Multiple release compositions for hypertension treatment

Abstract

The invention provides a multi-release composition for treating hypertension. The composition contains a sustained release part and a quick release part. The slow release part contains sacubitril valsartan or a salt thereof, and the quick release part contains sacubitril valsartan or a salt thereof and amlodipine or a salt thereof; according to the multi-release composition disclosed by the invention, different drugs can meet specific release characteristics. The invention also relates to application of the composition in preparation of medicaments for treating cardiovascular diseases.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a multiple-release drug composition, wherein the composition contains sacubitril / valsartan or its salt and amlodipine or its salt, and contains a sustained-release portion and a rapid-release portion. The present invention also relates to a use of the composition in preparing a drug for treating cardiovascular diseases. Background Art

[0002] Sacubitril-valsartan sodium (also known as LCZ696) is a co-crystal compound of sacubitril and valsartan, which is disclosed in Patent Document 1. It is a dual inhibitor of angiotensin II receptor and enkephalinase. It was approved by the FDA for marketing on July 7, 2015, and the marketing dosage form is a rapid-release coated tablet. Its chemical name is [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propanoic acid-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazolyl-5-yl)biphenyl-4'-ylmethyl}amino)butanoic acid] trisodium.

[0003] The chemical name of amlodipine is 6-methyl-2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid methyl ethyl ester, which can be used to treat hypertension and chronic angina pectoris.

[0004] Document 1 discloses a pharmaceutical composition of a sacubitril-valsartan sodium complex and amlodipine besylate.

[0005] Reference 2 describes that LCZ696 can be co-administered with amlodipine, hydrochlorothiazide, and carvedilol without safety risks and with good tolerability.

[0006] Reference 3 describes that LCZ696 and amlodipine (200 / 5 mg) can be taken together for antihypertensive treatment of hypertensive patients, and proves the effectiveness and safety of the two drugs in treating hypertension together.

[0007] Document 4 discloses a sustained-release preparation containing LCZ696, using hydroxypropylmethylcellulose, a hydrophilic gel skeleton material, as the sustained-release material, and the content of the hydrophilic gel skeleton material is 10 wt%-50 wt%.

[0008] Document 5 describes a multiple release formulation containing sacubitril and valsartan, wherein the ratio of sacubitril to valsartan in the immediate release portion and in the sustained release portion is 1:3-1:9, preferably 1:6. However, it is not possible to determine whether this ratio range is applicable to the case where the formulation contains both sacubitril-valsartan sodium and amlodipine.

[0009] The inventors described in Patent Document 6 a sustained-release preparation containing sacubitril-valsartan sodium, amlodipine or its salt. In an in vitro release experiment of the preparation in a pH 6.8 buffer solution, the release time T of 85 wt% of amlodipine or its salt was 2.3 %. 0.85 Not less than 5 hours; release time T for releasing 85 wt% of amlodipine or its salt 0.85 No more than 24 hours.

[0010] In the prior art, the reported sustained-release preparation of LCZ696 and amlodipine used together for the treatment of patients with hypertension cannot achieve a specific release effect.

[0011] Document 1: CN101098689 A

[0012] Document 2: Clinical Pharmacology in Drug Development

[0013] Reference 3: Journal of Hypertension 2017, 35: 877–885

[0014] Document 4: CN105935358 A

[0015] Document 5: WO2021172960 A1

[0016] Document 6: CN202211542055.6 Summary of the invention

[0017] When amlodipine or its salt and sacubitril valsartan or its salt are prepared into a pharmaceutical composition, both need to meet specific release characteristics to achieve the effectiveness and synergistic effect of the drug. Therefore, the present invention provides a multiple release composition, the composition comprises a sustained release part and a rapid release part, the sustained release part comprises sacubitril valsartan or its salt; the rapid release part comprises sacubitril valsartan or its salt and amlodipine or its salt; the weight ratio of sacubitril valsartan or its salt in the rapid release part to that in the sustained release part is 1:1 to 1:9;

[0018] Preferably, the weight ratio of the sacubitril-valsartan or its salt in the immediate-release portion to the sustained-release portion is 1:1 to 1:3.

[0019] A further preferred weight ratio of sacubitril-valsartan or its salt in the immediate-release portion and the sustained-release portion is 1:1.5 to 1:2.5.

[0020] A further preferred weight ratio of sacubitril-valsartan or its salt in the immediate-release portion and the sustained-release portion is 4:6 to 3:7.

