Sacubitril valsartan sodium sustained-release composition, method for producing the same, and applications

Abstract

To provide a composition that can achieve synchronous sustained release of sacubitril and valsartan, and a method for producing the same. [Solution] A sustained-release composition of sacubitril valsartan sodium, comprising a drug-containing layer core having a pore on one side of the drug-containing layer, a booster layer core, and a coating film; The drug-containing layer core comprises a pharmacoactive ingredient and a carrier, the pharmacoactive ingredient being selected from sacubitril valsartan sodium or other pharmaceutically acceptable salt forms thereof; the content of the pharmacoactive ingredient in the drug-containing layer core is 10.00% to 80.00%; The composition is a 24-hour sustained-release drug. The dissolution of sacubitril and valsartan is A) Dissolve 40% or less of the drug active ingredient within 2 hours. B) 20% to 75% of the drug active ingredient is eluted within 8 hours. It simultaneously satisfies three characteristics: C) It releases more than 65% of the drug active ingredient within 24 hours.

Description

Detailed Description of the Invention

[0001] This application claims the priority of a prior application filed with the China National Intellectual Property Administration on July 12, 2021, with a patent application number of 202110784642.5 and an invention title of "Sacubitril valsartan sodium sustained-release composition, its manufacturing method and application". The above prior application is incorporated into this application by reference in its entirety.

[0002] [Technical Field] The present invention relates to a sacubitril valsartan sodium sustained-release composition, its manufacturing method and application.

[0003] [Background Art] Sacubitril valsartan sodium is suitable for the treatment of adult patients with heart failure with reduced ejection fraction (HF-REF), and reduces the risk of cardiovascular death and hospitalization for heart failure. Sacubitril is a neprilysin inhibitor, and valsartan is an angiotensin II receptor blocker. Sacubitril valsartan sodium can be used in place of an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor antagonist (ARB), and can be used in combination with other heart failure medications.

[0004] Heart failure, or simply heart failure, is a condition where the heart is unable to pump enough blood to the rest of the body, potentially leading to symptoms such as shortness of breath, fatigue, and fluid retention, which gradually worsen and significantly impact quality of life. Statistics show that $108 billion is spent globally on heart failure annually. A large-scale epidemiological study in 2003 indicated that the prevalence of heart failure among adults in mainland China reached 0.9%, with approximately 4.5 million people suffering from heart failure. Meanwhile, hypertension is one of the leading causes of heart failure and is a major public health problem worldwide. According to Framingham's report, hypertension accounts for 75% of heart failure cases, and in China, this figure ranges from 60% to 88.5%, six times higher than normal blood pressure. The five-year mortality rate after the onset of heart failure is over 50%. The prevalence of hypertension in China is currently about 11.88%, and it is estimated that there are nearly 100 million people with hypertension nationwide.

[0005] Approximately half of heart failure patients have heart failure with reduced ejection fraction, and current anti-heart failure drugs only block the adverse effects caused by activation of the RAAS system (renin-angiotensin-aldosterone system). This is equivalent to having only the "spear" to attack and no "shield" to protect the heart, and patient mortality rates remain very high even after treatment. Data shows that 50% of patients die within 5 years of being diagnosed with heart failure.

[0006] The Paradigm-HF clinical study, presented at the 2014 European Society of Cardiology (ESC) General Assembly, involved 8,442 patients worldwide, 353 of whom were Chinese. The study showed that, compared to the enalapril-treated group, patients with low ejection fraction heart failure (HF-REF) treated with Novartis' innovative heart failure drug LCZ696 had a 20% lower risk of cardiovascular death and a 21% lower risk of hospitalization for heart failure. This data has also been published in the prestigious journal, the New England Journal of Medicine.

[0007] Sacubitril (valsartan sodium) acts in a unique multi-faceted manner, suppressing adverse effects caused by activation of the RAAS system while simultaneously enhancing the effects of the cardiac-protective neuroendocrine system (natriuretic peptide system). This is equivalent to having both a "spear" and a "shield." New research indicates that LCZ696 has good tolerance, is easy to manage side effects, and has a low rate of patient dropout from studies due to adverse events.

[0008] The chemical name of sacubitril valsartan sodium is octadeca sodium hexakis(4-{[(1S,3R)-1-([1,1'-biphenyl)-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)hexakis(N-pentanoyl-N-{[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-L-valinate)-water(1 / 15), and its structural formula is as follows.

[0009] [ka]

[0010] Currently, Novartis has already developed a standard immediate-release tablet of sacubitril (valsartan sodium), with a dosage of 50 mg to 200 mg twice daily, resulting in a large dose and frequent administration.

[0011] Patent document CN105748420A proposes a method for manufacturing LCZ696, a sustained-release matrix tablet for the treatment of heart failure. This sustained-release dosage form uses a gel matrix as the drug release mechanism, resulting in a relatively short sustained-release time, with the active ingredient being completely released within just 8 hours, and failing to achieve stable release for 24 hours. Furthermore, the gel matrix tablet is susceptible to factors such as food extrusion in vivo, leading to varying degrees of increase in drug release rate, resulting in a relatively poor sustained-release effect and a relatively poor in vitro-in vivo correlation.

[0012] Finding a drug dosage form that exhibits good sustained-release effects, a gentle release, and good compliance in patients with chronic heart failure is an urgent technical problem that needs to be solved.

[0013] [Overview of the prefecture] The present invention provides a sacubitril-valsartan sodium sustained-release composition, which is a 24-hour sustained-release drug, and the dissolution of sacubitril and valsartan is as follows: A) Dissolve 40% or less of the drug active ingredient within 1 hour. B) Dissolve 10% to 70% of the drug active ingredient within 6 hours. C) More than 65% of the drug active ingredient is eluted within 24 hours. It satisfies these three characteristics simultaneously, The above-mentioned pharmacoactive ingredient may be sacubitril valsartan sodium, or one, two, or more selected from other pharmaceutically acceptable salts, solvates, and hydrates thereof.

[0014] According to one embodiment of the present invention, the elution of sacubitril in the sacubitril valsartan sodium sustained-release composition is A) Dissolve 35% or less of the drug active ingredient within 1 hour. B) Dissolve 10% to 70% of the drug active ingredient within 6 hours. C) More than 70% of the drug active ingredient is eluted within 24 hours. It satisfies these three characteristics simultaneously, The dissolution of valsartan is A) Dissolve 35% or less of the drug active ingredient within 1 hour. B) Dissolve 15% to 70% of the drug active ingredient within 6 hours. C) More than 75% of the drug active ingredient is eluted within 24 hours. It simultaneously satisfies these three characteristics.

[0015] According to one embodiment of the present invention, the elution of sacubitril in the sacubitril valsartan sodium sustained-release composition is A) Dissolve 25% or less of the drug active ingredient within 1 hour. B) elute 10% - 65% of the drug active ingredient within 6 h, C) elute 75% or more of the drug active ingredient within 24 h, simultaneously satisfy the following three characteristics, the elution of valsartan, A) elute 30% or less of the drug active ingredient within 1 h, B) elute 10% - 65% of the drug active ingredient within 6 h, C) elute 75% or more of the drug active ingredient within 24 h, simultaneously satisfy the following three characteristics.

[0016] According to one embodiment of the present invention, the elution of sacubitril in the above-mentioned sacubitril valsartan sodium sustained-release composition, A) elute 25% or less of the drug active ingredient within 1 h, B) elute 10% - 65% of the drug active ingredient within 6 h, C) elute 80% or more of the drug active ingredient within 24 h, simultaneously satisfy the following three characteristics, the elution of valsartan, A) elute 25% or less of the drug active ingredient within 1 h, B) elute 15% - 65% of the drug active ingredient within 6 h, C) elute 80% or more of the drug active ingredient within 24 h simultaneously satisfy the following three characteristics.

[0017] Preferably, the elution of the above-mentioned sacubitril and valsartan is synchronous release.

[0018] According to one embodiment of the present invention, the above-mentioned sustained-release composition is a 24 h sustained-release drug, and the elution of sacubitril and valsartan, A) elute 40% or less of the drug active ingredient within 2 h, B) elute 20% - 75% of the drug active ingredient within 8 h, C) elute 65% or more of the drug active ingredient within 24 h, simultaneously satisfy the following three characteristics, The above-mentioned pharmacoactive ingredient may be sacubitril valsartan sodium, or one, two, or more selected from other pharmaceutically acceptable salts, solvates, and hydrates thereof.

[0019] In one embodiment, the elution of sacubitril in the above sacubitril valsartan sodium sustained-release composition is A) Dissolve 35% or less of the drug active ingredient within 2 hours. B) 20% to 70% of the drug active ingredient is eluted within 8 hours. C) More than 75% of the drug active ingredient is eluted within 24 hours. It satisfies these three characteristics simultaneously, The dissolution of valsartan is A) Dissolve 35% or less of the drug active ingredient within 2 hours. B) 20% to 70% of the drug active ingredient is eluted within 8 hours. C) More than 75% of the drug active ingredient is eluted within 24 hours. It simultaneously satisfies these three characteristics.

