WO2023284724A1 - 沙库巴曲缬沙坦钠缓释组合物、其制备方法及应用 - Google Patents

沙库巴曲缬沙坦钠缓释组合物、其制备方法及应用 Download PDF

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WO2023284724A1
WO2023284724A1 PCT/CN2022/105144 CN2022105144W WO2023284724A1 WO 2023284724 A1 WO2023284724 A1 WO 2023284724A1 CN 2022105144 W CN2022105144 W CN 2022105144W WO 2023284724 A1 WO2023284724 A1 WO 2023284724A1
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sacubitril
drug
valsartan
tablet core
containing layer
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PCT/CN2022/105144
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English (en)
French (fr)
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郭桢
谢文凤
肖小玲
王婷婷
应述欢
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上海博志研新药物技术有限公司
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Priority to EP22841360.5A priority Critical patent/EP4371558A1/en
Publication of WO2023284724A1 publication Critical patent/WO2023284724A1/zh

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Definitions

  • the invention relates to a sacubitril-valsartan sodium sustained-release composition, a preparation method and application thereof.
  • Sacubitril valsartan sodium is indicated for the treatment of adult patients with chronic heart failure with reduced ejection fraction (HF-REF), reducing the risk of cardiovascular death and hospitalization for heart failure.
  • Sacubitril is a neprilysin inhibitor
  • valsartan is an angiotensin II receptor blocker.
  • Sacubitril-valsartan sodium can replace angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB), and it can be used in combination with other drugs for the treatment of heart failure.
  • ACEI angiotensin-converting enzyme inhibitor
  • ARB angiotensin II receptor blocker
  • Heart failure (heart failure) is referred to as heart failure. Patients with heart failure cannot pump enough blood to supply the whole body. Symptoms of dyspnea, fatigue and fluid retention may occur, which will gradually aggravate and seriously affect the quality of life. According to statistics, the global annual expenditure on heart failure is 108 billion US dollars. A large-scale epidemiological survey in 2003 showed that the prevalence of heart failure among adults in mainland China has reached 0.9%, and there are about 4.5 million heart failure patients. . On the other hand, hypertension is one of the most important causes of heart failure (heart failure), and is a major public health problem worldwide. According to the Framingham report, hypertension accounts for 75% of heart failure diseases, and 60% to 88.5% in my country, which is 6 times that of normal blood pressure. After heart failure occurs, the 5-year mortality rate is more than 50%. And the incidence of hypertension in my country is about 11.88% at present, and it is estimated that there are nearly more than 100 million hypertensive patients in the whole country.
  • RAAS renin-angiotensin-aldosterone system
  • Sacubitril valsartan sodium acts in a unique multiple way, while inhibiting the harmful effects caused by the activation of the RAAS system, it can also enhance the neuroendocrine system (natriuretic peptide system) that protects the heart. This is equivalent to having both a "spear” and a “shield”.
  • the new study shows that LCZ696 is well tolerated and the side effects are easy to manage, and the proportion of patients withdrawing from the study due to adverse events is low.
  • sacubitril valsartan sodium is octadecadecasodium hexa(4- ⁇ [(1S,3R)-1-([1,1'-biphenyl)-4-ylmethyl)-4-ethane Oxy-3-methyl-4-oxobutyl]amino ⁇ -4-oxobutanoic acid)hexa(N-pentanoyl-N- ⁇ [2'-(1H-tetrazol-5-yl) Biphenyl-4-yl] methyl ⁇ -L-valine)-water (1/15), its structural formula is as follows:
  • Novartis has developed sacubitril-valsartan sodium ordinary immediate-release tablets, the dosage of which is 50 mg to 200 mg taken twice a day, and the dosage is large and the number of times of medication is large.
  • the CN105748420A patent literature proposes a preparation method of LCZ696 sustained-release matrix tablets for the treatment of heart failure.
  • the sustained-release dosage form uses the gel matrix as the release mechanism, and the sustained-release time is relatively short.
  • the active ingredient is only released completely in 8 hours, which cannot reach 24-hour stable release; the gel matrix tablet is easily affected by food extrusion and other factors in the body, resulting in increased release speed of the drug or to varying degrees, poor sustained release effect, and poor correlation between in vivo and in vitro.
  • the invention provides a sustained-release composition of sacubitril-valsartan sodium, which is a 24-hour slow-release drug, and the dissolution of sacubitril and valsartan satisfies the following three characteristics at the same time:
  • the active pharmaceutical ingredient can be selected from one, two or more of sacubitril-valsartan sodium, or other pharmaceutically acceptable salt forms, solvates and hydrates thereof.
  • the dissolution of sacubitril satisfies the following three characteristics at the same time:
  • the dissolution of sacubitril satisfies the following three characteristics at the same time:
  • the dissolution of sacubitril satisfies the following three characteristics at the same time:
  • the dissolution of sacubitril and valsartan is synchronous release.
  • the sustained-release composition is a 24-hour slow-release drug, and the dissolution of sacubitril and valsartan simultaneously meets the following three characteristics:
  • the active pharmaceutical ingredient can be selected from one, two or more of sacubitril-valsartan sodium, or other pharmaceutically acceptable salt forms, solvates and hydrates thereof.
  • the dissolution of sacubitril satisfies the following three characteristics at the same time:
  • the dissolution of sacubitril satisfies the following three characteristics at the same time:
  • the dissolution of sacubitril satisfies the following three characteristics at the same time:
  • the dissolution of sacubitril and valsartan is synchronous release.
  • the “dissolution” refers to the cumulative dissolution rate of pharmaceutical active ingredients, such as the cumulative dissolution rate of sacubitril and the cumulative dissolution rate of valsartan; further, the cumulative dissolution rate is in pH 6.8 phosphate buffer Measured. Those skilled in the art can understand that, as time increases, the dissolution rate of the sacubitril-valsartan sodium gradually increases.
  • the sacubitril-valsartan sodium sustained-release composition comprises a drug-containing layer tablet core and a coating film, and is perforated on one side of the drug-containing layer;
  • the drug-containing layer tablet core Contains a pharmaceutical active ingredient and a carrier;
  • the pharmaceutical active ingredient can be selected from sacubitril valsartan sodium, or one, two, or More;
  • the carrier is, for example, one or more of osmotic pressure regulators, swelling agents, thickeners, glidants and lubricants;
  • the coating film is a semi-permeable film;
  • the sustained-release composition optionally includes or does not include a booster layer tablet core, and the booster layer tablet core includes one or more of an osmotic pressure regulator, a swelling agent, a colorant and a lubricant.
  • the active pharmaceutical ingredient is preferably sacubitril-valsartan sodium.
  • the content of the active pharmaceutical ingredient is 10.00% to 80.00%, such as 28.25%, 33.93%, 37.67%, 37.70%, 40.39%, 56.50% , 67.87%, or 75.40%, the content refers to the percentage of the mass of the active pharmaceutical ingredient in the total mass of the drug-containing layer tablet core.
  • the osmotic pressure regulator in the drug-containing layer tablet core, can be selected from sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose One or more of , sucrose and lactose.
  • the lactose is lactose monohydrate.
  • the osmotic pressure regulator may be a mixture of sorbitol, lactose monohydrate and sodium chloride, a mixture of sorbitol and sodium chloride, or sodium chloride.
  • the content of the osmotic pressure regulator is 1.00% to 60.00%, such as 48.75%, 40.34%, 31.50%, 27.50%, 3.00% or 1.50% %, the content refers to the percentage of the mass of the osmotic pressure regulator in the total mass of the drug-containing layer tablet core.
  • the thickener in the drug-containing layer tablet core, can increase the viscosity of the dispersion medium to reduce the sedimentation velocity of the particles or Additives that increase the hydrophilicity of the microparticles, for example selected from the group consisting of hypromellose, hypromellose, hydroxyethylcellulose, ethylcellulose, copovidone, acacia, pregelatinized starch and polyvinylpyrrolidone one or more of .
  • the thickener is selected from hypromellose, or a mixture of copovidone and hydroxyethyl cellulose.
  • the content of the thickener is 10.00% to 70.00%, such as 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%, the content refers to the percentage of the mass of the thickener in the total mass of the drug-containing layer tablet core.
  • the swelling agent in the drug-containing layer tablet core, can be a substance capable of absorbing a solvent and swelling, preferably polyoxyethylene, carbomer, One or more of sodium starch glycolate, crospovidone and sodium alginate.
  • the content of the swelling agent is preferably 0.00% to 70.00%, such as 48.06%, 24.02% or 19.93%, and the content refers to the content of the swelling agent.
  • Mass as a percentage of the total mass of the drug-containing layer tablet core.
  • the drug-containing layer tablet core may further contain a coloring agent.
  • the colorant in the drug-containing layer tablet core, can be a substance capable of coloring, preferably one or more of iron oxide red, iron oxide yellow, and iron oxide black .
  • the content of the coloring agent is 0% to 5.00%, such as 0.10%. % of total core mass.
  • the glidant in the drug-containing layer tablet core, may be an adjuvant that can reduce the friction between particles and improve the fluidity of powder or granules, preferably talcum powder, micropowder silica gel, One or more of colloidal silicon dioxide.
  • the content of the glidant is preferably 0% to 5.00%, such as 0 to 1.00%, and the content is 0.30%, 0.50%, and 1.57% as examples , 1.67%, 3.00%, 3.54% or 3.57%, the content refers to the percentage of the mass of the glidant in the total mass of the drug-containing layer tablet core.
  • the lubricant in the drug-containing layer tablet core, may be a substance having a lubricating effect, preferably metal stearate, stearic acid, talcum powder, stearate, hard One or more of acyl fumarate and micronized silica gel.
  • the metal stearate is preferably magnesium stearate and/or calcium stearate.
  • the preferred stearic acid ester of stearic acid ester is particularly preferred.
  • the content of the lubricant is preferably 0.50% to 60.00%, such as 1.00 to 30.00%, and the content is 1.00%, 1.20%, 2.00%, 2.14%, 2.33% or 3.00%, the said content refers to the percentage of the mass of the lubricant in the total mass of the drug-containing layer tablet core.
  • the sum of the content of the drug active ingredient and the carrier is 100%.
  • the sustained-release composition when the sustained-release composition contains a booster layer tablet core, the drug-containing layer tablet core does not contain an osmotic pressure regulator.