[0021] In a preferred embodiment of the present invention, the weight ratio of sacubitril valsartan or its salt in the immediate-release portion and the sustained-release portion is 4:6.

[0022] In another preferred embodiment of the present invention, the weight ratio of sacubitril valsartan or its salt in the rapid-release portion and the sustained-release portion is 3:7.

[0023] The sustained-release part of the multiple-release composition contains a sustained-release material, and the sustained-release material is selected from glyceryl behenate, hydroxypropyl methylcellulose (HPMC), polyoxyethylene (PEO), carbomer, hydroxyethyl cellulose (HEC), methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polymethacrylate, etc. Preferably, the sustained-release material is selected from glyceryl behenate and polyoxyethylene (PEO). More preferably, the sustained-release material is selected from glyceryl behenate.

[0024] In the sustained-release part of the multiple-release composition, the weight ratio of the sustained-release material in the sustained-release part is 10%-80%.

[0025] In a preferred embodiment of the present invention, the multiple release composition contains a sustained release portion and a rapid release portion, the sustained release portion contains sacubitril valsartan or its salt and a sustained release material selected from glyceryl behenate; the rapid release portion contains sacubitril valsartan or its salt and amlodipine or its salt; the weight ratio of sacubitril valsartan or its salt in the rapid release portion to that in the sustained release portion is 4:6 to 3:7.

[0026] The sustained-release portion of the multiple-release composition of the present invention has at least one of the following release characteristics:

[0027] In vitro release experiment in pH 6.8 buffer solution, the release time T of 85 wt% valsartan or sacubitril was released 0.85 Not less than 2 hours;

[0028] And / or, in vitro release test in pH 6.8 buffer solution, the release time T of 85 wt% valsartan or sacubitril 0.85 Not less than 3 hours.

[0029] The sustained-release portion of the multiple-release composition of the present invention has at least one of the following release characteristics:

[0030] In vitro release experiment in pH 6.8 buffer solution, the release time T of 85 wt% valsartan or sacubitril was released 0.85 No more than 12 hours;

[0031] And / or, in vitro release test in pH 6.8 buffer solution, the release time T of 85 wt% valsartan or sacubitril 0.85 No more than 10 hours;

[0032] And / or, in vitro release test in pH 6.8 buffer solution, the release time T of 85 wt% valsartan or sacubitril 0.85 No more than 8 hours;

[0033] The immediate release portion of the multiple release composition of the present invention has at least one of the following release characteristics:

[0034] In vitro release experiment in pH 6.8 buffer solution, the release time T of 85 wt% amlodipine or its salt is released 0.85 No more than 2 hours;

[0035] And / or, in vitro release test in pH 6.8 buffer solution, the release time T for releasing 85 wt% of amlodipine or its salt 0.85 Not more than 1 hour.

[0036] The sustained-release part and the immediate-release part of the multiple-release composition of the present invention optionally contain pharmaceutical excipients such as fillers, glidants, lubricants, retardants, disintegrants, adhesives, etc.

[0037] Suitable fillers are selected from microcrystalline cellulose, mannitol, lactose or its hydrates, lactose-cellulose, starch, pregelatinized starch, microcrystalline cellulose, dextrin, sucrose, glucose, maltose, sorbitol, powdered sugar, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; preferred fillers include: microcrystalline cellulose, mannitol, lactose or its hydrates.

[0038] Suitable glidants are selected from colloidal silicon dioxide, talc, stearic acid and the like.

[0039] Suitable lubricants are selected from magnesium stearate, gelatinized starch, calcium stearate, colloidal silicon dioxide, polyethylene glycol, talc, docusate sodium, sodium lauryl sulfate, sodium stearyl fumarate, sodium carboxymethylcellulose and the like.

[0040] Suitable binders are selected from low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, copovidone, polyvinyl alcohol, ethyl cellulose, starch.

[0041] Suitable disintegrants are selected from crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0042] Suitable retardants are selected from methylcellulose, ethylcellulose, cellulose acetate.

[0043] The multiple-release composition of the present invention can be prepared into tablets, capsules, and granules; preferably, it is a tablet; the tablet includes a single-layer tablet and a multi-layer tablet; preferably, the tablet is a multi-layer tablet.