[0020] In one embodiment, the elution of sacubitril in the above sacubitril valsartan sodium sustained-release composition is A) Elute 25% or less of the drug active ingredient within 2 hours. B) 25% to 65% of the drug active ingredient is eluted within 8 hours. C) More than 75% of the drug active ingredient is eluted within 24 hours. It satisfies these three characteristics simultaneously, The dissolution of valsartan is A) Elute 25% or less of the drug active ingredient within 2 hours. B) 25% to 65% of the drug active ingredient is eluted within 8 hours. C) More than 75% of the drug active ingredient is eluted within 24 hours. It satisfies these three characteristics simultaneously, In one embodiment, the elution of sacubitril in the above sacubitril valsartan sodium sustained-release composition is A) Elute 25% or less of the drug active ingredient within 2 hours. B) 30% to 65% of the drug active ingredient is eluted within 8 hours. C) More than 80% of the drug active ingredient is eluted within 24 hours. It satisfies these three characteristics simultaneously, The dissolution of valsartan is A) Elute 25% or less of the drug active ingredient within 2 hours. B) 30% to 65% of the drug active ingredient is eluted within 8 hours. C) More than 80% of the drug active ingredient is eluted within 24 hours. It satisfies these three characteristics simultaneously, Preferably, the elution of sacubitril and valsartan is synchronous release.

[0021] In this context, "dissolution" refers to the cumulative dissolution rate of the active drug components, such as the cumulative dissolution rate of sacubitril and the cumulative dissolution rate of valsartan. Furthermore, the cumulative dissolution rate is measured in a phosphate buffer solution at pH 6.8. Those skilled in the art will understand that the dissolution rate of sacubitril valsartan sodium gradually increases over time.

[0022] According to embodiments of the present invention, the sacubitril valsartan sodium sustained-release composition comprises a drug-containing layer core and a coating film having pores on one side of the drug-containing layer, wherein the drug-containing layer core comprises a drug-active component and a carrier, the drug-active component may be sacubitril valsartan sodium or one, two or more selected from other pharmaceutically acceptable salt forms, solvates and hydrates thereof, the carrier is, for example, one or more of osmotic pressure regulators, swelling agents, thickeners, flow promoters and lubricants, and the coating film is a semipermeable film. The above sustained-release composition may optionally include or exclude a booster layer core, the booster layer core containing one or more of an osmotic pressure regulator, a swelling agent, a coloring agent, and a lubricant.

[0023] According to embodiments of the present invention, in the drug-containing layer core, the drug-active component is preferably sacubitril valsartan sodium.

[0024] According to embodiments of the present invention, the content of the drug-active component in the drug-containing layer core is 10.00% to 80.00%, for example, 28.25%, 33.93%, 37.67%, 37.70%, 40.39%, 56.50%, 67.87%, or 75.40%, and the above content is the mass percentage of the drug-active component relative to the total mass of the drug-containing layer core.

[0025] According to embodiments of the present invention, in the drug-containing layer core, the osmotic pressure adjusting agent may be one or more selected from sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose, and lactose. In one embodiment, the lactose is lactose monohydrate. For example, the osmotic pressure adjusting agent may be a mixture of sorbitol, lactose monohydrate, and sodium chloride, a mixture of sorbitol and sodium chloride, or sodium chloride.

[0026] According to embodiments of the present invention, the content of the osmotic pressure regulator in the drug-containing layer core is 1.00% to 60.00%, for example, 48.75%, 40.34%, 31.50%, 27.50%, 3.00%, or 1.50%, and the above content is the mass percentage of the osmotic pressure regulator relative to the total mass of the drug-containing layer core.

[0027] According to embodiments of the present invention, in the drug-containing layer core, the thickening agent (also called a suspension agent or binder) is an additive that can reduce the settling rate of fine particles or increase the hydrophilicity of fine particles by increasing the viscosity of the dispersion medium, and is, for example, one or more selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, copovidone, gum arabic, pregelatinized starch, and polyvinylpyrrolidone. For example, the thickening agent is selected from hydroxypropyl methylcellulose or a mixture of copovidone and hydroxyethyl cellulose.

[0028] According to embodiments of the present invention, in the drug-containing layer core, the content of the thickening agent is 10.00% to 70.00%, for example, 21.50%, 10.50%, 21.00%, 15.00%, 13.81%, 57.30%, 34.80%, 25.00%, 53.90%, 56.87%, 19.93%, 18.83%, or 5.41%, and the above content is the mass percentage of the thickening agent relative to the total mass of the drug-containing layer core.

[0029] According to embodiments of the present invention, in the drug-containing layer core, the swelling agent (also called a propellant) may be a substance that absorbs a solvent and expands, and is preferably one or more of polyoxyethylene, carbomer, sodium carboxymethyl starch, crospovidone, and sodium alginate.

[0030] According to embodiments of the present invention, the content of the swelling agent in the drug-containing layer core is preferably 0.00% to 70.00%, for example, 48.06%, 24.02%, or 19.93%, and the above content is the mass percentage of the swelling agent relative to the total mass of the drug-containing layer core.

[0031] According to embodiments of the present invention, the drug-containing layer core may further contain a coloring agent.

[0032] According to embodiments of the present invention, in the drug-containing layer core, the coloring agent may be a substance capable of achieving the purpose of coloring, and is preferably one or more of red iron oxide, yellow iron oxide, and black iron oxide.

[0033] According to embodiments of the present invention, in the drug-containing layer core, the content of the coloring agent is 0% to 5.00%, for example, 0.10%, and the content is the mass percentage of the coloring agent relative to the total mass of the drug-containing layer core.

[0034] According to embodiments of the present invention, in the drug-containing layer core, the flow promoter may be an auxiliary agent that can improve the fluidity of the powder or particles by reducing the frictional force between particles, and is preferably one or more of talc powder, fine silica gel powder, and colloidal silica.

[0035] According to embodiments of the present invention, in the drug-containing layer core, the content of the flow promoter is preferably 0% to 5.00%, for example, 0 to 1.00%, and exemplary content is 0.30%, 0.50%, 1.57%, 1.67%, 3.00%, 3.54%, or 3.57%, where the above content is the mass percentage of the flow promoter relative to the total mass of the drug-containing layer core.

[0036] According to embodiments of the present invention, in the drug-containing layer core, the lubricant may be a substance having a lubricating effect, and is preferably one or more of the following: metal stearate, stearic acid, talc powder, stearate ester, stearoyl fumarate, and fine silica gel powder. For example, the metal stearate is preferably magnesium stearate and / or calcium stearate. For example, the stearate ester is preferably glyceride stearate.

[0037] According to embodiments of the present invention, in the drug-containing layer core, the content of the lubricant is preferably 0.50% to 60.00%, for example, 1.00% to 30.00%, and exemplary content is 1.00%, 1.20%, 2.00%, 2.14%, 2.33%, or 3.00%, where the above content is the mass percentage of the lubricant relative to the total mass of the drug-containing layer core.

[0038] In the drug-containing core described above, the total content of the drug active ingredient and the carrier is 100%.

[0039] According to one embodiment of the present invention, when the sustained-release composition includes a booster layer core, the drug-containing layer core does not contain an osmotic pressure regulator.

[0040] According to embodiments of the present invention, in the booster layer core, the osmotic pressure adjusting agent may be a substance that adjusts the osmotic action, and is preferably one or more of sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose, and lactose, for example, sodium chloride. In one embodiment, the lactose may be lactose monohydrate.

[0041] According to embodiments of the present invention, the content of the osmotic pressure regulator in the booster layer core is 1.00% to 60.00%, for example, 31.74%, 29.17%, 25.00%, or 5.00%, and the above content is the mass percentage of the osmotic pressure regulator relative to the total mass of the booster layer core.

[0042] According to embodiments of the present invention, in the booster layer core, the swelling agent (also called a propellant) may be a substance that absorbs a solvent and expands, and is preferably one or more of polyvinylpyrrolidone, hydroxyethylcellulose, copovidone, hydroxypropylmethylcellulose, gum arabic, carbomer, sodium carboxymethyl starch, sodium alginate, and polyoxyethylene.

[0043] According to embodiments of the present invention, the content of the swelling agent in the booster layer core is 0.00% to 90.00%, for example, 0.00% to 80.00%, and examples include 8.33%, 10.00%, 20.00%, and 65%. The percentages are 87%, 63.00%, 73.00%, 60.83%, or 82.00%, where the above percentages represent the mass percentage of the swelling agent relative to the total mass of the booster layer core.

[0044] According to embodiments of the present invention, in the booster layer core, the coloring agent may be a substance capable of achieving the purpose of coloring, and is preferably one or more of red iron oxide, yellow iron oxide, and black iron oxide.

[0045] According to embodiments of the present invention, the content of the coloring agent in the booster layer core is preferably 0.10% to 10.00%, for example, 1.20%, 1.00%, or 0.83%, and the above content is the mass percentage of the coloring agent relative to the total mass of the booster layer core.

[0046] According to embodiments of the present invention, in the booster layer core, the lubricant may be a substance having a general lubricating effect in the art, and is preferably one or more of the following: metal stearate, stearic acid, talc powder, stearate ester, stearoyl fumarate, and fine silica gel powder. For example, the metal stearate is preferably magnesium stearate and / or calcium stearate. For example, the stearate ester is preferably glyceride stearate.

[0047] According to embodiments of the present invention, the content of the lubricant in the booster layer core is preferably 0.10% to 10.00%, for example 2.00%, 1.20%, 1.00%, or 0.84%, and the above content is the mass percentage of the lubricant relative to the total mass of the booster layer core.

[0048] In the booster layer core described above, the total content of each composition is 100%.