  • the osmotic pressure regulator may be a substance that regulates osmosis, preferably sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, One or more of magnesium sulfate, glucose, fructose, sucrose and lactose, such as sodium chloride.
  • the lactose may be lactose monohydrate.
  • the content of the osmotic pressure regulator is 1.00% to 60.00%, such as 31.74%, 29.17%, 25.00% or 5.00%, and the content Refers to the percentage of the mass of the osmotic pressure regulator in the total mass of the core of the booster layer.
  • the swelling agent in the booster layer tablet core, can be a substance capable of absorbing a solvent and swelling, preferably polyvinylpyrrolidone, hydroxyethyl cellulose
  • a solvent and swelling preferably polyvinylpyrrolidone, hydroxyethyl cellulose
  • sodium starch glycolate, copovidone, hypromellose, gum arabic, carbomer, sodium starch glycolate, sodium alginate and polyoxyethylene preferably sodium starch glycolate, copovidone, hypromellose, gum arabic, carbomer, sodium starch glycolate, sodium alginate and polyoxyethylene.
  • the content of the swelling agent is 0.00% to 90.00%, such as 0.00% to 80.00%, as examples are 8.33%, 10.00%, 20.00%, 65.87%, 63.00%, 73.00%, 60.83% or 82.00%, the said content refers to the percentage of the mass of the swelling agent to the total mass of the core of the booster layer.
  • the coloring agent in the booster layer tablet core, can be a substance capable of achieving the purpose of coloring, preferably one or more of iron oxide red, iron oxide yellow and iron oxide black .
  • the content of the colorant is preferably 0.10% to 10.00%, such as 1.20%, 1.00% or 0.83%, and the content refers to the content of the colorant Mass as a percentage of the total mass of the booster core.
  • the lubricant in the booster layer tablet core, may be a conventional substance with a lubricating effect in the art, preferably metal stearate, stearic acid, talcum powder, hard One or more of fatty acid esters, stearyl fumarate and micronized silica gel.
  • the metal stearate is preferably magnesium stearate and/or calcium stearate.
  • the stearic acid ester is preferably glyceryl stearate.
  • the content of the lubricant is preferably 0.10% to 10.00%, such as 2.00%, 1.20%, 1.00% or 0.84%, and the content refers to The mass of the lubricant accounts for the percentage of the total mass of the booster layer core.
  • the sum of the contents of each component is 100%.
  • the semi-permeable membrane comprises one or more of a membrane-forming material, a porogen and a plasticizer.
  • the film-forming material in the coating film, can be a material that can be dispersed on a solid surface and solidified to form a film, preferably cellulose acetate, ethyl cellulose, and phthalate acetate One or more of polyvinyl acetate, acrylic resin and methacrylic resin.
  • the porogen in the coating film, can be a substance capable of forming pores when the material encounters water, preferably polyethylene glycol, hydroxypropyl cellulose, povidone and One or more of polyvinyl alcohol.
  • the plasticizer in the coating film, can be a substance that can increase the plasticity of the polymer, preferably glyceryl triacetate, glyceryl citrate, glyceride, phthalic acid One or more of dibutyl ester and diethyl phthalate.
  • the polyethylene glycol is polyethylene glycol 4000.
  • the film coating comprises cellulose acetate and polyethylene glycol 4000.
  • the coating film can also be selected from the cellulose acetate full formula coating premix provided by Colorcon ( CA).
  • the sacubitril-valsartan sodium sustained-release composition of the present invention is in a pH 6.8 phosphate buffer solution with a volume of 900ml, and the dissolution test is carried out at a speed of 50rpm in the USP second method, sacubitril and valsartan
  • the 24-hour cumulative release of valsartan can reach more than 85%.
  • the drug-containing layer tablet core can be any of the following formulations:
  • Formula 1 28.25% sacubitril valsartan sodium, 25.00% sorbitol, 21.25% lactose monohydrate, 2.50% sodium chloride, 21.50% hypromellose, 0.50% colloidal silicon dioxide, 1.00% hard Magnesium fatty acid, described percentage refers to the percentage that the quality of each component accounts for drug-containing layer tablet core gross mass;
  • Formula 2 56.50% sacubitril valsartan sodium, 20.00% sorbitol, 10.00% lactose monohydrate, 1.50% sodium chloride, 10.50% hypromellose, 0.50% colloidal silicon dioxide, 1.00% hard Magnesium fatty acid, described percentage refers to the percentage that the quality of each component accounts for drug-containing layer tablet core gross mass;
  • Formula three 37.67% sacubitril-valsartan sodium, 36.66% sorbitol, 3.67% sodium chloride, 21.00% hypromellose, 1.00% magnesium stearate, the percentages mentioned refer to the The percentage of the mass in the total mass of the drug-containing layer tablet core;
  • Formula four 56.50% sacubitril valsartan sodium, 25.00% sorbitol, 2.50% sodium chloride, 15.00% hypromellose, 1.00% magnesium stearate, the percentages mentioned refer to the The percentage of the mass in the total mass of the drug-containing layer tablet core;
  • Formula five 33.93% sacubitril valsartan sodium, 48.06% polyoxyethylene, 3.00% sodium chloride, 13.81% hypromellose, 1.20% magnesium stearate, the percentages mentioned refer to the components The mass of the percentage of the total mass of the drug-containing layer tablet core;
  • Formula 6 67.87% sacubitril valsartan sodium, 24.02% polyoxyethylene, 1.5% sodium chloride, 5.41% hypromellose, 1.20% magnesium stearate, the percentages mentioned refer to the components The mass of the percentage of the total mass of the drug-containing layer tablet core;
  • Formula 7 37.70% sacubitril valsartan sodium, 38.63% copovidone, 18.67% hydroxyethyl cellulose, 2.33% talcum powder, 0.67% colloidal silicon dioxide, 2.00% magnesium stearate, the The percentage refers to the percentage of the mass of each component in the total mass of the drug-containing layer tablet core;
  • Formula eight 75.40% sacubitril-valsartan sodium, 11.60% copovidone, 8.33% hydroxyethyl cellulose, 1.00% talc, 0.67% colloidal silicon dioxide, 3.00% magnesium stearate, the The percentage refers to the percentage of the mass of each component in the total mass of the drug-containing layer tablet core;
  • Formula 9 40.39% sacubitril-valsartan sodium, 26.90% copovidone, 27.00% hydroxyethyl cellulose, 2.86% talcum powder, 0.71% colloidal silicon dioxide, 2.14% magnesium stearate, the The percentage refers to the percentage of the mass of each component in the total mass of the drug-containing layer tablet core;
  • Formula ten 75.40% sacubitril valsartan sodium, 19.93% polyoxyethylene, 1.00% talc, 0.67% colloidal silicon dioxide, 3.00% magnesium stearate, the percentages mentioned refer to the The percentage of the mass in the total mass of the drug-containing layer tablet core;
  • Formula eleven 37.70% sacubitril valsartan sodium, 28.20% copovidone, 28.66% hydroxyethyl cellulose, 2.67% talc, 0.67% colloidal silicon dioxide, 2.00% magnesium stearate, 0.10 % yellow iron oxide, said percentage refers to the percentage that the quality of each component accounts for the total mass of drug-containing layer tablet core;
  • Formula 12 75.40% sacubitril valsartan sodium, 6.83% copovidone, 12.00% hydroxyethyl cellulose, 2.67% talc, 0.67% colloidal silicon dioxide, 2.33% magnesium stearate, 0.10 % yellow iron oxide, said percentage refers to the percentage of the mass of each component in the total mass of the drug-containing layer tablet core.
  • the described booster layer tablet core is any one of the following formulations:
  • Formula 1 65.86% polyoxyethylene, 31.74% sodium chloride, 1.20% red iron oxide, 1.20% magnesium stearate, the percentages mentioned refer to the percentages of the weight of each component in the total weight of the booster layer core;
  • Formula 2 73.00% polyoxyethylene, 20.00% copovidone, 1.00% red iron oxide, 5.00% sodium chloride, 1.00% magnesium stearate, the percentages mentioned refer to the mass of each component in the booster layer The percentage of the total mass of the core;
  • Formula 3 60.83% polyoxyethylene, 8.33% copovidone, 29.17% sodium chloride, 0.83% red iron oxide, 0.84% magnesium stearate, the percentages mentioned refer to the mass of each component in the booster layer The percentage of the total mass of the core;
  • Formula 4 82.00% polyoxyethylene, 10.00% copovidone, 5.00% sodium chloride, 1.00% red iron oxide, 2.00% magnesium stearate, the percentages mentioned refer to the mass of each component in the booster layer The percentage of the total mass of the core;
  • Formula five 63.00% polyoxyethylene, 10.00% copovidone, 25.00% sodium chloride, 1.00% red iron oxide, 1.00% magnesium stearate, the percentages mentioned refer to the weight of each component in the booster layer % of total core mass.
  • the coating is any one of the following compositions:
  • Coating 1 9.00% cellulose acetate, 1.00% polyethylene glycol 4000, the percentage refers to the percentage of the weight of each component in the total weight of the tablet core;
  • the coating solvent is acetone and water, for example, the mass ratio of acetone to water is 9:1; the solid content of the coating solution is 5%, and the solid content is the percentage of the total mass of solid matter in the total mass of the coating solution;
  • the coating solvent is acetone and water, for example, the mass ratio of acetone to water is 9:1; the solid content of the coating solution is 5%, and the solid content is the percentage of the total mass of solid matter in the total mass of the coating solution.
  • the coating solvent is acetone and water, for example, the mass ratio of acetone to water is 9:1; the solid content of the coating solution is 5%, and the solid content is the percentage of the total mass of solid matter in the total mass of the coating solution.
  • the coating solution is a mixed solution of coating solvent, cellulose acetate and polyethylene glycol 4000.
  • the above-mentioned tablet core is composed of a drug-containing layer core and a booster layer core; when there is no booster layer core, the tablet core is a drug-containing layer core.
  • the present invention also provides a preparation method of the above-mentioned slow-release composition, comprising the following steps:
  • the preparation process can be powder direct compression, dry granulation, wet granulation, etc.