[0044] In another aspect, the present invention provides a use of a multiple-release composition in preparing a drug for treating cardiovascular diseases, wherein the cardiovascular diseases include heart failure and hypertension. DETAILED DESCRIPTION

[0045] The weight ratio unit in the present invention is mg / mg. For example, if the immediate-release portion contains 60 mg of sacubitril-valsartan or its salt and the sustained-release portion contains 140 mg, the weight ratio of sacubitril-valsartan or its salt in the immediate-release portion to the sustained-release portion is 3:7.

[0046] When the content of free base or free acid is calculated in the present invention, for example, when 6.93 mg of amlodipine besylate is contained, 5 mg of amlodipine free base is contained.

[0047] Sacubitril valsartan or its salt may be sodium salt, calcium salt or potassium salt, preferably sodium salt. Sacubitril valsartan sodium is disclosed in WO2007056546.

[0048] AHU377 of the present invention refers to sacubitril or sacubitril, and its chemical name is 4-(((2S,4R)-1-(1,1'-biphenyl-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid.

[0049] T 0.85 It refers to the time required to release 85 wt% of the active pharmaceutical ingredient in an in vitro release experiment.

[0050] Release time T 0.85 Not less than 2 hours, refers to the release time T 0.85 The minimum time is 2 hours (including 2 hours), any release time T 0.85 Any time exceeding 2 hours is within the scope of the present invention. Non-limiting examples include release time T 0.85 3 hours, or release time T 0.85 Wait for 4 hours.

[0051] Release time T 0.85 No more than 12 hours, refers to the release time T 0.85 The maximum time is 12 hours (including 12 hours), any release time T 0.85 The range of less than 12 hours is within the scope of the present invention. Non-limiting examples include release time T 0.85 12 hours, or release time T 0.85 is 11 hours, or the release time T 0.85 10 hours, or release time T 0.85 9 hours, or the release time T 0.85 8 hours, or release time T 0.85 7 hours, or release time T0.85 Wait for 6 hours.

[0052] The multiple release composition of the present invention contains 50 mg, 100 mg, 200 mg, 300 mg or 400 mg of sacubitril valsartan or its salt; optionally contains 1.0 mg, 2.5 mg, 5 mg, 7.5 mg or 10 mg of amlodipine or its salt. Preferably, it contains 100 mg or 200 mg of sacubitril valsartan or its salt, or contains 2.5 mg, 5 mg or 10 mg of amlodipine or its salt; more preferably, the pharmaceutical composition contains 100 mg or 200 mg of sacubitril valsartan or its salt, and contains 2.5 mg or 5 mg of amlodipine or its salt.

[0053] In some specific embodiments, the weight ratio of sacubitril / valsartan or its salt in the immediate-release portion to the sustained-release portion is 1:1.5 to 1:2.5.

[0054] In some specific embodiments, the weight ratio of sacubitril valsartan or its salt in the immediate-release portion to the sustained-release portion is 3:7.

[0055] Amlodipine or its salts include levoamlodipine and racemic amlodipine. The salts include organic acid salts, such as benzenesulfonate and benzoate. As a specific embodiment of the present invention, amlodipine or its salt is levoamlodipine benzenesulfonate.

[0056] In some specific embodiments, the sustained-release part of the multiple-release composition contains the sustained-release material glyceryl behenate or polyoxyethylene, and the weight ratio of the sustained-release part is 10%-80%, and the preferred weight ratio is 20%-60%.

[0057] In some specific embodiments, the sustained-release portion of the multiple-release composition contains the sustained-release material glyceryl behenate, and the weight ratio of glyceryl behenate in the sustained-release portion is 10%-80%, and the preferred weight ratio is 20%-60%.

[0058] In some specific embodiments, the sustained-release portion of the multiple-release composition contains a retardant; the retardant is at least one of methyl cellulose, ethyl cellulose, and cellulose acetate, and its weight ratio in the sustained-release portion is 1%-20%; the preferred weight ratio is 3%-15%; and the further preferred weight ratio is 5%-15%.

[0059] In some embodiments, the multiple release composition comprises a retardant selected from ethylcellulose. In some embodiments, the multiple release composition comprises no retardant. The addition of a retardant can slow down the dissolution of the drug to a certain extent, for example, the dissolution rate of the same prescription in 4 hours is about 74% when no retardant is added.

[0060] In some specific embodiments, the multiple-release composition contains a filler, optionally selected from microcrystalline cellulose, mannitol, lactose or a hydrate thereof, wherein the weight ratio of the filler in the multiple-release composition is 5%-50%; the weight ratio of the filler in the sustained-release portion is 0.5%-30%; and the weight ratio of the filler in the immediate-release portion is 5%-40%.