[0049] According to embodiments of the present invention, the semipermeable membrane comprises one or more of the film-forming material, pore-forming agent, and plasticizer.

[0050] According to embodiments of the present invention, in the above-mentioned coating film, the film-forming material may be a material that can be dispersed on a solid surface and solidify to form a film, and is preferably one or more of cellulose acetate, ethylcellulose, phthalic cellulose acetate, polyvinyl acetate, acrylic resin, and methacrylic resin.

[0051] According to embodiments of the present invention, in the coating film described above, the pore-forming agent may be a substance that can form pores in the material when exposed to water, and is preferably one or more of polyethylene glycol, hydroxypropyl cellulose, povidone, and polyvinyl alcohol.

[0052] According to embodiments of the present invention, in the above-mentioned coating film, the plasticizer may be a substance capable of increasing the plasticity of the polymer, and is preferably one or more of glyceride triacetate, glyceride citrate, glyceride, dibutyl phthalate, and diethyl phthalate.

[0053] In one embodiment, the polyethylene glycol is polyethylene glycol 4000.

[0054] In one embodiment, the coating film comprises cellulose acetate and polyethylene glycol 4000.

[0055] In one embodiment, the coating film may be a fully formulated cellulose acetate coating premix (Opadry® CA) provided by Colorcon.

[0056] According to embodiments of the present invention, the sacubitril-valsartan sodium sustained-release composition of the present invention can be subjected to dissolution experiments using the USP II method at a rotation speed of 50 rpm in 900 mL of pH 6.8 phosphate buffer, and the 24-hour cumulative release rates of both sacubitril and valsartan can reach 85% or more.

[0057] According to an exemplary embodiment of the present invention, the drug-containing layer core is The formulation consists of 28.25% sacubitril valsartan sodium, 25.00% sorbitol, 21.25% lactose monohydrate, 2.50% sodium chloride, 21.50% hydroxypropyl methylcellulose, 0.50% colloidal silica, and 1.00% magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. Formulation 2 consists of 56.50% sacubitril valsartan sodium, 20.00% sorbitol, 10.00% lactose monohydrate, 1.50% sodium chloride, 10.50% hydroxypropyl methylcellulose, 0.50% colloidal silica, and 1.00% magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. Composition 3 consists of 37.67% sacubitril valsartan sodium, 36.66% sorbitol, 3.67% sodium chloride, 21.00% hydroxypropyl methylcellulose, and 1.00% magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. Formula IV consists of 56.50% sacubitril valsartan sodium, 25.00% sorbitol, 2.50% sodium chloride, 15.00% hydroxypropyl methylcellulose, and 1.00% magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. Formulation V consists of 33.93% sacubitril valsartan sodium, 48.06% polyoxyethylene, 3.00% sodium chloride, 13.81% hydroxypropyl methylcellulose, and 1.20% magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. Formulation VI consists of 67.87% sacubitril valsartan sodium, 24.02% polyoxyethylene, 1.5% sodium chloride, 5.41% hydroxypropyl methylcellulose, and 1.20% magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. Formula 7 consists of 37.70% sacubitril valsartan sodium, 38.63% copovidone, 18.67% hydroxyethylcellulose, 2.33% talc powder, 0.67% colloidal silica, and 2.00% magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. Formula 8 consists of 75.40% sacubitril valsartan sodium, 11.60% copovidone, 8.33% hydroxyethylcellulose, 1.00% talc powder, 0.67% colloidal silica, and 3.00% magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. The formulation consists of 40.39% sacubitril valsartan sodium, 26.90% copovidone, 27.00% hydroxyethylcellulose, 2.86% talc powder, 0.71% colloidal silica, and 2.14% magnesium stearate. The above percentages represent the mass percentage of each component relative to the total mass of the drug-containing core. The formulation consists of 75.40% sacubitril valsartan sodium, 19.93% polyoxyethylene, 1.00% talc powder, 0.67% colloidal silica, and 3.00% magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. Formula 11 consists of 37.70% sacubitril valsartan sodium, 28.20% copovidone, 28.66% hydroxyethylcellulose, 2.67% talc powder, 0.67% colloidal silica, 2.00% magnesium stearate, and 0.10% yellow iron oxide. The above percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. Formula 12 consists of 75.40% sacubitril valsartan sodium, 6.83% copovidone, 12.00% hydroxyethylcellulose, 2.67% talc powder, 0.67% colloidal silica, 2.33% magnesium stearate, and 0.10% yellow iron oxide. The above percentages represent the mass percentage of each component relative to the total mass of the drug-containing core. Any one of these combinations is acceptable.

[0058] According to an exemplary embodiment of the present invention, the booster layer core is The composition consists of 65.86% polyoxyethylene, 31.74% sodium chloride, 1.20% red iron oxide, and 1.20% magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the booster layer core. The composition is 73.00% polyoxyethylene, 20.00% copovidone, 1.00% red iron oxide, 5.00% sodium chloride, and 1.00% magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the booster layer core. The composition is 60.83% polyoxyethylene, 8.33% copovidone, 29.17% sodium chloride, 0.83% red iron oxide, and 0.84% ​​magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the booster layer core. The composition is 82.00% polyoxyethylene, 10.00% copovidone, 5.00% sodium chloride, 1.00% red iron oxide, and 2.00% magnesium stearate. The above percentages represent the mass percentage of each composition relative to the total mass of the booster layer core. The composition is 63.00% polyoxyethylene, 10.00% copovidone, 25.00% sodium chloride, 1.00% red iron oxide, and 1.00% magnesium stearate. The above percentages represent the mass percentage of each component relative to the total mass of the booster layer core. It is one of the following combinations.

[0059] According to an exemplary embodiment of the present invention, the coating is The coating consists of 9.00% cellulose acetate and 1.00% polyethylene glycol 4000, where the above percentages represent the mass percentage of each composition relative to the total mass of the tablet core. The coating solvent is acetone and water, for example, the mass ratio of acetone to water is 9:1, and the solid content of the coating solution is 5%, which is the percentage of the total mass of solid matter relative to the total mass of the coating solution. The coating consists of 7.20% cellulose acetate and 0.80% polyethylene glycol 4000, where the above percentages represent the mass percentage of each composition relative to the total mass of the tablet core. The coating solvent is acetone and water, for example, the mass ratio of acetone to water is 9:1, and the solid content of the coating solution is 5%, which is the percentage of the total mass of solid material relative to the total mass of the coating solution.

[0060] Coating 3 consists of 6% cellulose acetate and 3% polyethylene glycol 4000, where the above percentages represent the mass percentage of each composition relative to the total mass of the tablet core. The coating solvent is acetone and water, for example, the mass ratio of acetone to water is 9:1, and the solid content of the coating solution is 5%, which is the percentage of the total mass of solid matter relative to the total mass of the coating solution. It is one of the following compositions.

[0061] In one embodiment, the coating solution is a mixed solution of a coating solvent, cellulose acetate, and polyethylene glycol 4000.

[0062] The above-mentioned tablet core consists of a drug-containing layer core and a booster layer core. If the booster layer core is not included, the tablet core consists solely of the drug-containing layer core.

[0063] The present invention further provides a method for producing the sustained-release composition described above, The present invention provides a manufacturing method comprising the steps of: mixing the composition of the drug-containing layer core individually and then pressurizing it to obtain the drug-containing layer core (the manufacturing process may include direct pressurization of powder, dry granulation, wet granulation, etc.); and coating the drug-containing layer core (semipermeable coating) and then creating holes on one side of the drug-containing layer to obtain the sacubitril valsartan sodium sustained-release composition.

[0064] In one embodiment, the above manufacturing method specifically includes the following steps: Step 1) After sieving and mixing the components of the drug-containing layer core other than the lubricant, the mixture is further mixed with the lubricant to obtain the drug-containing layer mixture. Alternatively, the drug-containing layer core, excluding the flow promoter and lubricant, is sieved and mixed, and then further mixed with the flow promoter and lubricant to obtain the drug-containing layer mixture.

[0065] Step 2) The drug-containing layer mixture obtained in Step 1 is mixed with a lubricant, compressed into tablets, and a drug-containing core is obtained.

[0066] In step 3), the drug-containing layer core obtained in step 2) is coated and aged to obtain coated tablets.

[0067] Step 4) The coated tablets obtained in Step 3) are perforated to obtain sacubitril valsartan sodium sustained-release tablets.

[0068] According to embodiments of the present invention, in step 1), the sieve may be a 60-mesh sieve or a 40-mesh sieve.

[0069] According to embodiments of the present invention, in step 1), the mixing may be performed in a mixer, for example, a mixing tank. The mixing speed may be 18 r / min, and the mixing time may be 1 min to 2 h, for example, 20 min.

[0070] According to an embodiment of the present invention, in step 2), the hardness of the drug-containing core is 100 N to 160 N.

[0071] According to embodiments of the present invention, in step 3), the temperature of the coating is preferably 25°C to 45°C, for example, 30°C.

[0072] According to embodiments of the present invention, in step 3), the coating preferably has a weight increase of 6% to 20%, where the percentage is (weight of sacubitril valsartan sodium coated tablet - weight of drug-containing layer core) / weight of drug-containing layer core × 100%.

[0073] According to embodiments of the present invention, in step 3), the aging temperature is preferably 20°C to 60°C, for example, 45°C.