  • the drug-containing layer tablet core coating semi-permeable membrane coating
  • punch holes on the side of the drug-containing layer to obtain the sacubitril-valsartan sodium sustained-release composition.
  • the preparation method includes the following specific steps:
  • Step 2) mixing the drug-containing layer mixture obtained in step 1 with a lubricant, and tableting to obtain a drug-containing tablet core;
  • Step 3) Coating and aging the drug-containing layer tablet core obtained in step 2) to obtain a coated tablet;
  • Step 4) punching the coated tablet obtained in step 3) to obtain sacubitril-valsartan sodium sustained-release tablet.
  • the sieving may be a 60-mesh sieve or a 40-mesh sieve.
  • the mixing in step 1), can be performed in a mixer, such as a mixing tank.
  • the mixing speed may be 18 r/min, and the mixing time may be 1 minute to 2 hours, such as 20 minutes.
  • the hardness of the drug-containing tablet core in step 2) is 100N ⁇ 160N.
  • the temperature of the coating is preferably 25°C-45°C, for example, 30°C.
  • the preferred coating weight gain of the coating is 6% to 20%, and the percentage refers to (the weight of the sacubitril-valsartan sodium coating tablet-containing The weight of drug-layer tablet core)/the weight of drug-containing layer tablet core ⁇ 100%.
  • the aging temperature is preferably 20°C-60°C, for example, 45°C.
  • the aging time is preferably 10 hours to 30 hours, such as 24 hours.
  • the perforation in step 4), may be perforated at the center of one side of the drug-containing layer.
  • the hole diameter of the perforated holes may be 0.4mm-0.7mm.
  • the present invention also provides a preparation method of the sustained-release composition, comprising: mixing the components of the drug-containing layer tablet core and the components of the booster layer tablet core separately, and then compressing to obtain a double-layer tablet core (each layer is mixed).
  • the preparation process of the powder can be powder direct compression, dry granulation, wet granulation, etc.); after the double-layer tablet core coating (semi-permeable membrane coating), punch holes on the side of the drug-containing layer to obtain the Described sacubitril valsartan sodium sustained-release composition.
  • the preparation method includes the following specific steps:
  • Step A1) sieving and mixing the components in the drug-containing layer tablet core except the lubricant, and then mixing with the lubricant to obtain the drug-containing layer mixture;
  • Step A3) compressing the drug-containing layer mixture obtained in step A1) and the booster layer mixture obtained in step A2), to obtain a drug-containing tablet core;
  • Step A4) Coating and aging the drug-containing tablet core obtained in step A3) to obtain a coated tablet;
  • Step A5) The coated tablet obtained in step A4) is punched on the side of the drug-containing layer to obtain sacubitril-valsartan sodium sustained-release tablets.
  • the sieving may be 40 mesh or 60 mesh sieve.
  • the mixing in step A1) and step A2), can be performed in a mixer, such as a mixing tank.
  • the mixing speed may be 18 r/min, and the mixing time may be 1 minute to 2 hours, such as 5 minutes, 10 minutes or 15 minutes.
  • the temperature of the coating is preferably 25°C-45°C, for example 30°C.
  • the preferred coating weight gain of the coating is 6% to 20%, and the percentage refers to (weight of sacubitril valsartan sodium coating tablet-containing weight of the tablet core)/weight of the tablet core containing the drug ⁇ 100%.
  • the aging temperature is preferably 20°C-60°C, such as 45°C.
  • the aging time is preferably 10 hours to 30 hours, such as 24 hours.
  • the hole in step A5), may be punched at the center of the drug-containing surface.
  • the diameter of the perforated holes may be 0.4 mm to 0.7 mm.
  • the present invention also provides a sacubitril-valsartan sodium sustained-release preparation, which comprises the sacubitril-valsartan sodium sustained-release composition.
  • the sustained-release preparation of sacubitril-valsartan sodium may be a sustained-release tablet, sustained-release pellet, sustained-release capsule, and the like.
  • the present invention also provides the preparation of the sacubitril-valsartan sustained-release composition or the sacubitril-valsartan sustained-release preparation for the treatment and/or prevention of chronic heart failure with reduced ejection fraction. in the application.
  • the present invention also provides a method for treating and preventing chronic heart failure with reduced ejection fraction, which comprises administering an effective dose of the sacubitril-valsartan sustained-release preparation to patients in need.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the invention provides a sacubitril-valsartan sodium sustained-release composition different from the prior art, which has good sustained-release effect, stable release and good compliance of patients with chronic heart failure, its preparation method and application.
  • the sustained-release composition of sacubitril and valsartan sodium of the present invention is not affected by factors such as medium environment pH, gastrointestinal peristalsis, food, etc., and has good correlation in vivo and in vitro, and can make sacubitril and valsartan sodium Sartan sodium is released synchronously and slowly within 24 hours to achieve a better therapeutic effect; compared with ordinary immediate-release preparations, its advantages lie in: (1) It reduces the number of doses and can achieve a good therapeutic effect through sustained release , to improve patient compliance; (2) for the elderly or children with dysphagia, it is beneficial to improve their medication compliance; (3) to prevent patients from arbitrarily interrupting medication, and to prevent disease recurrence and progression of malignant complications; (4) Once a day, choose the appropriate specification according to the clinical manifestations
  • Fig. 1 shows in pH6.8 phosphate buffer solution, the stripping profile of sacubitril and valsartan in embodiment I-1;
  • Fig. 2 shows in pH6.8 phosphate buffer saline, the stripping profile of sacubitril and valsartan in embodiment 1-2;
  • Fig. 3 shows in pH6.8 phosphate buffer, the stripping profile of sacubitril and valsartan in embodiment 1-3;
  • Fig. 4 shows in the pH6.8 phosphate buffer saline, the stripping profile of sacubitril and valsartan in the embodiment 1-4;
  • Fig. 5 shows in pH6.8 phosphate buffer, the stripping profile of sacubitril and valsartan in embodiment 1-5;
  • Fig. 6 shows in pH6.8 phosphate buffer solution, the stripping profile of sacubitril and valsartan in embodiment 1-6;
  • Fig. 7 shows in pH6.8 phosphate buffer solution, the stripping profile of sacubitril and valsartan in embodiment II-1;
  • Fig. 8 shows in pH6.8 phosphate buffer solution, the stripping profile of sacubitril and valsartan in embodiment II-2;
  • Fig. 9 shows in pH6.8 phosphate buffer solution, the stripping profile of sacubitril and valsartan in embodiment II-3;
  • Figure 10 shows the dissolution profile of sacubitril and valsartan in Example II-3 in acetate buffer at pH 4.5;
  • Figure 11 shows the dissolution profile of sacubitril and valsartan in an aqueous solution in Example II-3;
  • Fig. 12 shows in pH6.8 phosphate buffer solution, the stripping profile of sacubitril and valsartan in embodiment II-4;
  • Figure 13 shows the dissolution profile of sacubitril and valsartan in Example II-5 in a pH6.8 phosphate buffer
  • Fig. 14 shows in pH6.8 phosphate buffer solution, the stripping profile of sacubitril and valsartan in embodiment II-6;
  • Figure 15 shows the dissolution profiles of sacubitril and valsartan in Example II-6 in acetate buffer at pH 4.5;
  • Figure 16 shows the dissolution profiles of sacubitril and valsartan in an aqueous solution in Example II-6;
  • Figure 17 shows the dissolution profiles of sacubitril and valsartan in Example II-7 in a pH6.8 phosphate buffer
  • Figure 18 shows the dissolution profiles of sacubitril and valsartan in Example II-8 in phosphate buffer at pH 6.8.
  • the sacubitril-valsartan sodium slow-release composition of the present invention adopts a pH 6.8 phosphate buffer solution with a volume of 900ml, and adopts the dissolution method of USP second method rotating speed 50rpm to carry out the dissolution test.
  • sacubitril-valsartan sodium is processed through a 60-mesh sieve; sorbitol and colloidal silicon dioxide are passed through a 40-mesh to remove lumps.
  • Step 1 Put sacubitril-valsartan sodium, sorbitol, lactose monohydrate, sodium chloride, and hypromellose in the above prescription in a mixing pot, set the mixing speed to 18r/min, and mix for 20 minutes. Obtain drug-containing layer mixture;
  • Step 2 Mix the drug-containing layer mixture obtained in step 1 with colloidal silicon dioxide, set the mixing speed to 18r/min, and mix for 5 minutes; then add magnesium stearate, set the mixing speed to 18r/min, and mix for 5 minutes; then Put it on a rotary tablet press, press it into a single tablet of 400 mg, hardness 100N-160N, and press a shallow arc-shaped drug-containing tablet core;
  • Coat the drug-containing tablet cores obtained in step 2 with the above-mentioned sustained-release coating solution rotate at a speed of 8rpm to 15rpm, and control the air intake volume at 30m 3 /h to 120m 3 /h, and control the temperature of the tablet bed.
  • At 25°C to 35°C set the spray speed at 5rpm to 20rpm for spraying, and continue coating so that the coating weight gain is 10.3% and 10.1% respectively.
  • °C for 5 minutes to 10 minutes, and the tablets are produced; then placed in a blast drying oven with a set temperature of 45 °C for aging, and after 24 hours, the coated tablets are obtained;
  • Step 4 The coated tablet obtained in step 3 is subjected to laser drilling, and the small hole size is 0.4-0.7 mm to obtain sacubitril-valsartan sodium sustained-release tablet.
  • the above-mentioned sacubitril-valsartan sodium is processed through a 60-mesh sieve; the sorbitol is passed through a 40-mesh to remove lumps.
  • Step 1 Put sacubitril valsartan sodium, sorbitol, sodium chloride, and hypromellose in the above prescription in a mixing pot, set the mixing speed to 18r/min, mix for 20 minutes, and then add Magnesium stearate, setting mixing speed 18r/min, mixing 5 minutes; Obtain drug-containing layer mixture;
  • Step 2 Place the drug-containing layer mixture obtained in step 1 in a dry granulator, adjust the equipment parameters so that it can be pressed into a large piece with a certain hardness, and then use a 1.0mm screen to carry out granulation; then mix with stearic acid Magnesium is mixed, and the mixing speed is set at 18r/min, and mixed for 5 minutes; then placed on a rotary tablet press, compressed into a shallow arc-shaped drug-containing tablet core;
  • Coat the drug-containing tablet cores obtained in step 2 with the above-mentioned sustained-release coating solution rotate at a speed of 8rpm to 15rpm, and control the air intake volume at 30m 3 /h to 120m 3 /h, and control the temperature of the tablet bed.