[0061] In some specific embodiments, the multiple-release composition contains a lubricant, which is selected from magnesium stearate, gelatinized starch, calcium stearate, colloidal silicon dioxide, polyethylene glycol, talc, sodium docusate, sodium lauryl sulfate, sodium stearyl fumarate, and sodium carboxymethyl cellulose; the preferred lubricants are magnesium stearate and sodium lauryl sulfate; the weight ratio of the lubricant in the multiple-release composition is 1%-20%; the preferred weight ratio is 1%-15%.

[0062] In some specific embodiments, the multiple release composition contains sacubitril / valsartan or its salt in the sustained release portion, and a pharmaceutical excipient selected from glyceryl behenate, ethylcellulose, a filler, a glidant, and a lubricant.

[0063] In some specific embodiments, the multiple release composition contains sacubitril / valsartan or its salt and amlodipine or its salt in the immediate release portion, and optional pharmaceutical excipients such as fillers, binders, disintegrants, glidants, and lubricants.

[0064] In some embodiments, the multiple-release composition is a multi-layer tablet comprising an immediate-release layer and a sustained-release layer.

[0065] In some embodiments, the multiple-release composition is a capsule comprising sustained-release granules and immediate-release granules.

[0066] In some embodiments, the sustained-release portion of the multiple-release composition has the following release characteristics:

[0067] In vitro release experiment in pH 6.8 buffer solution, the release time T of 85 wt% valsartan or sacubitril was released 0.85 Not less than 2 hours; Release time T for releasing 85wt% valsartan or sacubitril 0.85 No more than 12 hours.

[0068] In some embodiments, the sustained-release portion of the multiple-release composition has the following release characteristics:

[0069] In vitro release experiment in pH 6.8 buffer solution, the release time T of 85 wt% valsartan or sacubitril was released 0.85 Not less than 2 hours; Release time T for releasing 85wt% valsartan or sacubitril0.85 No more than 10 hours.

[0070] In some embodiments, the sustained-release portion of the multiple-release composition has the following release characteristics:

[0071] In vitro release experiment in pH 6.8 buffer solution, the release time T of 85 wt% valsartan or sacubitril was released 0.85 Not less than 2 hours; Release time T for releasing 85wt% valsartan or sacubitril 0.85 No more than 8 hours.

[0072] In some embodiments, the immediate release portion of the multiple release composition has the following release characteristics:

[0073] In vitro release experiment in pH 6.8 buffer solution, the release time T of 85 wt% amlodipine or its salt is released 0.85 No more than 2 hours.

[0074] In some embodiments, the immediate release portion of the multiple release composition has the following release characteristics:

[0075] In vitro release experiment in pH 6.8 buffer solution, the release time T of 85 wt% amlodipine or its salt is released 0.85 Not more than 1 hour.

[0076] In some embodiments, the multiple release composition is prepared by the following method:

[0077] 1) Preparation of the immediate-release part: mixing sacubitril-valsartan or its salt, amlodipine or its salt and pharmaceutical excipients;

[0078] 2) Preparation of the sustained-release portion: mixing sacubitril / valsartan or its salt, glyceryl behenate and pharmaceutical excipients;

[0079] 3) granulating the immediate-release part and the sustained-release part by dry or wet granulation respectively;

[0080] 4) filling capsules with the immediate-release granules and the sustained-release granules of step 3) or performing double-layer tableting; or filling capsules with the mixture of step 1) and step 2) or performing double-layer tableting;

[0081] 5) If necessary, coat the tablets.

[0082] In some embodiments, the multiple-release composition is prepared as a bilayer tablet by the following method:

[0083] 1) Preparation of immediate-release layer granules: LCZ696, colloidal silicon dioxide, amlodipine besylate, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, talc and magnesium stearate are mixed; dry granulation is performed and the mixture is mixed for later use.

[0084] 2) Preparation of sustained-release layer granules: LCZ696, colloidal silicon dioxide, ethyl cellulose, magnesium stearate, glyceryl behenate and microcrystalline cellulose were mixed; the mixture was dry granulated and then set aside.

[0085] 3) The quick-release layer granules and the sustained-release layer granules are double-compressed into tablets and then coated.

[0086] The present invention is further described and understood by the following examples, which should not be construed as limiting the concept of the present invention.

