144] Determined with reference to the method of the dissolution test, tablets 8 and 9 have dissolution characteristics similar to those of Example 3-1.

[0145] Example 10

[0146] Further prepare the following tablets with reference to the same method:

[0147]

[0148]

[0149] Determine its dissolution data using the in vitro dissolution study method of the present invention as follows:

[0150]

[0151] Example 11

[0152] Preclinical trial of sacubitril / valsartan and amlodipine tablets in humans: Use the sacubitril / valsartan and amlodipine tablets of the example (specification: 400 mg / 5 mg), orally administer the test drug or the control drug once on an empty stomach, and take it with 240 mL of warm water. Take 4 mL of venous blood for detection at 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 24 h, 36 h, 48 h, 72 h, 96 h (a total of 19 times) after administration. The Cmax and AUC data are as follows:

[0153] Valsartan absorption Example 8 Example 10 Cmax (ng / ml) 8684.3 5881.2 AUC (h*ng / ml) 51106.0 36534.4

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 having a pH of 6.8 and a rotation speed of 75 rpm using a basket method, the dissolution rate of 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%; Glidant and / or lubricant 0.1 - 15%.

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

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

15. The immediate-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, calculated as the free form, the medicament contains 400 mg of sacubitril / valsartan; 5 mg of amlodipine.

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