  • set the spray speed at 5rpm to 20rpm for spraying, and continue coating so that the coating weight gain is 7.9% and 8.2% respectively.
  • °C for 5 minutes to 10 minutes, and the tablets are produced; then placed in a blast drying oven with a set temperature of 45 °C for aging, and coated tablets are obtained after 24 hours;
  • Step 4 The coated tablet obtained in step 3 is subjected to laser drilling, and the hole size is 0.4-0.7 mm to obtain sacubitril-valsartan sodium sustained-release tablets.
  • the above-mentioned sacubitril-valsartan sodium is processed through a 60-mesh sieve.
  • Step 1 Put sacubitril-valsartan sodium, polyoxyethylene, sodium chloride, and hypromellose in the drug-containing layer in the above prescription in a mixing pot, set the mixing speed to 18r/min, and mix for 20 minutes; Then add the magnesium stearate of the drug-containing layer, set the mixing speed to 18r/min, and mix for 5 minutes to obtain the drug-containing layer mixture;
  • Step 2 Put the polyoxyethylene, sodium chloride, and red iron oxide in the booster layer in the above prescription in a mixing pot, set the mixing speed to 18r/min, and mix for 10 minutes; then add the magnesium stearate in the booster layer, Set the mixing speed to 18r/min, and mix for 5 minutes to obtain the booster layer mixture;
  • Step 3 Put the drug-containing layer mixture obtained in step 1 and the booster layer mixture obtained in step 2 on the rotary tablet press, and adjust the equipment parameters so that the tablet weight of the drug-containing layer is 333 mg, and the tablet weight of the booster layer is 167 mg , the total tablet weight is 500mg, the hardness is 100N-180N, and the tablet core is compressed into a shallow arc shape;
  • Coat the drug-containing tablet core obtained in step 3 with the above-mentioned slow-release coating solution rotate at a speed of 8rpm-15rpm, control the temperature of the tablet bed at 25°C-35°C, and set the spray speed at 5rpm-20rpm Spray liquid, continue coating to increase coating weight by 8.2% and 8.0%, stop spraying liquid, then dry at tablet bed temperature 30°C-35°C for 5 minutes to 10 minutes, and release tablet; then place at set temperature 45°C In the air-blast drying oven, carry out aging, obtain coated tablet after 24 hours;
  • Step 5 Perform laser drilling on the coated tablet obtained in step 4.
  • the perforated surface should be the drug-containing layer (the white corresponding surface) with a small hole size of 0.4-0.7 mm to obtain sacubitril-valsartan sodium sustained-release tablets.
  • the above-mentioned sacubitril-valsartan sodium is processed through a 60-mesh sieve.
  • Step 1 Put sacubitril-valsartan sodium, copovidone, hydroxyethyl cellulose, colloidal silicon dioxide, and talcum powder in the drug-containing layer in the above prescription into a mixing pot, and set the mixing speed to 18r/min , mixed for 20 minutes; then the mixed material was subjected to dry granulation and granulation, and finally the magnesium stearate of the drug-containing layer was added, the mixing speed was set to 18r/min, and the mixture was mixed for 5 minutes to obtain the drug-containing layer mixture;
  • Step 2 Put the polyoxyethylene, sodium chloride, copovidone, and red iron oxide of the booster layer in the above prescription into a mixing pot, set the mixing speed to 18r/min, and mix for 10 minutes; then add the hard Magnesium fatty acid, set mixing speed 18r/min, mix for 5 minutes, obtain booster layer mixture;
  • Step 3 Put the drug-containing layer mixture obtained in step 1 and the booster layer mixture obtained in step 2 on the rotary tablet press, and adjust the equipment parameters so that the tablet weight of the drug-containing layer is 300 mg, and the tablet weight of the booster layer is 100 mg , with a total tablet weight of 400mg, a hardness of 100N-180N, and a shallow arc-shaped tablet core containing medicine;
  • Coat the drug-containing tablet core obtained in step 3 with the above-mentioned slow-release coating solution rotate at a speed of 8rpm-15rpm, control the temperature of the tablet bed at 25°C-35°C, and set the spray speed at 5rpm-20rpm Spray liquid, continue coating so that the weight gain of the coating is 8.0% to 11.0%, stop spraying liquid, and then dry at a tablet bed temperature of 30°C to 35°C for 5 minutes to 10 minutes, and then release the tablet; then place it at the set temperature In a blast drying oven at 45°C, aging is carried out, and coated tablets are obtained after 24 hours;
  • Step 5 Perform laser drilling on the coated tablet obtained in step 4.
  • the perforated surface should be the drug-containing layer (the white corresponding surface) with a small hole size of 0.4-0.7 mm to obtain sacubitril-valsartan sodium sustained-release tablets.
  • the above-mentioned sacubitril-valsartan sodium is processed through a 60-mesh sieve.
  • Step 1 Put the raw and auxiliary materials of the drug-containing layer in the above prescription except the lubricant magnesium stearate in a mixing pot, set the mixing speed at 18r/min, and mix for 20 minutes; then carry out dry granulation of the mixed materials, and finally Add the magnesium stearate of the drug-containing layer, set the mixing speed to 18r/min, and mix for 5 minutes to obtain the drug-containing layer mixture;
  • Step 2 Put the polyoxyethylene, sodium chloride, copovidone, and red iron oxide of the booster layer in the above prescription into a mixing pot, set the mixing speed to 18r/min, and mix for 10 minutes; then add the hard Magnesium fatty acid, set mixing speed 18r/min, mix for 5 minutes, obtain booster layer mixture;
  • Step 3 Put the drug-containing layer mixture obtained in step 1 and the booster layer mixture obtained in step 2 on the rotary tablet press, and adjust the equipment parameters so that the tablet weight of the drug-containing layer is 280 mg, and the tablet weight of the booster layer is 120 mg , with a total tablet weight of 400mg, a hardness of 100N-180N, and a shallow arc-shaped tablet core containing medicine;
  • Coat the drug-containing tablet core obtained in step 3 with the above-mentioned slow-release coating solution rotate at a speed of 8rpm-15rpm, control the temperature of the tablet bed at 25°C-35°C, and set the spray speed at 5rpm-20rpm Spray liquid, continue coating so that the weight gain of the coating is 8.0% to 11.0%, stop spraying liquid, and then dry at a tablet bed temperature of 30°C to 35°C for 5 minutes to 10 minutes, and then release the tablet; then place it at the set temperature In a blast drying oven at 45°C, aging is carried out, and coated tablets are obtained after 24 hours;
  • Step 5 Perform laser drilling on the coated tablet obtained in step 4.
  • the perforated surface should be the drug-containing layer (the white corresponding surface) with a small hole size of 0.4-0.7 mm to obtain sacubitril-valsartan sodium sustained-release tablets.
  • the above-mentioned sacubitril-valsartan sodium is processed through a 60-mesh sieve.
  • Step 1 Put the sacubitril-valsartan sodium, copovidone, hydroxyethyl cellulose, yellow iron oxide, colloidal silicon dioxide, and talcum powder in the drug-containing layer in the above prescription into a mixing pot, set the mixing Mix at a speed of 18r/min for 20 minutes; then carry out dry granulation of the mixed material, and finally add magnesium stearate in the drug-containing layer, set the mixing speed at 18r/min, and mix for 5 minutes to obtain a drug-containing layer mixture;
  • Step 2 Put the polyoxyethylene, sodium chloride, copovidone, and red iron oxide of the booster layer in the above prescription into a mixing pot, set the mixing speed to 18r/min, and mix for 10 minutes; then add the hard Magnesium fatty acid, set mixing speed 18r/min, mix for 5 minutes, obtain booster layer mixture;
  • Step 3 Put the drug-containing layer mixture obtained in step 1 and the booster layer mixture obtained in step 2 on the rotary tablet press, and adjust the equipment parameters so that the tablet weight of the drug-containing layer is 300 mg, and the tablet weight of the booster layer is 100 mg , with a total tablet weight of 400mg, a hardness of 100N-180N, and a shallow arc-shaped tablet core containing medicine;
  • Coat the drug-containing tablet core obtained in step 3 with the above-mentioned slow-release coating solution rotate at a speed of 8rpm-15rpm, control the temperature of the tablet bed at 25°C-35°C, and set the spray speed at 5rpm-20rpm Spray liquid, continue coating so that the weight gain of the coating is 8.0% to 14.0%, stop spraying liquid, and then dry at a tablet bed temperature of 30°C to 35°C for 5 minutes to 10 minutes, and then release the tablet; then place it at the set temperature In a blast drying oven at 45°C, aging is carried out, and coated tablets are obtained after 24 hours;
  • Step 5 Perform laser drilling on the coated tablet obtained in step 4.
  • the perforated surface should be the drug-containing layer (the white corresponding surface) with a small hole size of 0.4-0.7 mm to obtain sacubitril-valsartan sodium sustained-release tablets.
  • the above-mentioned sacubitril-valsartan sodium is processed through a 60-mesh sieve.
  • Step 1 Put sacubitril-valsartan sodium, copovidone, hydroxyethyl cellulose, colloidal silicon dioxide, and talcum powder in the drug-containing layer in the above prescription into a mixing pot, and set the mixing speed to 18r/min , mixed for 20 minutes; then the mixed material was subjected to dry granulation and granulation, and finally the magnesium stearate of the drug-containing layer was added, the mixing speed was set to 18r/min, and the mixture was mixed for 5 minutes to obtain the drug-containing layer mixture;
  • Step 2 Put the polyoxyethylene, sodium chloride, copovidone, and red iron oxide of the booster layer in the above prescription into a mixing pot, set the mixing speed to 18r/min, and mix for 10 minutes; then add the hard Magnesium fatty acid, set mixing speed 18r/min, mix for 5 minutes, obtain booster layer mixture;
  • Step 3 Put the drug-containing layer mixture obtained in step 1 and the booster layer mixture obtained in step 2 on the rotary tablet press, and adjust the equipment parameters so that the tablet weight of the drug-containing layer is 300 mg, and the tablet weight of the booster layer is 100 mg , with a total tablet weight of 400mg, a hardness of 100N-180N, and a shallow arc-shaped tablet core containing medicine;
  • Coat the drug-containing tablet core obtained in step 3 with the above-mentioned slow-release coating solution rotate at a speed of 8rpm-15rpm, control the temperature of the tablet bed at 25°C-35°C, and set the spray speed at 5rpm-20rpm Spray liquid, continue coating so that the weight gain of the coating is 8.0% to 11.0%, stop spraying liquid, and then dry at a tablet bed temperature of 30°C to 35°C for 5 minutes to 10 minutes, and then release the tablet; then place it at the set temperature In a blast drying oven at 45°C, aging is carried out, and coated tablets are obtained after 24 hours;
  • Step 5 Perform laser drilling on the coated tablet obtained in step 4.