[0087] The present invention adopts the following conditions to measure the in vitro dissolution:

[0088] Dissolution apparatus: FADT-800RC;

[0089] Dissolution apparatus: rotating basket;

[0090] Dissolution medium volume: 900 mL, temperature: 37℃±0.5, rotation speed: 75 rpm; dissolution medium: pH 6.8 phosphate buffer; sampling time points: 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h.

[0091] Example 1

[0092] Prescription composition (200mg):

[0093]

[0094]

[0095] Prepared as follows

[0096] 1) Preparation of immediate-release layer granules: LCZ696, colloidal silicon dioxide, amlodipine besylate, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, talc and magnesium stearate are mixed; dry granulation is performed and the mixture is set aside.

[0097] 2) Preparation of sustained-release layer granules: LCZ696, colloidal silicon dioxide, ethyl cellulose, magnesium stearate, glyceryl behenate and microcrystalline cellulose are mixed; dry granulation is performed and the mixture is set aside.

[0098] 3) The quick-release layer granules and the sustained-release layer granules are double-compressed into tablets and then coated.

[0099] The dissolution of the formulation was determined:

[0100] Time / h 0.5 1 2 3 4 6 8 10 12 Valsartan 50.3％ 59.6％ 70.2％ 77.4％ 82.8％ 90.3％ 94.8％ 97.3％ 98.5％ AHU377 50.1％ 59.3％ 69.8％ 76.9％ 82.1％ 89.5％ 93.9％ 96.3％ 97.6％ Amlodipine 92.5％ 95.9％ / / / / / / /

[0101] The valsartan and sacubitril in the multiple release composition of the present invention have substantially the same solubility at different time points. The amlodipine in the immediate release portion can be rapidly dissolved without being affected. The release time T for releasing 85 wt% of amlodipine or its salt is 0.85 Not more than 1 hour.

[0102] Example 2

[0103] Prescription composition (100mg):

[0104]

[0105]

[0106] Prepare as follows:

[0107] 1) Preparation of immediate-release layer granules: LCZ696, colloidal silicon dioxide, amlodipine besylate, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, talc and magnesium stearate were mixed and set aside.

[0108] 2) Preparation of sustained-release layer particles: LCZ696, colloidal silicon dioxide, ethyl cellulose, magnesium stearate, glyceryl behenate and microcrystalline cellulose were mixed and set aside.

[0109] 3) The quick-release layer granules and the sustained-release layer granules are double-compressed into tablets and then coated.

[0110] Determine the dissolution rate of the formulation:

[0111]

[0112]

[0113] The valsartan and sacubitril in the multiple release composition of the present invention have substantially the same solubility at different time points. The amlodipine in the immediate release portion can be rapidly dissolved without being affected, and the release time T of 85 wt% of the amlodipine or its salt is 0.85 Not more than 1 hour.

[0114] Example 3

[0115] Prescription composition

[0116]

[0117]

[0118] Tablets were prepared in a similar manner as in Example 1, and the dissolution was determined as follows:

[0119] Time / h 0.5h 1h 2h 3h 4h 6h 8h Valsartan 60.1％ 70.1％ 81.5％ 88.6％ 91.6％ 100.1％ 100.5％ AHU 60.1％ 70.1％ 81.1％ 87.8％ 90.3％ 99.5％ 100.3％

[0120] Example 5

[0121] Prescription composition

[0122]

[0123]

[0124] Double-layer coated tablets were prepared using a method similar to that of Example 1, and the dissolution of amlodipine was determined as follows:

[0125]

[0126] In the multiple release composition of the present invention, the weight ratio of sacubitril / valsartan or its salt in the immediate release portion and the sustained release portion has a significant effect on the release of amlodipine. For example, at 1:1, it is found that amlodipine in the immediate release portion cannot meet the release requirements of the present invention.

[0127] Example 6

[0128] The tablets of the following formulation were prepared in a similar manner to Example 1.

[0129]

[0130]

[0131] Comparative Example 1

[0132] Preparation of LCZ696-Amlodipine Sustained Release Tablets

[0133] prescription

[0134]

[0135] Preparation process:

[0136] (1) LCZ696, amlodipine besylate, polyoxyethylene, microcrystalline cellulose 102, and anhydrous lactose are sieved and set aside;

[0137] (2) Weigh the prescription amount of LCZ696, polyoxyethylene, amlodipine besylate, anhydrous lactose and microcrystalline cellulose 102, add them into a multi-directional motion mixer in sequence, and then add part of the magnesium stearate. After mixing evenly, dry granulate is performed. After granulation, the remaining magnesium stearate is added to the granules and mixed evenly;

[0138] (3) tabletting to obtain LCZ696-amlodipine sustained-release tablets.