[0074] According to an embodiment of the present invention, in step 3), the aging time is preferably 10 to 30 hours, for example, 24 hours.

[0075] According to embodiments of the present invention, in step 4), the hole may be drilled at the center of one side of the drug-containing layer. The diameter of the hole may be 0.4 mm to 0.7 mm.

[0076] The present invention further provides a method for producing a sustained-release composition, comprising: mixing the composition of both the drug-containing layer core and the booster layer core separately, then pressurizing them to obtain a double core (the production process for the mixed powder of each layer may be direct pressurization of the powder, dry granulation, wet granulation, etc.); and after coating the double core (semipermeable membrane coating), creating a hole on one side of the drug-containing layer to obtain the sacubitril valsartan sodium sustained-release composition.

[0077] In one embodiment, the above manufacturing method specifically includes the following steps: Step A1) The drug-containing layer core is mixed by sieving the components other than the lubricant, and then mixed with the lubricant to obtain the drug-containing layer mixture.

[0078] Step A2) After sieving and mixing the components of the booster layer core other than the lubricant, the mixture is further mixed with the lubricant to obtain the booster layer mixture.

[0079] The drug-containing layer mixture obtained in step A3) and step A1) and the booster layer mixture obtained in step A2) are compressed into tablets to obtain a drug-containing core.

[0080] The drug-containing cores obtained in steps A4) and A3) are coated and aged to obtain coated tablets.

[0081] In step A5), a hole is made in one side of the drug-containing layer of the coated tablet obtained in step A4) to obtain a sacubitril valsartan sodium sustained-release tablet.

[0082] According to embodiments of the present invention, in steps A1) and A2), the sieve may be a 40-mesh or 60-mesh sieve.

[0083] According to embodiments of the present invention, in steps A1) and A2), the mixing may be carried out in a mixer, for example, a mixing tank. The mixing speed may be 18 r / min, and the mixing time may be 1 min to 2 h, for example, 5 min, 10 min, or 15 min.

[0084] According to embodiments of the present invention, in step A4), the temperature of the coating is preferably 25°C to 45°C, for example, 30°C.

[0085] According to embodiments of the present invention, in step A4), the coating preferably has a weight increase of 6% to 20%, where the percentage is (weight of sacubitril valsartan sodium coated tablet - weight of drug-containing core) / weight of drug-containing core × 100%.

[0086] According to an embodiment of the present invention, in step A4), the aging temperature is preferably 20°C to 60°C, for example, 45°C.

[0087] According to an embodiment of the present invention, in step A4), the aging time is preferably 10 to 30 hours, for example, 24 hours.

[0088] According to embodiments of the present invention, in step A5), the hole may be drilled at the center of the drug-containing surface. For example, the diameter of the hole may be 0.4 mm to 0.7 mm.

[0089] The present invention further provides a sacubitril valsartan sodium sustained-release formulation comprising the above-mentioned sacubitril valsartan sodium sustained-release composition.

[0090] According to embodiments of the present invention, the sacubitril valsartan sodium sustained-release formulation may be a sustained-release tablet, a sustained-release micropellet, a sustained-release capsule, or the like.

[0091] The present invention further provides applications of the sacubitril valsartan sustained-release composition or the sacubitril valsartan sustained-release formulation in the manufacture of drugs for treating and / or preventing chronic heart failure with reduced ejection fraction.

[0092] The present invention further provides a method for treating and / or preventing chronic heart failure with reduced ejection fraction, comprising administering an effective amount of the sacubitril valsartan sustained-release formulation to a patient in need thereof.

[0093] The reagents and raw materials used in this invention are all commercially available.

[0094] Beneficial effects of the present invention: This invention provides a sacubitril-valsartan sodium sustained-release composition, a method for producing the same, and its applications, which differ from the prior art in that it has a good sustained-release effect, a gentle release, and good compliance in patients with chronic heart failure. The sacubitril-valsartan sodium sustained-release composition of this invention has a drug release behavior that is not affected by factors such as pH of the medium environment, gastrointestinal motility, and food, has a good in vitro-in vivo correlation, can release sacubitril and valsartan sodium synchronously and gently within 24 hours, and can achieve a relatively good therapeutic effect. Compared to conventional immediate-release formulations, its advantages are as follows: (1) it can reduce the number of doses, achieve a good therapeutic effect through sustained-release action, and improve patient compliance; (2) it is advantageous for improving medication compliance in patients who have difficulty swallowing, such as the elderly or children; (3) it prevents patients from arbitrarily discontinuing medication, preventing disease recurrence and progression of malignant complications; and (4) it can be administered once a day, with an appropriate strength selected according to clinical symptoms, has fewer doses, is easy to administer, and has relatively low toxicity and side effects.

[0095] [Brief description of the drawing] [Figure 1] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example I-1.

[0096] [Figure 2] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example I-2.

[0097] [Figure 3] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example I-3.

[0098] [Figure 4] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example I-4.

[0099] [Figure 5] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example I-5.

[0100] [Figure 6] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example I-6.

[0101] [Figure 7] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example II-1.

[0102] [Figure 8] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example II-2.

[0103] [Figure 9] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example II-3.

[0104] [Figure 10] This figure shows the elution curves of sacubitril and valsartan in an acetate buffer solution at pH 4.5 in Example II-3.

[0105] [Figure 11] This figure shows the elution curves of sacubitril and valsartan in aqueous solution in Example II-3.

[0106] [Figure 12] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example II-4.

[0107] [Figure 13] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example II-5.

[0108] [Figure 14] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example II-6.

[0109] [Figure 15] This figure shows the elution curves of sacubitril and valsartan in an acetate buffer solution at pH 4.5 in Example II-6.

[0110] [Figure 16] This figure shows the elution curves of sacubitril and valsartan in aqueous solution in Example II-6.

[0111] [Figure 17] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example II-7.

[0112] [Figure 18] This figure shows the elution curves of sacubitril and valsartan in a phosphate buffer solution at pH 6.8 in Example II-8.

[0113] [Modes for carrying out the invention] The technical aspects of the present invention will be described in more detail below, in accordance with specific embodiments. The embodiments described below are merely illustrative and interpretable to illustrate the present invention, and should not be interpreted as limiting the scope of the claims. Any technology realized based on the above-described aspects of the present invention falls within the scope of the claims according to the present invention.

[0114] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be manufactured by known methods.

[0115] Dissolution experiment: The sacubitril valsartan sodium sustained-release composition of the present invention was subjected to an dissolution experiment using the USP 2 method at a rotation speed of 50 rpm in 900 mL of pH 6.8 phosphate buffer.

[0116] Examples I-1~2

[0117] [Table 1]

[0118] Manufacturing process: The above sacubitril valsartan sodium was sieved through a 60-mesh sieve, and sorbitol and colloidal silica were sieved through a 40-mesh sieve to remove aggregates.

[0119] Step 1: The above formulation of sacubitril valsartan sodium, sorbitol, lactose monohydrate, sodium chloride, and hydroxypropyl methylcellulose was placed in a mixing vessel, the mixing speed was set to 18 r / min, and the mixture was mixed for 20 minutes to obtain a drug-containing layer mixture.

[0120] Step 2: The drug-containing layer mixture obtained in Step 1 was mixed with colloidal silica, the mixing speed was set to 18 r / min, and the mixture was mixed for 5 minutes. Then magnesium stearate was added, the mixing speed was set to 18 r / min, and the mixture was mixed for another 5 minutes. Next, the mixture was placed in a rotary press and a drug-containing core with a hardness of 100 N to 160 N and a slightly curved shape was pressed into place.

[0121] Step 3: Prepare the sustained-release coating solution according to the following steps: Add purified water to a flask and stir with a magnetic stirrer. Add acetone during the stirring process, and after adding all of it, stir for 5 minutes to mix uniformly. Then, gradually add Opadry® CA and continue stirring for 30 to 120 minutes until completely dissolved to obtain the sustained-release coating solution.

[0122] The drug-containing core obtained in Step 2 is coated with the sustained-release coating solution described above, and the coating is performed using a coating kettle at a rotational speed of 8 rpm to 15 rpm with an airflow of 30 m³. 3 / h~120 m 3The process involved controlling the flow rate to 1 / h, controlling the bed temperature to 25°C to 35°C, setting the ejection speed to 5 rpm to 20 rpm, and continuing the coating until the weight increase of the coating reached 10.3% and 10.1%, respectively. The coating was then dried for 5 to 10 minutes at a bed temperature of 30°C to 35°C, the tablets were removed, and then placed in a forced-air drying box at a set temperature of 45°C for aging. After 24 hours, coated tablets were obtained.

[0123] Step 4: Laser perforation was performed on the coated tablets obtained in Step 3, and pore sizes were 0.4 mm to 0.7 mm, resulting in sacubitril valsartan sodium sustained-release tablets.

[0124] The dissolution data for sacubitril valsartan sodium sustained-release tablets manufactured using the above steps are shown in Table 1 and Figures 1-2.

[0125] [Table 2]

[0126] Examples I-3~4

[0127] [Table 3]

[0128] Manufacturing process: The above sacubitril valsartan sodium was sieved through a 60-mesh sieve, and sorbitol was sieved through a 40-mesh sieve to remove aggregates.