  • the perforated surface should be the drug-containing layer (corresponding to the white surface) with a small hole size of 0.4-0.7 mm to obtain sacubitril-valsartan sodium sustained-release tablets.
  • the above-mentioned sacubitril-valsartan sodium is processed through a 60-mesh sieve.
  • Step 1 Put the raw and auxiliary materials of the drug-containing layer in the above prescription except the lubricant magnesium stearate in a mixing pot, set the mixing speed at 18r/min, and mix for 20 minutes; then carry out dry granulation of the mixed materials, and finally Add the magnesium stearate of the drug-containing layer, set the mixing speed to 18r/min, and mix for 5 minutes to obtain the drug-containing layer mixture;
  • Step 2 Put the polyoxyethylene, sodium chloride, copovidone, and red iron oxide of the booster layer in the above prescription into a mixing pot, set the mixing speed to 18r/min, and mix for 10 minutes; then add the hard Magnesium fatty acid, set mixing speed 18r/min, mix for 5 minutes, obtain booster layer mixture;
  • Step 3 Put the drug-containing layer mixture obtained in step 1 and the booster layer mixture obtained in step 2 on a rotary tablet press, adjust the equipment parameters, and press the target weight of the drug-containing layer and booster layer to obtain the total tablet
  • the weight is 400mg
  • the hardness is 100N ⁇ 180N
  • the drug-containing tablet core is compressed into a shallow arc
  • Coat the drug-containing tablet core obtained in step 3 with the above-mentioned slow-release coating solution rotate at a speed of 8rpm-15rpm, control the temperature of the tablet bed at 25°C-35°C, and set the spray speed at 5rpm-20rpm Spray liquid, continue coating so that the weight gain of the coating is 8.0% to 11.0%, stop spraying liquid, and then dry at a tablet bed temperature of 30°C to 35°C for 5 minutes to 10 minutes, and then release the tablet; then place it at the set temperature In a blast drying oven at 45°C, aging is carried out, and coated tablets are obtained after 24 hours;
  • Step 5 Perform laser drilling on the coated tablet obtained in step 4.
  • the perforated surface should be the drug-containing layer (the white corresponding surface) with a small hole size of 0.4-0.7 mm to obtain sacubitril-valsartan sodium sustained-release tablets.
  • the above-mentioned sacubitril-valsartan sodium is processed through a 60-mesh sieve.
  • Step 1 Put the sacubitril-valsartan sodium, copovidone, hydroxyethyl cellulose, yellow iron oxide, colloidal silicon dioxide, and talcum powder in the drug-containing layer in the above prescription into a mixing pot, set the mixing Mix at a speed of 18r/min for 20 minutes; then carry out dry granulation of the mixed material, and finally add magnesium stearate in the drug-containing layer, set the mixing speed at 18r/min, and mix for 5 minutes to obtain a drug-containing layer mixture;
  • Step 2 Put the polyoxyethylene, sodium chloride, copovidone, and red iron oxide of the booster layer in the above prescription into a mixing pot, set the mixing speed to 18r/min, and mix for 10 minutes; then add the hard Magnesium fatty acid, set mixing speed 18r/min, mix for 5 minutes, obtain booster layer mixture;
  • Step 3 Put the drug-containing layer mixture obtained in step 1 and the booster layer mixture obtained in step 2 on the rotary tablet press, and adjust the equipment parameters so that the tablet weight of the drug-containing layer is 300 mg, and the tablet weight of the booster layer is 100 mg , with a total tablet weight of 400mg, a hardness of 100N-180N, and a shallow arc-shaped tablet core containing medicine;
  • Coat the drug-containing tablet core obtained in step 3 with the above-mentioned slow-release coating solution rotate at a speed of 8rpm-15rpm, control the temperature of the tablet bed at 25°C-35°C, and set the spray speed at 5rpm-20rpm Spray liquid, continue coating so that the weight gain of the coating is 8.0% to 14.0%, stop spraying liquid, and then dry at a tablet bed temperature of 30°C to 35°C for 5 minutes to 10 minutes, and then release the tablet; then place it at the set temperature In a blast drying oven at 45°C, aging is carried out, and coated tablets are obtained after 24 hours;
  • Step 5 Perform laser drilling on the coated tablet obtained in step 4.
  • the perforated surface should be the drug-containing layer (the white corresponding surface) with a small hole size of 0.4-0.7 mm to obtain sacubitril-valsartan sodium sustained-release tablets.
  • Sacubitril-valsartan sodium is prepared into gastric retention sustained-release tablets, and the prescription design is as follows:
  • the above-mentioned sacubitril-valsartan sodium is processed through a 60-mesh sieve.