[0139] Dissolution Assay:

[0140] This product was taken to determine the dissolution of valsartan and AHU377. The results are as follows:

[0141]

[0142]

[0143] From the dissolution of Comparative Example 1, it can be seen that although sustained release is achieved, at the same time point, the dissolution of valsartan and sacubitril is not synchronized, and there is a significant difference between the two. The multiple release composition of the present invention effectively reduces the difference in the dissolution of valsartan and sacubitril at various time points, and amlodipine or its salt can achieve rapid dissolution without being affected.

[0144] Animal experiments

[0145] AUC (ng*h / ml) of valsartan and sacubitril determined by dog ​​PK study

[0146] Example Example 6 Example 1 Example 3 Shakubaqu 709 1400 1539 Valsartan 6943 14532 18059

[0147] In the multiple release composition of the present invention, the ratio of sacubitril valsartan sodium in the sustained-release portion and the immediate-release portion has a significant effect on the AUC in animals, especially at 2:8, the AUC indicates that a good drug therapeutic effect may not be achieved.

Claims

1. A multiple release composition comprising a sustained release portion and a rapid release portion, wherein the sustained release portion comprises sacubitril / valsartan or a salt thereof; The immediate release portion contains sacubitril / valsartan or its salt and amlodipine or its salt; The weight ratio of the sacubitril / valsartan or its salt in the immediate-release portion to the sustained-release portion is 1:1 to 1:

9. 2 . The multiple-release composition according to claim 1 , wherein the weight ratio of sacubitril valsartan or its salt in the immediate-release portion and the sustained-release portion is 1:1 to 1:

3.

3. The multiple-release composition according to any one of claim 2, wherein the weight ratio of sacubitril valsartan or its salt in the immediate-release portion and the sustained-release portion is 1:1.5 to 1:2.

5.

4. The multiple-release composition according to any one of claims 1 to 3, wherein the sustained-release portion contains a sustained-release material, and the sustained-release material is selected from glyceryl behenate and polyoxyethylene.

5. The multiple release composition according to claim 1, wherein the composition comprises a sustained release portion and an immediate release portion, wherein the sustained release portion comprises sacubitril valsartan or a salt thereof and a sustained release material selected from glyceryl behenate; the immediate release portion comprises sacubitril valsartan or a salt thereof and amlodipine or a salt thereof; and the weight ratio of the sacubitril valsartan or a salt thereof in the immediate release portion to that in the sustained release portion is 4:6 to 3:

7.

6. A multiple release composition, comprising a sustained release portion and an immediate release portion, wherein the sustained release portion comprises sacubitril valsartan or a salt thereof; and the immediate release portion comprises sacubitril valsartan or a salt thereof and amlodipine or a salt thereof, wherein the composition has at least one of the following release characteristics: In vitro release experiment in pH 6.8 buffer solution, the release time T of 85 wt% valsartan or sacubitril was released 0.85 Not less than 2 hours; And / or, in vitro release test in pH 6.8 buffer solution, the release time T of 85 wt% valsartan or sacubitril 0.85 No more than 12 hours; And / or, in vitro release test in pH 6.8 buffer solution, the release time T of 85 wt% valsartan or sacubitril 0.85 No more than 10 hours.

7. A multiple release composition, comprising a sustained release portion and an immediate release portion, wherein the sustained release portion comprises sacubitril valsartan or a salt thereof; and the immediate release portion comprises sacubitril valsartan or a salt thereof and amlodipine or a salt thereof, wherein the composition has at least one of the following release characteristics: In vitro release experiment in pH 6.8 buffer solution, the release time T of 85 wt% amlodipine or its salt is released 0.85 No more than 2 hours; And / or, in vitro release test in pH 6.8 buffer solution, the release time T for releasing 85 wt% of amlodipine or its salt 0.85 Not more than 1 hour.

8. The multiple-release composition according to claim 1 or 6, wherein the sustained-release portion further comprises at least one pharmaceutical excipient selected from the group consisting of methyl cellulose, ethyl cellulose and cellulose acetate.

9. The multiple release composition of claim 1, which is a tablet.

10. Use of the multiple-release composition according to claim 1 in preparing a medicament for treating cardiovascular diseases.

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