[0129] Step 1: The above formulation of sacubitril valsartan sodium, sorbitol, sodium chloride, and hydroxypropyl methylcellulose was placed in a mixing vessel, the mixing speed was set to 18 r / min, and the mixture was mixed for 20 minutes. Then, magnesium stearate was added internally, the mixing speed was set to 18 r / min, and the mixture was mixed for 5 minutes to obtain a drug-containing layer mixture.

[0130] Step 2: The drug-containing layer mixture obtained in Step 1 was placed in a dry granulator, the equipment parameters were adjusted so that it could be pressed into large tablets with a certain hardness, the mixture was then sized using a 1.0 mm sieve, and then mixed with magnesium stearate. The mixing speed was set to 18 r / min and mixed for 5 minutes. Next, the mixture was placed in a rotary press and the lightly curved, circular drug-containing core was pressed.

[0131] Step 3: Prepare the sustained-release coating solution according to the following steps: Add purified water to a flask and stir with a magnetic stirrer. Add acetone during the stirring process, and after adding all of it, stir for 5 minutes to mix uniformly. Then, gradually add Opadry® CA and continue stirring for 30 to 120 minutes until completely dissolved to obtain the sustained-release coating solution.

[0132] The drug-containing core obtained in Step 2 is coated with the sustained-release coating solution described above, and the coating is performed using a coating kettle at a rotational speed of 8 rpm to 15 rpm with an airflow of 30 m³. 3 / h~120 m 3 The process involved controlling the flow rate to 25°C to 35°C, setting the ejection speed to 5 rpm to 20 rpm, and continuing the coating until the weight increase of the coating reached 7.9% and 8.2%, respectively. The coating was then dried for 5 to 10 minutes at a bed temperature of 30°C to 35°C, the tablets were removed, and then placed in a forced-air drying box at a set temperature of 45°C for aging. After 24 hours, coated tablets were obtained.

[0133] Step 4: Laser perforation was performed on the coated tablets obtained in Step 3, and pore sizes were 0.4 mm to 0.7 mm, resulting in sacubitril valsartan sodium sustained-release tablets.

[0134] The dissolution data for sacubitril valsartan sodium sustained-release tablets manufactured using the above steps are shown in Table 2 and Figures 3-4.

[0135] [Table 4]

[0136] Examples I-5~6

[0137] [Table 5]

[0138] Manufacturing process: The above sacubitril valsartan sodium was processed by passing it through a 60-mesh sieve.

[0139] Step 1: In the above formulation, sacubitril valsartan sodium, polyoxyethylene, sodium chloride, and hydroxypropyl methylcellulose were placed in a mixing pot, the mixing speed was set to 18 r / min, and the mixture was mixed for 20 minutes. Then, magnesium stearate from the drug-containing layer was added, the mixing speed was set to 18 r / min, and the mixture was mixed for 5 minutes to obtain the drug-containing layer mixture.

[0140] Step 2: The booster layer of polyoxyethylene, sodium chloride, and red iron oxide in the above formulation was placed in a mixing pot, the mixing speed was set to 18 r / min, and it was mixed for 10 minutes. Then, magnesium stearate from the booster layer was added, the mixing speed was set to 18 r / min, and it was mixed for 5 minutes to obtain the booster layer mixture.

[0141] Step 3: The drug-containing layer mixture obtained in Step 1 and the booster layer mixture obtained in Step 2 were placed in a rotary press. The equipment parameters were adjusted so that the weight of the drug-containing layer was 333 mg, the weight of the booster layer was 167 mg, the total weight was 500 mg, and the hardness was 100 N to 180 N. A light arc-shaped drug-containing core was then pressed.

[0142] Step 4: Prepare the sustained-release coating solution according to the following steps: Add purified water to a flask and stir with a magnetic stirrer. Add acetone during the stirring process, and after adding all of it, stir for 5 minutes to mix uniformly. Then, gradually add Opadry® CA and continue stirring for 30 to 90 minutes until completely dissolved to obtain the sustained-release coating solution.

[0143] The drug-containing core obtained in step 3 is coated with the above sustained-release coating solution, and 8 The machine rotated at a rotational speed of rpm to 15 rpm, the bed temperature was controlled to 25°C to 35°C, and the ejection speed was set to a range of 5 rpm to 20 rpm. The coating was continued until the weight increase of the coating reached 8.2% and 8.0%, at which point the ejection was stopped. The tablets were then dried for 5 to 10 minutes at a bed temperature of 30°C to 35°C, removed, and placed in a forced-air drying box at a set temperature of 45°C for aging. After 24 hours, coated tablets were obtained.

[0144] Step 5: Laser perforation was performed on the coated tablets obtained in Step 4. The perforated surface was the drug-containing layer (white opposing surface), and the pore size was 0.4 mm to 0.7 mm, resulting in sacubitril valsartan sodium sustained-release tablets.

[0145] The dissolution data for sacubitril valsartan sodium sustained-release tablets manufactured using the above steps are shown in Table 1 and Figures 5-6.

[0146] [Table 6]

[0147] Example II-1

[0148] [Table 7]

[0149] Manufacturing process: The above sacubitril valsartan sodium was processed by passing it through a 60-mesh sieve.

[0150] Step 1: In the above formulation, the drug-containing layer of sacubitril valsartan sodium, copovidone, hydroxyethylcellulose, colloidal silica, and talc powder were placed in a mixing vessel, the mixing speed was set to 18 r / min, and the mixture was mixed for 20 minutes. The mixed material was then granulated using dry granulation, and finally, the magnesium stearate of the drug-containing layer was added, the mixing speed was set to 18 r / min, and the mixture was mixed for 5 minutes to obtain the drug-containing layer mixture.

[0151] Step 2: The booster layer of polyoxyethylene, sodium chloride, copovidone, and red iron oxide in the above formulation was placed in a mixing pot, the mixing speed was set to 18 r / min, and it was mixed for 10 minutes. Then, magnesium stearate from the booster layer was added, the mixing speed was set to 18 r / min, and it was mixed for 5 minutes to obtain the booster layer mixture.

[0152] Step 3: The drug-containing layer mixture obtained in Step 1 and the booster layer mixture obtained in Step 2 were placed in a rotary press. The equipment parameters were adjusted so that the weight of the drug-containing layer was 300 mg, the weight of the booster layer was 100 mg, the total weight was 400 mg, and the hardness was 100 N to 180 N. A light arc-shaped drug-containing core was then pressed.

[0153] Step 4: Prepare the sustained-release coating solution according to the following steps: Add purified water to a flask and stir with a magnetic stirrer. Add acetone during the stirring process, and after adding all of it, stir for 5 minutes to mix uniformly. Then, gradually add Opadry® CA and continue stirring for 30 to 90 minutes until completely dissolved to obtain the sustained-release coating solution.

[0154] The drug-containing core obtained in step 3 is coated with the above sustained-release coating solution, and 8 The machine rotates at a rotation speed of rpm to 15 rpm, controls the bed temperature to 25°C to 35°C, sets the spray speed to a range of 5 rpm to 20 rpm, continues coating until the coating weight increase reaches 8.0% to 11.0%, then stops spraying, and finally dries for 5 to 10 minutes at a bed temperature of 30°C to 35°C. The tablets were removed and then placed in a forced-air drying box at a set temperature of 45°C for aging, and coated tablets were obtained after 24 hours.

[0155] Step 5: Laser perforation was performed on the coated tablets obtained in Step 4. The perforated surface was the drug-containing layer (white opposing surface), and the pore size was 0.4 mm to 0.7 mm, resulting in sacubitril valsartan sodium sustained-release tablets.

[0156] The dissolution data in phosphate at pH 6.8 for sacubitril valsartan sodium sustained-release tablets manufactured using the above steps are shown in Table 4 and Figure 7.

[0157] [Table 8]

[0158] Example II-2

[0159] [Table 9]

[0160] Manufacturing process: The above sacubitril valsartan sodium was processed by passing it through a 60-mesh sieve.

[0161] Step 1: Place all raw materials and auxiliary materials except magnesium stearate, which is the lubricant for the drug-containing layer in the above formulation, into a mixing pot, set the mixing speed to 18 r / min, and mix for 20 minutes. Further granulation of the mixed materials is performed by dry granulation. Finally, the magnesium stearate for the drug-containing layer is added, set the mixing speed to 18 r / min, and mix for 5 minutes to obtain the drug-containing layer mixture.

[0162] Step 2: The booster layer of polyoxyethylene, sodium chloride, copovidone, and red iron oxide in the above formulation was placed in a mixing pot, the mixing speed was set to 18 r / min, and it was mixed for 10 minutes. Then, magnesium stearate from the booster layer was added, the mixing speed was set to 18 r / min, and it was mixed for 5 minutes to obtain the booster layer mixture.

[0163] Step 3: The drug-containing layer mixture obtained in Step 1 and the booster layer mixture obtained in Step 2 were placed in a rotary press. The equipment parameters were adjusted so that the weight of the drug-containing layer was 280 mg, the weight of the booster layer was 120 mg, the total weight was 400 mg, and the hardness was 100 N to 180 N. A light arc-shaped drug-containing core was then pressed.

[0164] Step 4: Prepare the sustained-release coating solution according to the following steps: Add purified water to a flask and stir with a magnetic stirrer. Add acetone during the stirring process, and after adding all of it, stir for 5 minutes to mix uniformly. Then, gradually add Opadry® CA and continue stirring for 30 to 90 minutes until completely dissolved to obtain the sustained-release coating solution.