  • Step 1 Put the raw and auxiliary materials in the above prescription except the lubricant in a mixing pot, set the mixing speed to 18r/min, and mix for 20 minutes; then add the prescribed amount of magnesium stearate, set the mixing speed to 18r/min, and mix for 5 Minutes to obtain the material mixture;
  • Step 2 Put the mixture obtained in Step 1 on a rotary tablet press, adjust the equipment parameters, adjust the tablet weight to 1000 mg, and press the tablet to a hardness of 140-220N.
  • Sacubitril-valsartan sodium is prepared into ordinary gel matrix sustained-release tablets, and the prescription design is as follows:
  • the above-mentioned sacubitril-valsartan sodium is processed through a 60-mesh sieve.
  • Step 1 Put the raw and auxiliary materials in the above prescription except the lubricant in a mixing pot, set the mixing speed to 18r/min, and mix for 20 minutes; then add the prescribed amount of magnesium stearate, set the mixing speed to 18r/min, and mix for 5 Minutes to obtain the material mixture;
  • Step 2 Put the mixture obtained in Step 1 on a rotary tablet press, adjust the equipment parameters, adjust the tablet weight to 500 mg, and press the tablet to a hardness of 100-180N.
  • Example I-1 ⁇ Example I-6 and Example II-1 ⁇ Example II-6 that in the in vitro dissolution, in the osmotic pump dosage form developed by the present invention, sacubitril valsartan sodium slowly
  • the sacubitril and valsartan in the release tablet can achieve long-acting synchronous release, meeting the requirement of once-a-day dosing; and the drug release behavior is not affected by the pH of the medium environment.

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Abstract

一种沙库巴曲缬沙坦钠缓释组合物、其制备方法及应用，该组合物为24小时缓慢释放药物，沙库巴曲和缬沙坦的溶出同时满足以下三个特征：A)在2小时内溶出不超过40％的药物活性成分；B)在8小时内溶出20％～75％的药物活性成分；C)在24小时内溶出不低于65％的药物活性成分。相比普通凝胶缓释剂型，该组合物中沙库巴曲和缬沙坦可达到同步缓慢释放，且释药行为不受介质环境pH、胃肠蠕动、食物等因素的影响，体内外相关性好，在24小时内平缓释放，治疗效果好；相比普通速释制剂而言，减少了服药次数，提高患者的顺应性，对于老人或儿童等吞咽困难的人群，有利于提高其服药依从性，用药方便，毒副作用较小，市场化前景好。

Description

沙库巴曲缬沙坦钠缓释组合物、其制备方法及应用
本申请要求享有2021年7月12日向中国国家知识产权局提交的，专利申请号为202110784642.5，发明名称为“沙库巴曲缬沙坦钠缓释组合物、其制备方法及应用”的在先申请的优先权权益。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及沙库巴曲缬沙坦钠缓释组合物、其制备方法及应用。
背景技术
沙库巴曲缬沙坦钠适用于治疗射血分数降低(HF-REF)的慢性心力衰竭的成年患者，降低心血管死亡和心力衰竭住院的风险。沙库巴曲是脑啡肽酶抑制剂，缬沙坦是一种血管紧张素II受体阻滞剂。沙库巴曲缬沙坦钠可代替血管紧张素转化酶抑制剂(ACEI)或血管紧张素Ⅱ受体拮抗剂(ARB)，与其他心力衰竭治疗药物合用。
心力衰竭(heart failure)简称心衰，心衰患者的心脏不能泵出足够血液供给全身，可能出现呼吸困难、乏力和体液潴留症状，并逐渐加重，严重影响生活质量。据统计，全球每年花费在心衰上的资金为1080亿美元，2003年一项大型流行病学调查显示，中国内地成年人心衰患病率已达0.9％，约有心衰患者450万人。另一方面，高血压是引起心力衰竭(心衰)最主要的病因之一，是全球范围内的重大公共卫生问题。根据Framingham报告，高血压在心力衰竭疾病中占75％，我国为60％～88.5％，为血压正常者6倍。心力衰竭发生后，5年死亡率为50％以上。而我国高血压病发病率目前大概在11.88％左右，估计全国大约有将近一亿多高血压病患者。
约半数心衰患者为射血分数降低的心衰，目前的抗心衰药物只能阻断RAAS系统(肾素-血管紧张素-醛固酮系统)激活而引发的有害作用，相当于只有攻击的“矛”，缺乏保护心脏的“盾”，治疗后患者死亡率仍很高。数据显示，50％的患者在诊断心衰5年内死亡。
在2014年欧洲心脏病学会(ESC)大会公布的心力衰竭临床研究(PARADIGM-HF)中，该研究涉及全球范围内8442例患者，其中353例为中国患者。研究显示，与依那普利治疗组相比，接受诺华的革命性心衰治疗药LCZ696治疗的射血分数降低心衰(HF-REF)患者，心血管死亡风险降低20％，心衰住院风险降低21％。该数据同时发表在权威期刊《新英格兰医学杂志》上。
沙库巴曲缬沙坦钠以独特的多重方式发挥作用，在抑制RAAS系统激活引发的有害作用的同时，还能增强保护心脏的神经内分泌系统(利钠肽系统)作用。这相当于既有了“矛”，又有了“盾”。新研究显示，LCZ696的耐受性良好且副作用易于管理，患者因不良事件退出研究的比例低。
沙库巴曲缬沙坦钠化学名称为十八钠六(4-{[(1S,3R)-1-([1,1’-联苯基)-4-基甲基)-4-乙氧基-3-甲基-4-氧代丁基]氨基}-4-氧代丁酸)六(N-戊酰基-N-{[2’-(1H-四氮唑-5-基)联苯-4-基]甲基}-L-缬氨酸)-水(1/15)，其结构式如下：
Figure PCTCN2022105144-appb-000001
目前诺华已经开发了沙库巴曲缬沙坦钠普通速释片剂，其用量为50mg至200mg每天服药两次，服药剂量大且服药次数多。
CN105748420A专利文献中提出一种治疗心力衰竭的LCZ696缓释骨架片的制备方法，其缓释剂型以凝胶骨架为释药机理，缓释时间较短，活性成分仅在8小时完全释放，不能达到24小时平稳释放；凝胶骨架片在体内易受食物挤压等因素影响，造成药物或不同程度的提高释放速度，缓释效果较差，体内外相关性较差。
寻找缓释效果好、释放平稳、慢性心力衰竭患者顺应性好的药物剂型是目前急需解决的技术问题。
发明内容
本发明提供了一种沙库巴曲缬沙坦钠缓释组合物，其为24小时缓慢释放药物，沙库巴曲和缬沙坦的溶出同时满足以下三个特征：
A)在1小时内溶出不超过40％的药物活性成分；
B)在6小时内溶出10％～70％的药物活性成分；
C)在24小时内溶出不低于65％的药物活性成分；
所述的药物活性成分可以选自沙库巴曲缬沙坦钠、或其药学上可接受的其他盐型、溶剂合物及水合物中的一种、两种或更多种。
根据本发明的一种实施方案，所述的沙库巴曲缬沙坦钠缓释组合物，沙库巴曲的溶出同时满足以下三个特征：
A)在1小时内溶出不超过35％的药物活性成分；
B)在6小时内溶出10％～70％的药物活性成分；
C)在24小时内溶出不低于70％的药物活性成分；
缬沙坦的溶出同时满足以下三个特征：
A)在1小时内溶出不超过35％的药物活性成分；
B)在6小时内溶出15％～70％的药物活性成分；
C)在24小时内溶出不低于75％的药物活性成分。
根据本发明的一种实施方案，所述的沙库巴曲缬沙坦钠缓释组合物，沙库巴曲的溶出同时满足以下三个特征：
A)在1小时内溶出不超过25％的药物活性成分；
B)在6小时内溶出10％～65％的药物活性成分；
C)在24小时内溶出不低于75％的药物活性成分；
缬沙坦的溶出同时满足以下三个特征：
A)在1小时内溶出不超过30％的药物活性成分；
B)在6小时内溶出10％～65％的药物活性成分；
C)在24小时内溶出不低于75％的药物活性成分。
根据本发明的一种实施方案，所述的沙库巴曲缬沙坦钠缓释组合物，沙库巴曲的溶出同时满足以下三个特征：
A)在1小时内溶出不超过25％的药物活性成分；
B)在6小时内溶出10％～65％的药物活性成分；
C)在24小时内溶出不低于80％的药物活性成分；
缬沙坦的溶出同时满足以下三个特征：
A)在1小时内溶出不超过25％的药物活性成分；
B)在6小时内溶出15％～65％的药物活性成分；
C)在24小时内溶出不低于80％的药物活性成分。
优选地，所述沙库巴曲和缬沙坦的溶出为同步释放。
根据本发明的一种实施方案，所述缓释组合物为24小时缓慢释放药物，沙库巴曲和缬沙坦的溶出同时满足以下三个特征：
A)在2小时内溶出不超过40％的药物活性成分；
B)在8小时内溶出20％～75％的药物活性成分；
C)在24小时内溶出不低于65％的药物活性成分；
所述的药物活性成分可以选自沙库巴曲缬沙坦钠、或其药学上可接受的其他盐型、溶剂合物及水合物中的一种、两种或更多种。
在一种实施方案中，所述的沙库巴曲缬沙坦钠缓释组合物，沙库巴曲的溶出同时满足以下三个特征：
A)在2小时内溶出不超过35％的药物活性成分；
B)在8小时内溶出20％～70％的药物活性成分；
C)在24小时内溶出不低于75％的药物活性成分；
缬沙坦的溶出同时满足以下三个特征：
A)在2小时内溶出不超过35％的药物活性成分；
B)在8小时内溶出20％～70％的药物活性成分；
C)在24小时内溶出不低于75％的药物活性成分。
在一种实施方案中，所述的沙库巴曲缬沙坦钠缓释组合物，沙库巴曲的溶出同时满足以下三个特征：
A)在2小时内溶出不超过25％的药物活性成分；
B)在8小时内溶出25％～65％的药物活性成分；
C)在24小时内溶出不低于75％的药物活性成分；
缬沙坦的溶出同时满足以下三个特征：
A)在2小时内溶出不超过25％的药物活性成分；
B)在8小时内溶出25％～65％的药物活性成分；
C)在24小时内溶出不低于75％的药物活性成分；
在一种实施方案中，所述的沙库巴曲缬沙坦钠缓释组合物，沙库巴曲的溶出同时满足以下三个特征：