[0165] The drug-containing core obtained in step 3 is coated with the above sustained-release coating solution, and 8 The machine rotates at a rotation speed of rpm to 15 rpm, controls the bed temperature to 25°C to 35°C, sets the spray speed to a range of 5 rpm to 20 rpm, continues coating until the coating weight increase reaches 8.0% to 11.0%, then stops spraying, and finally dries for 5 to 10 minutes at a bed temperature of 30°C to 35°C. The tablets were removed and then placed in a forced-air drying box at a set temperature of 45°C for aging, and coated tablets were obtained after 24 hours.

[0166] Step 5: Laser perforation was performed on the coated tablets obtained in Step 4. The perforated surface was the drug-containing layer (white opposing surface), and the pore size was 0.4 mm to 0.7 mm, resulting in sacubitril valsartan sodium sustained-release tablets.

[0167] The dissolution data in phosphate at pH 6.8 for sacubitril valsartan sodium sustained-release tablets manufactured using the above steps are shown in Table 5 and Figure 8.

[0168] [Table 10]

[0169] Example II-3

[0170] [Table 11]

[0171] Manufacturing process: The above sacubitril valsartan sodium was processed by passing it through a 60-mesh sieve.

[0172] Step 1: In the above formulation, sacubitril valsartan sodium, copovidone, hydroxyethylcellulose, yellow iron oxide, colloidal silica, and talc powder for the drug-containing layer were placed in a mixing pot, the mixing speed was set to 18 r / min, and the mixture was mixed for 20 minutes. The mixed materials were then granulated by dry granulation, and finally, magnesium stearate for the drug-containing layer was added, the mixing speed was set to 18 r / min, and the mixture was mixed for 5 minutes to obtain the drug-containing layer mixture.

[0173] Step 2: The booster layer of polyoxyethylene, sodium chloride, copovidone, and red iron oxide in the above formulation was placed in a mixing pot, the mixing speed was set to 18 r / min, and it was mixed for 10 minutes. Then, magnesium stearate from the booster layer was added, the mixing speed was set to 18 r / min, and it was mixed for 5 minutes to obtain the booster layer mixture.

[0174] Step 3: The drug-containing layer mixture obtained in Step 1 and the booster layer mixture obtained in Step 2 were placed in a rotary press. The equipment parameters were adjusted so that the weight of the drug-containing layer was 300 mg, the weight of the booster layer was 100 mg, the total weight was 400 mg, and the hardness was 100 N to 180 N. A light arc-shaped drug-containing core was then pressed.

[0175] Step 4: Prepare the sustained-release coating solution according to the following steps: Add purified water to a flask and stir with a magnetic stirrer. Add acetone during the stirring process, and after adding all of it, stir for 5 minutes to mix uniformly. Then, gradually add Opadry® CA and continue stirring for 30 to 90 minutes until completely dissolved to obtain the sustained-release coating solution.

[0176] The drug-containing core obtained in step 3 is coated with the above sustained-release coating solution, and 8 The machine rotates at a rotation speed of rpm to 15 rpm, controls the bed temperature to 25°C to 35°C, sets the ejection speed to a range of 5 rpm to 20 rpm, continues coating until the coating weight increase reaches 8.0% to 14.0%, then stops ejecting, and finally dries for 5 to 10 minutes at a bed temperature of 30°C to 35°C. The tablets were removed and then placed in a forced-air drying box at a set temperature of 45°C for aging, and coated tablets were obtained after 24 hours.

[0177] Step 5: Laser perforation was performed on the coated tablets obtained in Step 4. The perforated surface was the drug-containing layer (white opposing surface), and the pore size was 0.4 mm to 0.7 mm, resulting in sacubitril valsartan sodium sustained-release tablets.

[0178] Dissolution data for sacubitril valsartan sodium sustained-release tablets manufactured using the above steps in phosphate at pH 6.8, water, and acetate at pH 4.5 are shown in Table 6 and Figures 9, 11, and 10.

[0179] [Table 12]

[0180] Example II-4

[0181] [Table 13]

[0182] Manufacturing process: The above sacubitril valsartan sodium was processed by passing it through a 60-mesh sieve.

[0183] Step 1: In the above formulation, the drug-containing layer of sacubitril valsartan sodium, copovidone, hydroxyethylcellulose, colloidal silica, and talc powder were placed in a mixing vessel, the mixing speed was set to 18 r / min, and the mixture was mixed for 20 minutes. The mixed material was then granulated using dry granulation, and finally, the magnesium stearate of the drug-containing layer was added, the mixing speed was set to 18 r / min, and the mixture was mixed for 5 minutes to obtain the drug-containing layer mixture.

[0184] Step 2: The booster layer of polyoxyethylene, sodium chloride, copovidone, and red iron oxide in the above formulation was placed in a mixing pot, the mixing speed was set to 18 r / min, and it was mixed for 10 minutes. Then, magnesium stearate from the booster layer was added, the mixing speed was set to 18 r / min, and it was mixed for 5 minutes to obtain the booster layer mixture.

[0185] Step 3: The drug-containing layer mixture obtained in Step 1 and the booster layer mixture obtained in Step 2 were placed in a rotary press. The equipment parameters were adjusted so that the weight of the drug-containing layer was 300 mg, the weight of the booster layer was 100 mg, the total weight was 400 mg, and the hardness was 100 N to 180 N. A light arc-shaped drug-containing core was then pressed.

[0186] Step 4: Prepare the sustained-release coating solution according to the following steps: Add purified water to a flask and stir with a magnetic stirrer. Add acetone during the stirring process, and after adding all of it, stir for 5 minutes to mix uniformly. Then, gradually add Opadry® CA and continue stirring for 30 to 90 minutes until completely dissolved to obtain the sustained-release coating solution.

[0187] The drug-containing core obtained in step 3 is coated with the above sustained-release coating solution, and 8 The machine rotates at a rotation speed of rpm to 15 rpm, controls the bed temperature to 25°C to 35°C, sets the spray speed to a range of 5 rpm to 20 rpm, continues coating until the coating weight increase reaches 8.0% to 11.0%, then stops spraying, and finally dries for 5 to 10 minutes at a bed temperature of 30°C to 35°C. The tablets were removed and then placed in a forced-air drying box at a set temperature of 45°C for aging, and coated tablets were obtained after 24 hours.

[0188] Step 5: Laser perforation was performed on the coated tablets obtained in Step 4. The perforated surface was the drug-containing layer (white opposing surface), and the pore size was 0.4 mm to 0.7 mm, resulting in sacubitril valsartan sodium sustained-release tablets.

[0189] The dissolution data in phosphate at pH 6.8 for sacubitril valsartan sodium sustained-release tablets manufactured using the above steps are shown in Table 7 and Figure 12.

[0190] [Table 14]

[0191] Example II-5

[0192] [Table 15]

[0193] Manufacturing process: The above sacubitril valsartan sodium was processed by passing it through a 60-mesh sieve.

[0194] Step 1: Place all raw materials and auxiliary materials except magnesium stearate, which is the lubricant for the drug-containing layer in the above formulation, into a mixing pot, set the mixing speed to 18 r / min, and mix for 20 minutes. Further granulation of the mixed materials is performed by dry granulation. Finally, the magnesium stearate for the drug-containing layer is added, set the mixing speed to 18 r / min, and mix for 5 minutes to obtain the drug-containing layer mixture.

[0195] Step 2: The booster layer of polyoxyethylene, sodium chloride, copovidone, and red iron oxide in the above formulation was placed in a mixing pot, the mixing speed was set to 18 r / min, and it was mixed for 10 minutes. Then, magnesium stearate from the booster layer was added, the mixing speed was set to 18 r / min, and it was mixed for 5 minutes to obtain the booster layer mixture.

[0196] Step 3: The drug-containing layer mixture obtained in Step 1 and the booster layer mixture obtained in Step 2 were placed in a rotary press, and tablets were compressed according to the target weight of the drug-containing layer and booster layer. The equipment parameters were adjusted to achieve a total weight of 400 mg and a hardness of 100 N to 180 N, and a light arc-shaped drug-containing core was pressed.

[0197] Step 4: Prepare the sustained-release coating solution according to the following steps: Add purified water to a flask and stir with a magnetic stirrer. Add acetone during the stirring process, and after adding all of it, stir for 5 minutes to mix uniformly. Then, gradually add Opadry® CA and continue stirring for 30 to 90 minutes until completely dissolved to obtain the sustained-release coating solution.

[0198] The drug-containing core obtained in step 3 is coated with the above sustained-release coating solution, and 8 The machine rotates at a rotation speed of rpm to 15 rpm, controls the bed temperature to 25°C to 35°C, sets the spray speed to a range of 5 rpm to 20 rpm, continues coating until the coating weight increase reaches 8.0% to 11.0%, then stops spraying, and finally dries for 5 to 10 minutes at a bed temperature of 30°C to 35°C. The tablets were removed and then placed in a forced-air drying box at a set temperature of 45°C for aging, and coated tablets were obtained after 24 hours.

[0199] Step 5: Laser perforation was performed on the coated tablets obtained in Step 4. The perforated surface was the drug-containing layer (white opposing surface), and the pore size was 0.4 mm to 0.7 mm, resulting in sacubitril valsartan sodium sustained-release tablets.

[0200] The dissolution data in phosphate at pH 6.8 for sacubitril valsartan sodium sustained-release tablets manufactured using the above steps are shown in Table 8 and Figure 13.