A)在2小时内溶出不超过25％的药物活性成分；
B)在8小时内溶出30％～65％的药物活性成分；
C)在24小时内溶出不低于80％的药物活性成分；
缬沙坦的溶出同时满足以下三个特征：
A)在2小时内溶出不超过25％的药物活性成分；
B)在8小时内溶出30％～65％的药物活性成分；
C)在24小时内溶出不低于80％的药物活性成分；
优选地，所述沙库巴曲和缬沙坦的溶出为同步释放。
其中，所述“溶出”指药物活性成分的累积溶出度，例如沙库巴曲的累积溶出度和缬沙坦的累积溶出度；进一步地，所述累积溶出度在pH 6.8磷酸盐缓冲液中测得。本领域技术人员能够理解，随着时间增加，所述沙库巴曲缬沙坦钠的溶出度逐渐增加。
根据本发明的实施方案，所述沙库巴曲缬沙坦钠缓释组合物包括含药层片芯以及包衣膜，并在含药层一侧打孔；所述的含药层片芯包含药物活性成分以及载体；所述的药物活性成分可以选自沙库巴曲缬沙坦钠、或其药学上可接受的其他盐型、溶剂合物及水合物中的一种、两种或更多种；所述的载体例如为渗透压调节剂、溶胀剂、增稠剂、助流剂和润滑剂中的一种或多种；所述的包衣膜为半渗透膜；
所述缓释组合物还任选包括或不包括助推层片芯，所述的助推层片芯包括渗透压调节剂、溶胀剂、着色剂和润滑剂中的一种或多种。
根据本发明的实施方案，所述的含药层片芯中，所述的药物活性成分优选沙库巴曲缬沙坦钠。
根据本发明的实施方案，所述的含药层片芯中，所述的药物活性成分的含量为10.00％～80.00％，例如28.25％、33.93％、37.67％、37.70％、40.39％、56.50％、67.87％、或75.40％，所述的含量是指药物活性成分的质量占含药层片芯总质量的百分比。
根据本发明的实施方案，所述的含药层片芯中，所述的渗透压调节剂可以选自氯化 钠、氯化钾、甘露醇、山梨醇、硫酸钠、硫酸镁、葡萄糖、果糖、蔗糖和乳糖中的一种或多种。在一种实施方式中，所述乳糖为一水乳糖。作为示例，所述渗透压调节剂可以为山梨醇、一水乳糖和氯化钠的混合物，山梨醇和氯化钠的混合物，或者氯化钠。
根据本发明的实施方案，所述的含药层片芯中，所述的渗透压调节剂的含量为1.00％～60.00％，例如48.75％、40.34％、31.50％、27.50％、3.00％或1.50％，所述的含量是指渗透压调节剂的质量占含药层片芯总质量的百分比。
根据本发明的实施方案，所述的含药层片芯中，所述的增稠剂(也可以称为混悬剂或粘合剂)能够增加分散介质的黏度，以降低微粒的沉降速度或增加微粒亲水性的附加剂，例如选自羟丙甲纤维素、羟丙纤维素、羟乙基纤维素、乙基纤维素、共聚维酮、阿拉伯胶、预胶化淀粉和聚乙烯吡咯烷酮中的一种或多种。作为示例，所述的增稠剂选自羟丙甲纤维素，或者共聚维酮和羟乙基纤维素的混合物。
根据本发明的实施方案，所述的含药层片芯中，所述的增稠剂的含量为10.00％～70.00％，例如21.50％、10.50％、21.00％、15.00％、13.81％、57.30％、34.80％、25.00％、53.90％、56.87％、19.93％、18.83％、或5.41％，所述的含量是指增稠剂的质量占含药层片芯总质量的百分比。
根据本发明的实施方案，所述的含药层片芯中，所述的溶胀剂(也可以称为推动剂)可以为能够吸收溶剂而发生膨胀的物质，优选聚氧乙烯、卡波姆、羧甲淀粉钠、交联聚维酮和海藻酸钠中的一种或多种。
根据本发明的实施方案，所述的含药层片芯中，所述的溶胀剂的含量优选0.00％～70.00％，例如48.06％、24.02％或19.93％，所述的含量是指溶胀剂的质量占含药层片芯总质量的百分比。
根据本发明的实施方案，所述的含药层片芯还可以含有着色剂。
根据本发明的实施方案，所述的含药层片芯中，所述的着色剂可以为能够达到着色目的的物质，优选氧化铁红、氧化铁黄和氧化铁黑中的一种或多种。
根据本发明的实施方案，所述的含药层片芯中，所述的着色剂的含量为0％～5.00％，例如0.10％，所述的含量是指着色剂的质量占含药层片芯总质量的百分比。
根据本发明的实施方案，所述的含药层片芯中，所述的助流剂可以为能够降低粒子间的摩擦力而能改善粉末或颗粒流动性的辅料，优选滑石粉、微粉硅胶、胶态二氧化硅中的一种或多种。
根据本发明的实施方案，所述的含药层片芯中，所述的助流剂的含量优选0％～5.00％，例如0～1.00％，作为示例含量为0.30％、0.50％、1.57％、1.67％、3.00％、3.54％或3.57％，所述的含量是指助流剂的质量占含药层片芯总质量的百分比。
根据本发明的实施方案，所述的含药层片芯中，所述的润滑剂可以为具有润滑作用的物质，优选硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯、硬酯酰富马酸盐和微粉硅胶中的一种或多种。例如，所述的硬脂酸金属盐优选硬脂酸镁和/或硬脂酸钙。例如，所述的 硬脂酸酯优选硬脂酸甘油酯。
根据本发明的实施方案，所述的含药层片芯中，所述的润滑剂的含量优选0.50％～60.00％，例如1.00～30.00％，作为示例含量为1.00％、1.20％、2.00％、2.14％、2.33％或3.00％，所述的含量是指润滑剂的质量占含药层片芯总质量的百分比。
所述含药层片芯中，药物活性成分和载体的含量之和为100％。
根据本发明的一种实施方案，当所述缓释组合物含有助推层片芯时，所述含药层片芯中不含有渗透压调节剂。
根据本发明的实施方案，所述的助推层片芯中，所述的渗透压调节剂可以为调节渗透作用的物质，优选氯化钠、氯化钾、甘露醇、山梨醇、硫酸钠、硫酸镁、葡萄糖、果糖、蔗糖和乳糖中的一种或多种，例如为氯化钠。在一种实施方案中，所述的乳糖可以为一水乳糖。
根据本发明的实施方案，所述的助推层片芯中，所述的渗透压调节剂的含量为1.00％～60.00％，例如31.74％、29.17％、25.00％或5.00％，所述的含量是指渗透压调节剂的质量占助推层片芯总质量的百分比。
根据本发明的实施方案，所述的助推层片芯中，所述的溶胀剂(也可以称为推动剂)可以为能够吸收溶剂而发生膨胀的物质，优选聚乙烯吡咯烷酮、羟乙基纤维素、共聚维酮、羟丙甲基纤维素、阿拉伯胶、卡波姆、羧甲淀粉钠、海藻酸钠和聚氧乙烯中的一种或多种。
根据本发明的实施方案，所述的助推层片芯中，所述的溶胀剂的含量为0.00％～90.00％，例如0.00％～80.00％，作为实例为8.33％、10.00％、20.00％、65.87％、63.00％、73.00％、60.83％或82.00％，所述的含量是指溶胀剂的质量占助推层片芯总质量的百分比。
根据本发明的实施方案，所述的助推层片芯中，所述的着色剂可以为能够达到着色目的的物质，优选氧化铁红、氧化铁黄和氧化铁黑中的一种或多种。
根据本发明的实施方案，所述的助推层片芯中，所述的着色剂的含量优选0.10％～10.00％，例如1.20％、1.00％或0.83％，所述的含量是指着色剂的质量占助推层片芯总质量的百分比。
根据本发明的实施方案，所述的助推层片芯中，所述的润滑剂可以为本领域中常规的具有润滑作用的物质，优选硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯、硬酯酰富马酸盐和微粉硅胶中的一种或多种。例如，所述的硬脂酸金属盐优选硬脂酸镁和/或硬脂酸钙。例如，所述的硬脂酸酯优选硬脂酸甘油酯。
根据本发明的实施方案，所述的助推层片芯中，所述的润滑剂的含量优选0.10％～10.00％，例如2.00％、1.20％、1.00％或0.84％，所述的含量是指润滑剂的质量占助推层片芯总质量的百分比。
所述助推层片芯中，各组分的含量之和为100％。
根据本发明的实施方案，所述的半渗透膜包含成膜材料、致孔剂和增塑剂中的一种 或多种。
根据本发明的实施方案，所述的包衣膜中，所述的成膜材料可以为能够分散在固体表面固化成膜的材料，优选醋酸纤维素、乙基纤维素、邻苯二甲酸醋酸纤维素、聚醋酸乙烯酯、丙烯酸树脂和甲基丙烯酸树脂中的一种或多种。
根据本发明的实施方案，所述的包衣膜中，所述的致孔剂可以为能够使材料遇水后形成孔道的物质，优选聚乙二醇、羟丙基纤维素、聚维酮和聚乙烯醇中的一种或多种。
根据本发明的实施方案，所述的包衣膜中，所述的增塑剂可以为能使聚合物塑性增加的物质，优选三醋酸甘油酯、柠檬酸甘油酯、甘油酯、邻苯二甲酸二丁酯和邻苯二甲酸二乙酯中的一种或多种。
在一种实施方案中，所述聚乙二醇为聚乙二醇4000。
在一种实施方案中，所述包衣膜包含醋酸纤维素和聚乙二醇4000。
在一种实施方案中，所述的包衣膜也可选择卡乐康提供的醋酸纤维素全配方包衣预混剂(
Figure PCTCN2022105144-appb-000002
CA)。
根据本发明的实施方案，本发明的沙库巴曲缬沙坦钠缓释组合物在体积为900ml的pH 6.8磷酸盐缓冲液，采用USP第二法转速50rpm进行溶出实验，沙库巴曲和缬沙坦的24小时累积释放度均可达85％以上。
根据本发明示例性的实施方案，所述的含药层片芯可以为以下任一配方：
配方一：28.25％沙库巴曲缬沙坦钠、25.00％山梨醇、21.25％一水乳糖、2.50％氯化钠、21.50％羟丙甲纤维素、0.50％胶态二氧化硅、1.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
配方二：56.50％沙库巴曲缬沙坦钠、20.00％山梨醇、10.00％一水乳糖、1.50％氯化钠、10.50％羟丙甲纤维素、0.50％胶态二氧化硅、1.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
配方三：37.67％沙库巴曲缬沙坦钠、36.66％山梨醇、3.67％氯化钠、21.00％羟丙甲纤维素、1.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
配方四：56.50％沙库巴曲缬沙坦钠、25.00％山梨醇、2.50％氯化钠、15.00％羟丙甲纤维素、1.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
配方五：33.93％沙库巴曲缬沙坦钠、48.06％聚氧乙烯、3.00％氯化钠、13.81％羟丙甲纤维素、1.20％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
配方六：67.87％沙库巴曲缬沙坦钠、24.02％聚氧乙烯、1.5％氯化钠、5.41％羟丙甲纤维素、1.20％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
配方七：37.70％沙库巴曲缬沙坦钠、38.63％共聚维酮、18.67％羟乙基纤维素、2.33％滑石粉、0.67％胶态二氧化硅、2.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
配方八：75.40％沙库巴曲缬沙坦钠、11.60％共聚维酮、8.33％羟乙基纤维素、1.00％ 滑石粉、0.67％胶态二氧化硅、3.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
配方九：40.39％沙库巴曲缬沙坦钠、26.90％共聚维酮、27.00％羟乙基纤维素、2.86％滑石粉、0.71％胶态二氧化硅、2.14％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