[0201] [Table 16]

[0202] Example II-6

[0203] [Table 17]

[0204] Manufacturing process: The above sacubitril valsartan sodium was processed by passing it through a 60-mesh sieve.

[0205] Step 1: In the above formulation, sacubitril valsartan sodium, copovidone, hydroxyethylcellulose, yellow iron oxide, colloidal silica, and talc powder for the drug-containing layer were placed in a mixing pot, the mixing speed was set to 18 r / min, and the mixture was mixed for 20 minutes. The mixed materials were then granulated by dry granulation, and finally, magnesium stearate for the drug-containing layer was added, the mixing speed was set to 18 r / min, and the mixture was mixed for 5 minutes to obtain the drug-containing layer mixture.

[0206] Step 2: The booster layer of polyoxyethylene, sodium chloride, copovidone, and red iron oxide in the above formulation was placed in a mixing pot, the mixing speed was set to 18 r / min, and it was mixed for 10 minutes. Then, magnesium stearate from the booster layer was added, the mixing speed was set to 18 r / min, and it was mixed for 5 minutes to obtain the booster layer mixture.

[0207] Step 3: The drug-containing layer mixture obtained in Step 1 and the booster layer mixture obtained in Step 2 were placed in a rotary press. The equipment parameters were adjusted so that the weight of the drug-containing layer was 300 mg, the weight of the booster layer was 100 mg, the total weight was 400 mg, and the hardness was 100 N to 180 N. A light arc-shaped drug-containing core was then pressed.

[0208] Step 4: Prepare the sustained-release coating solution according to the following steps: Add purified water to a flask and stir with a magnetic stirrer. Add acetone during the stirring process, and after adding all of it, stir for 5 minutes to mix uniformly. Then, gradually add Opadry® CA and continue stirring for 30 to 90 minutes until completely dissolved to obtain the sustained-release coating solution.

[0209] The drug-containing core obtained in step 3 is coated with the above sustained-release coating solution, and 8 The machine rotates at a rotation speed of rpm to 15 rpm, controls the bed temperature to 25°C to 35°C, sets the ejection speed to a range of 5 rpm to 20 rpm, continues coating until the coating weight increase reaches 8.0% to 14.0%, then stops ejecting, and finally dries for 5 to 10 minutes at a bed temperature of 30°C to 35°C. The tablets were removed and then placed in a forced-air drying box at a set temperature of 45°C for aging, and coated tablets were obtained after 24 hours.

[0210] Step 5: Laser perforation was performed on the coated tablets obtained in Step 4. The perforated surface was the drug-containing layer (white opposing surface), and the pore size was 0.4 mm to 0.7 mm, resulting in sacubitril valsartan sodium sustained-release tablets.

[0211] Dissolution data for sacubitril valsartan sodium sustained-release tablets prepared using the above steps in pH 6.8 phosphate buffer, water, and pH 4.5 acetate media are shown in Table 9 and Figures 14, 16, and 15. This suggests that the sustained-release tablets are released under normal physiological conditions without being affected by environmental media.

[0212] [Table 18]

[0213] Example II-7 Sacubitril valsartan sodium was manufactured as a gastric-staying sustained-release tablet, and the formulation was designed as follows.

[0214] [Table 19]

[0215] Manufacturing process: The above sacubitril valsartan sodium was processed by passing it through a 60-mesh sieve.

[0216] Step 1: Put the raw materials and auxiliary materials other than the lubricant in the above formulation into a mixing kettle, set the mixing speed to 18 r / min, mix for 20 min, add magnesium stearate in the amount of the formulation, set the mixing speed to 18 r / min, and mix for 5 min to obtain a material mixture.

[0217] Step 2: Place the mixture obtained in Step 1 in a rotary press, adjust the equipment parameters, and tableting is carried out so that the tablet weight is 1000 mg and the hardness is 140 N - 220 N.

[0218] The dissolution data of the sustained-release tablets of sacubitril valsartan sodium produced in the above steps in a phosphate buffer solution with pH 6.8 are shown in Table 10 and Figure 17.

[0219]

Table 20

[0220] Example II - 8 Sacubitril valsartan sodium was produced into ordinary gel matrix sustained-release tablets, and the formulation was designed as follows.

[0221]

Table 21

[0222] Manufacturing process: The above sacubitril valsartan sodium was processed by sieving through a 60-mesh sieve.

[0223] Step 1: Put the raw materials and auxiliary materials other than the lubricant in the above formulation into a mixing kettle, set the mixing speed to 18 r / min, mix for 20 min, add magnesium stearate in the amount of the formulation, set the mixing speed to 18 r / min, and mix for 5 min to obtain a material mixture.

[0224] Step 2: The mixture obtained in Step 1 was placed in a rotary press, the equipment parameters were adjusted, and tableting was performed so that the tablet weight was 500 mg and the hardness was 100 N to 180 N.

[0225] The elution data of the sustained-release tablet of sacubitril valsartan sodium produced in the above steps in a phosphate buffer solution with pH 6.8 are shown in Table 11 and Figure 18.

[0226]

Table 22

[0227] From the results of Examples II-7 to II-8, it was found that the gastric retention sustained-release tablets and the ordinary gel matrix sustained-release tablets had a relatively large difference in the release rates of sacubitril and valsartan in in vitro dissolution and could not achieve synchronous release.

[0228] From the results of Examples I-1 to I-6 and Examples II-1 to II-6, in in vitro dissolution, in the osmotic pump dosage form developed according to the present invention, sacubitril and valsartan in the sustained-release tablet of sacubitril valsartan sodium were synchronously released for a long time, met the requirement of once-a-day administration, and the drug release behavior was not affected by the pH of the medium environment.

[0229] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle scope of the present invention shall be included within the scope of the claims of the present invention.

Brief Description of Drawings

[0230] [Figure 1] It shows the dissolution curve diagrams of sacubitril and valsartan in a phosphate buffer solution with pH 6.8 in Example I-1. [Figure 2] It shows the dissolution curve diagrams of sacubitril and valsartan in a phosphate buffer solution with pH 6.8 in Example I-2. [Figure 3] The elution curves for sacubitril and valsartan in a phosphate buffer at pH 6.8 in Example I-3 are shown. [Figure 4] The elution curves for sacubitril and valsartan in a phosphate buffer at pH 6.8 in Example I-4 are shown. [Figure 5] The elution curves for sacubitril and valsartan in a phosphate buffer at pH 6.8 in Example I-5 are shown. [Figure 6] The elution curves for sacubitril and valsartan in a phosphate buffer at pH 6.8 in Example I-6 are shown. [Figure 7] The elution curves of sacubitril and valsartan in a phosphate buffer at pH 6.8 in Example II-1 are shown. [Figure 8] The elution curves for sacubitril and valsartan in a phosphate buffer at pH 6.8 in Example II-2 are shown. [Figure 9] The elution curves of sacubitril and valsartan in a phosphate buffer at pH 6.8 in Example II-3 are shown. [Figure 10] The elution curves for sacubitril and valsartan in an acetate buffer solution at pH 4.5 in Example II-3 are shown. [Figure 11] The elution curves of sacubitril and valsartan in aqueous solution in Example II-3 are shown. [Figure 12] The elution curves for sacubitril and valsartan in a phosphate buffer at pH 6.8 in Example II-4 are shown. [Figure 13] The elution curves of sacubitril and valsartan in a phosphate buffer at pH 6.8 in Example II-5 are shown. [Figure 14] The elution curves of sacubitril and valsartan in a phosphate buffer at pH 6.8 in Example II-6 are shown. [Figure 15] The elution curves for sacubitril and valsartan in an acetate buffer solution at pH 4.5 in Example II-6 are shown. [Figure 16]The elution curves of sacubitril and valsartan in aqueous solution in Example II-6 are shown. [Figure 17] The elution curves for sacubitril and valsartan in a phosphate buffer at pH 6.8 in Example II-7 are shown. [Figure 18] The elution curves for sacubitril and valsartan in a phosphate buffer at pH 6.8 in Example II-8 are shown.

Claims

1. A sustained-release composition of sacubitril valsartan sodium, comprising a drug-containing layer core having a pore on one side of the drug-containing layer, a booster layer core, and a coating film; The drug-containing core comprises a pharmacoactive ingredient and a carrier, the pharmacoactive ingredient being selected from sacubitril valsartan sodium or other pharmaceutically acceptable salts thereof; the content of the pharmacoactive ingredient in the drug-containing core is 10.00% to 80.00%, the content being the mass percentage of the pharmacoactive ingredient relative to the total mass of the drug-containing core; The carrier is a thickener, or a mixture of a thickener and one or more of the following: an osmotic pressure regulator, a swelling agent, a flow promoter, and a lubricant; In the drug-containing layer core, the thickener is one or more of hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, and copovidone; In the drug-containing core, the swelling agent is one or more of polyoxyethylene, carbomer, sodium carboxymethyl starch, crospovidone, and sodium alginate; In the drug-containing layer core, the content of the thickener is 10.00% to 70.00%, and the content is the mass percentage of the thickener relative to the total mass of the drug-containing layer core; In the drug-containing core, the content of the swelling agent is 0.00% to 70.00%, and the content is the mass percentage of the swelling agent relative to the total mass of the drug-containing core; The booster layer core is a swelling agent, or a mixture of a swelling agent and one or more of the following: an osmotic pressure regulator, a colorant, and a lubricant; In the booster layer core, the swelling agent is one or more of hydroxyethylcellulose, copovidone, hydroxypropylmethylcellulose, carbomer, sodium carboxymethyl starch, sodium alginate, and polyoxyethylene; In the booster layer core, the content of the swelling agent is greater than 0% and 90.00% or less, and the content is the mass percentage of the swelling agent relative to the total mass of the booster layer core; The sustained-release composition is a 24-hour sustained-release drug, and the dissolution of sacubitril and valsartan is such that A) 40% or less of the drug active ingredient is dissolved within 1 hour. B) Dissolve 10% to 70% of the drug active ingredient within 6 hours. C) Dissolves 65% or more of the drug active ingredient within 24 hours. It satisfies these three characteristics simultaneously, The dissolution of sacubitril and valsartan is synchronous release. A sustained-release composition of sacubitril valsartan sodium characterized by the following features.

2. The sustained-release composition is a 24-hour sustained-release drug, and the dissolution of sacubitril and valsartan is such that A) 40% or less of the drug active ingredient is dissolved within 2 hours. B) 20% to 75% of the drug active ingredient is eluted within 8 hours. C) Dissolves 65% or more of the drug active ingredient within 24 hours. It satisfies these three characteristics simultaneously, The dissolution of sacubitril and valsartan is synchronous release. The sacubitril valsartan sodium sustained-release composition according to feature 1.

3. The drug-containing layer core further comprises a coloring agent. The sacubitril valsartan sodium sustained-release composition according to feature 1.

4. In the drug-containing core, the osmotic pressure adjusting agent is one or more of the following: sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose, and lactose. In the drug-containing layer core, the coloring agent is one or more selected from red iron oxide, yellow iron oxide, and black iron oxide. In the drug-containing core, the flow promoter is one or more of talc powder, fine silica gel powder, and colloidal silica. In the drug-containing layer core, the lubricant is one or more of the following: metal stearate, stearic acid, talc powder, stearic acid ester, stearoyl fumarate, and fine silica gel powder. In the booster layer core, the osmotic pressure adjusting agent is one or more of the following: sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose, and lactose. In the booster layer core, the coloring agent is one or more of the following: red iron oxide, yellow iron oxide, and black iron oxide. In the booster layer core, the lubricant is one or more selected from metal stearate, stearic acid, talc powder, stearic acid ester, stearoyl fumarate, and fine silica gel powder. The sacubitril valsartan sodium sustained-release composition according to feature 3.

5. In the drug-containing core, the content of the osmotic pressure regulator is 1.00% to 60.00%, and the content is the mass percentage of the osmotic pressure regulator relative to the total mass of the drug-containing core. In the drug-containing core, the content of the flow promoter is 0 to 5.00%, and the content is the mass percentage of the flow promoter relative to the total mass of the drug-containing core. In the drug-containing layer core, the lubricant content is 0.50% to 60.00%, and the content is the mass percentage of the lubricant relative to the total mass of the drug-containing layer core. In the drug-containing layer core, the content of the coloring agent is 0% to 5.00%, and the content is the mass percentage of the lubricant relative to the total mass of the drug-containing layer core. The sacubitril valsartan sodium sustained-release composition according to feature 3.

6. In the booster layer core, the content of the osmotic pressure regulator is 1.00% to 60.00%, and the content is the mass percentage of the osmotic pressure regulator relative to the total mass of the booster layer core. In the booster layer core, the content of the swelling agent is greater than 0% and 80.00% or less, and the content is the mass percentage of the swelling agent relative to the total mass of the booster layer core. In the booster layer core, the content of the coloring agent is 0.10% to 10.00%, and the content is the mass percentage of the coloring agent relative to the total mass of the booster layer core. In the booster layer core, the lubricant content is 0.10% to 10.00%, and the content is the mass percentage of the lubricant relative to the total mass of the booster layer core. The sacubitril valsartan sodium sustained-release composition according to feature 1.

7. The coating film is a semipermeable film, and the semipermeable film comprises one or more of a film-forming material, a pore-forming agent, and a plasticizer, wherein the film-forming material in the coating film is one or more of cellulose acetate, ethylcellulose, phthalic cellulose acetate, polyvinyl acetate, acrylic resin, and methacrylic resin. In the coating film, the pore-forming agent is one or more of polyethylene glycol, hydroxypropyl cellulose, povidone, and polyvinyl alcohol. The sacubitril valsartan sodium sustained-release composition according to claim 3, characterized in that the plasticizer in the coating film is one or more of glyceride triacetate, glyceride citrate, glyceride, dibutyl phthalate, and diethyl phthalate.

8. The drug-containing layer core is Formulation V consists of 33.93% sacubitril valsartan sodium, 48.06% polyoxyethylene, 3.00% sodium chloride, 13.81% hydroxypropyl methylcellulose, and 1.20% magnesium stearate, where the percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. Formulation VI consists of 67.87% sacubitril valsartan sodium, 24.02% polyoxyethylene, 1.5% sodium chloride, 5.41% hydroxypropyl methylcellulose, and 1.20% magnesium stearate, where the percentages represent the mass percentage of each composition relative to the total mass of the drug-containing layer core. Formula 7 consists of 37.70% sacubitril valsartan sodium, 38.63% copovidone, 18.67% hydroxyethylcellulose, 2.33% talc powder, 0.67% colloidal silica, and 2.00% magnesium stearate, where the percentages represent the mass percentage of each composition relative to the total mass of the drug-containing layer core. Formula 8 consists of 75.40% sacubitril valsartan sodium, 11.60% copovidone, 8.33% hydroxyethylcellulose, 1.00% talc powder, 0.67% colloidal silica, and 3.00% magnesium stearate, where the percentages represent the mass percentage of each composition relative to the total mass of the drug-containing layer core. The composition is 40.39% sacubitril valsartan sodium, 26.90% copovidone, 27.00% hydroxyethylcellulose, 2.86% talc powder, 0.71% colloidal silica, and 2.14% magnesium stearate, where the percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. The formulation consists of 75.40% sacubitril valsartan sodium, 19.93% polyoxyethylene, 1.00% talc powder, 0.67% colloidal silica, and 3.00% magnesium stearate, where the percentages represent the mass percentage of each composition relative to the total mass of the drug-containing core. Formula 11 consists of 37.70% sacubitril valsartan sodium, 28.20% copovidone, 28.66% hydroxyethylcellulose, 2.67% talc powder, 0.67% colloidal silica, 2.00% magnesium stearate, and 0.10% yellow iron oxide, where the percentages represent the mass percentage of each composition relative to the total mass of the drug-containing layer core. Formula 12 consists of 75.40% sacubitril valsartan sodium, 6.83% copovidone, 12.00% hydroxyethylcellulose, 2.67% talc powder, 0.67% colloidal silica, 2.33% magnesium stearate, and 0.10% yellow iron oxide, where the percentages represent the mass percentage of each component relative to the total mass of the drug-containing core. Choose one of the following combinations: The aforementioned booster layer core is The composition consists of 65.86% polyoxyethylene, 31.74% sodium chloride, 1.2% red iron oxide, and 1.20% magnesium stearate, where the percentages represent the mass percentage of each composition relative to the total mass of the booster layer core. The composition is 73.00% polyoxyethylene, 20.00% copovidone, 1.00% red iron oxide, 5.00% sodium chloride, and 1.00% magnesium stearate, where the percentages represent the mass percentage of each composition relative to the total mass of the booster layer core. The composition is 60.83% polyoxyethylene, 8.33% copovidone, 29.17% sodium chloride, 0.83% red iron oxide, and 0.84% ​​magnesium stearate, where the percentages represent the mass percentage of each composition relative to the total mass of the booster layer core. The composition is 82.00% polyoxyethylene, 10.00% copovidone, 5.00% sodium chloride, 1.00% red iron oxide, and 2.00% magnesium stearate, where the percentages represent the mass percentage of each composition relative to the total mass of the booster layer core. The composition is 63.00% polyoxyethylene, 10.00% copovidone, 25.00% sodium chloride, 1.00% red iron oxide, and 1.00% magnesium stearate, where the percentages represent the mass percentage of each composition relative to the total mass of the booster layer core. Choose one of the following combinations: The aforementioned coating is The coating consists of 9.00% cellulose acetate and 1.00% polyethylene glycol 4000, where the percentages represent the mass percentage of each composition relative to the total mass of the tablet core. The coating consists of 7.20% cellulose acetate and 0.80% polyethylene glycol 4000, where the percentages represent the mass percentage of each composition relative to the total mass of the tablet core. Coating 3 consists of 6% cellulose acetate and 3% polyethylene glycol 4000, where the percentages are the mass percentages of each composition relative to the total mass of the tablet core. It is one of the following compositions: The sacubitril valsartan sodium sustained-release composition according to feature 1.

9. Sacubitril valsartan sodium sustained-release formulation, The sacubitril valsartan sustained-release composition described in claim 1 comprises, The dosage form of the aforementioned sacubitril valsartan sodium sustained-release formulation is a sustained-release tablet, sustained-release micropellets, or sustained-release capsule. A sustained-release formulation of sacubitril valsartan sodium characterized by the following features.

10. Application of the sacubitril valsartan sustained-release composition according to claim 1 in the manufacture of a drug for treating and / or preventing chronic heart failure with reduced ejection fraction.

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