配方十：75.40％沙库巴曲缬沙坦钠、19.93％聚氧乙烯、1.00％滑石粉、0.67％胶态二氧化硅、3.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
配方十一：37.70％沙库巴曲缬沙坦钠、28.20％共聚维酮、28.66％羟乙基纤维素、2.67％滑石粉、0.67％胶态二氧化硅、2.00％硬脂酸镁、0.10％黄氧化铁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
配方十二：75.40％沙库巴曲缬沙坦钠、6.83％共聚维酮、12.00％羟乙基纤维素、2.67％滑石粉、0.67％胶态二氧化硅、2.33％硬脂酸镁、0.10％黄氧化铁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比。
根据本发明示例性的实施方案，所述的助推层片芯为以下配方中的任意一种：
配方一：65.86％聚氧乙烯、31.74％氯化钠、1.20％红氧化铁、1.20％硬脂酸镁，所述的百分比是指各组分的质量占助推层片芯总质量的百分比；
配方二：73.00％聚氧乙烯、20.00％共聚维酮、1.00％红氧化铁、5.00％氯化钠、1.00％硬脂酸镁，所述的百分比是指各组分的质量占助推层片芯总质量的百分比；
配方三：60.83％聚氧乙烯、8.33％共聚维酮、29.17％氯化钠、0.83％红氧化铁、0.84％硬脂酸镁，所述的百分比是指各组分的质量占助推层片芯总质量的百分比；
配方四：82.00％聚氧乙烯、10.00％共聚维酮、5.00％氯化钠、1.00％红氧化铁、2.00％硬脂酸镁，所述的百分比是指各组分的质量占助推层片芯总质量的百分比；
配方五：63.00％聚氧乙烯、10.00％共聚维酮、25.00％氯化钠、1.00％红氧化铁、1.00％硬脂酸镁，所述的百分比是指各组分的质量占助推层片芯总质量的百分比。
根据本发明示例性的实施方案，所述的包衣为以下任一组成：
包衣一：9.00％醋酸纤维素、1.00％聚乙二醇4000，所述的百分比是指各组分的质量占药片片芯总质量的百分比；
包衣溶剂为丙酮和水，例如丙酮与水的质量比为9:1；包衣溶液的固含量为5％，所述的固含量为固体物质总质量占包衣溶液总质量的百分比；
包衣二：7.20％醋酸纤维素和0.80％聚乙二醇4000，所述的百分比是指各组分的质量占药片片芯总质量的百分比；
包衣溶剂为丙酮和水，例如丙酮与水的质量比为9:1；包衣溶液的固含量为5％，所述的固含量为固体物质总质量占包衣溶液总质量的百分比。
包衣三：6％醋酸纤维素和3％聚乙二醇4000，所述的百分比是指各组分的质量占药片片芯总质量的百分比；
包衣溶剂为丙酮和水，例如丙酮与水的质量比为9:1；包衣溶液的固含量为5％，所述的固含量为固体物质总质量占包衣溶液总质量的百分比。
在一种实施方案中，所述包衣溶液为包衣溶剂和醋酸纤维素、聚乙二醇4000的混合溶液。
上述药片片芯由含药层片芯和助推层片芯组成；当不含有助推层片芯时，药片片芯即为含药层片芯。
本发明还提供上述缓释组合物的制备方法，包括如下步骤：
将含药层片芯的组分单独混合后，压制，得到含药层片芯(制备工艺可为粉末直压、干法制粒、湿法制粒等)；所述含药层片芯包衣(半透膜包衣)后在含药层一侧打孔，即可得到所述的沙库巴曲缬沙坦钠缓释组合物。
在一种实施方案中，所述制备方法包括如下具体步骤：
步骤1)：将含药层片芯中除了润滑剂之外的组分过筛、混合，然后再与润滑剂混合，得到含药层混合物；
或者，将含药层片芯中除了助流剂、润滑剂之外的组分过筛、混合，然后再与助流剂、润滑剂混合，得到含药层混合物；
步骤2)：将步骤1得到的含药层混合物与润滑剂混合、压片，得到含药片芯；
步骤3)：将步骤2)得到的含药层片芯进行包衣、老化，得到包衣片；
步骤4)将步骤3)得到的包衣片进行打孔，得到沙库巴曲缬沙坦钠缓释片。
根据本发明的实施方案，步骤1)中，所述的过筛，可以为60目的筛或40目的筛。
根据本发明的实施方案，步骤1)中，所述的混合可以在混合机，例如混合罐中进行。所述的混合的速度可以为18r/min，所述的混合的时间可以为1分钟～2小时，例如20分钟。
根据本发明的实施方案，步骤2)所述含药片芯的硬度为100N～160N。
根据本发明的实施方案，步骤3)中，所述的包衣的温度优选为25℃～45℃，例如30℃。
根据本发明的实施方案，步骤3)中，所述的包衣优选包衣增重6％～20％，所述的百分比是指(沙库巴曲缬沙坦钠包衣片的重量-含药层片芯的重量)/含药层片芯的重量×100％。
根据本发明的实施方案，步骤3)中，所述的老化的温度优选为20℃～60℃，例如45℃。
根据本发明的实施方案，步骤3)中，所述的老化的时间优选为10小时～30小时，例如24小时。
根据本发明的实施方案，步骤4)中，所述的打孔可以在含药层一侧中心位置打孔。所述的打孔的孔径可以为0.4毫米～0.7毫米。
本发明还提供一种缓释组合物的制备方法，包括：将含药层片芯的组分与助推层片 芯的组分均单独混合后，压制，得到双层片芯(各层混合粉的制备工艺可为粉末直压、干法制粒、湿法制粒等)；所述双层片芯包衣(半透膜包衣)后，在含药层一侧打孔，即可得到所述的沙库巴曲缬沙坦钠缓释组合物。
在一种实施方案中，所述制备方法包括如下具体步骤：
步骤A1)：将含药层片芯中除了润滑剂之外的组分过筛、混合，然后再与润滑剂混合，得到含药层混合物；
步骤A2)：将助推层片芯中除了润滑剂之外的组分过筛、混合，然后再与润滑剂混合，得到助推层混合物；
步骤A3)：将步骤A1)得到的含药层混合物与步骤A2)中得到的助推层混合物进行压片，得到含药片芯；
步骤A4)将步骤A3)得到的含药片芯进行包衣、老化，得到包衣片；
步骤A5)将步骤A4)得到的包衣片在含药层一侧进行打孔，得到沙库巴曲缬沙坦钠缓释片。
根据本发明的实施方案，步骤A1)和步骤A2)中，所述的过筛，可以为40目或60目的筛。
根据本发明的实施方案，步骤A1)和步骤A2)中，所述的混合可以在混合机，例如混合罐中进行。所述的混合的速度可以为18r/min，所述的混合的时间可以为1分钟～2小时，例如5分钟、10分钟或15分钟。
根据本发明的实施方案，步骤A4)中，所述的包衣的温度优选25℃～45℃，例如30℃。
根据本发明的实施方案，步骤A4)中，所述的包衣优选包衣增重6％～20％，所述的百分比是指(沙库巴曲缬沙坦钠包衣片的重量-含药片芯的重量)/含药片芯的重量×100％。
根据本发明的实施方案，步骤A4)中，所述的老化的温度优选为20℃～60℃，例如45℃。
根据本发明的实施方案，步骤A4)中，所述的老化的时间优选为10小时～30小时，例如24小时。
根据本发明的实施方案，步骤A5)中，所述的打孔可以在含药面中心位置打孔。例如，所述的打孔的孔径可以为0.4毫米～0.7毫米。
本发明还提供了一种沙库巴曲缬沙坦钠缓释制剂，其包含所述的沙库巴曲缬沙坦钠缓释组合物。
根据本发明的实施方案，所述的沙库巴曲缬沙坦钠缓释制剂可以为缓释片、缓释微丸、缓释胶囊等。
本发明还提供了所述的沙库巴曲缬沙坦缓释组合物或者所述的沙库巴曲缬沙坦缓释制剂在制备治疗和/或预防射血分数降低的慢性心力衰竭的药物中的应用。
本发明还提供了治疗和或预防射血分数降低的慢性心力衰竭的方法，其为给有需要的患者施用有效剂量的所述的沙库巴曲缬沙坦缓释制剂。
本发明所用试剂和原料均市售可得。
本发明的有益效果：
本发明提供了一种与现有技术不同的缓释效果好、释放平稳、慢性心力衰竭患者顺应性好的沙库巴曲缬沙坦钠缓释组合物、其制备方法及应用。本发明的沙库巴曲缬沙坦钠缓释组合物，其释药行为不受介质环境pH、胃肠蠕动、食物等因素的影响，体内外相关性好，可以使沙库巴曲和缬沙坦钠在24小时内同步、平缓释放，达到较好的治疗效果；相比普通速释制剂而言，其优势在于：(1)减少了服药次数，通过缓释作用能达到良好的治疗效果，提高患者的顺应性；(2)对于老人或儿童等吞咽困难的人群，有利于提高其服药依从性；(3)避免患者随意中断用药，预防疾病复发和恶性并发症进展；(4)每日一次，按照临床表现选用合适的规格，给药次数少，用药方便，毒副作用较小。
附图说明
图1示出了在pH6.8磷酸盐缓冲液中，实施例I-1中沙库巴曲和缬沙坦的溶出曲线图；
图2示出了在pH6.8磷酸盐缓冲液中，实施例I-2中沙库巴曲和缬沙坦的溶出曲线图；
图3示出了在pH6.8磷酸盐缓冲液中，实施例I-3中沙库巴曲和缬沙坦的溶出曲线图；
图4示出了在pH6.8磷酸盐缓冲液中，实施例I-4中沙库巴曲和缬沙坦的溶出曲线图；
图5示出了在pH6.8磷酸盐缓冲液中，实施例I-5中沙库巴曲和缬沙坦的溶出曲线图；
图6示出了在pH6.8磷酸盐缓冲液中，实施例I-6中沙库巴曲和缬沙坦的溶出曲线图；
图7示出了在pH6.8磷酸盐缓冲液中，实施例II-1中沙库巴曲和缬沙坦的溶出曲线图；
图8示出了在pH6.8磷酸盐缓冲液中，实施例II-2中沙库巴曲和缬沙坦的溶出曲线图；
图9示出了在pH6.8磷酸盐缓冲液中，实施例II-3中沙库巴曲和缬沙坦的溶出曲线图；
图10示出了在pH4.5醋酸盐缓冲液中，实施例II-3中沙库巴曲和缬沙坦的溶出曲线图；
图11示出了在水溶液中，实施例II-3中沙库巴曲和缬沙坦的溶出曲线图；
图12示在pH6.8磷酸盐缓冲液中，实施例II-4中沙库巴曲和缬沙坦的溶出曲线图；
图13示出了在pH6.8磷酸盐缓冲液中，实施例II-5中沙库巴曲和缬沙坦的溶出曲线图；
图14示出了在pH6.8磷酸盐缓冲液中，实施例II-6中沙库巴曲和缬沙坦的溶出曲线图；
图15示出了在pH4.5醋酸盐缓冲液中，实施例II-6中沙库巴曲和缬沙坦的溶出曲线图；
图16示出了在水溶液中，实施例II-6中沙库巴曲和缬沙坦的溶出曲线图；
图17示出了在pH6.8磷酸盐缓冲液中，实施例II-7中沙库巴曲和缬沙坦的溶出曲线图；
图18示出了在pH6.8磷酸盐缓冲液中，实施例II-8中沙库巴曲和缬沙坦的溶出曲线图。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
溶出实验：本发明的沙库巴曲缬沙坦钠缓释组合物采用在体积为900ml的pH 6.8磷酸盐缓冲液，采用USP第二法转速50rpm的溶出方法进行溶出实验。
实施例I-1～2
Figure PCTCN2022105144-appb-000003
Figure PCTCN2022105144-appb-000004
制备过程：
将上述沙库巴曲缬沙坦钠通过60目筛网处理；山梨醇、胶态二氧化硅过40目去团。
步骤1：将上述处方中的沙库巴曲缬沙坦钠、山梨醇、一水乳糖、氯化钠、羟丙甲纤维素置于混合锅中，设置混合速度18r/min，混合20分钟，得到含药层混合物；
步骤2：将步骤1得到的含药层混合物与胶态二氧化硅混合，设置混合速度18r/min，混合5分钟；再加入硬脂酸镁，设置混合速度18r/min，混合5分钟；然后置于旋转压片机上，压制成单片400mg、硬度100N～160N，压制浅弧圆形含药片芯；
步骤3：
根据以下步骤配制缓释包衣溶液：将纯化水加入烧杯中，使用磁力搅拌器进行搅拌，在搅拌过程中加入丙酮，全部加入后搅拌5分钟，使之混合均匀；再缓慢加入
Figure PCTCN2022105144-appb-000005
CA，持续搅拌30分钟～120分钟使之完全溶解，得到缓释包衣溶液；
对步骤2得到的含药片芯用上述缓释包衣溶液进行包衣，使用8rpm～15rpm的包衣锅转速进行转动，进风风量控制在30m 3/h～120m 3/h，片床温度控制在25℃～35℃，喷液速度设定在5rpm～20rpm范围进行喷液，持续包衣使之包衣增重分别为10.3％和10.1％停止喷液，再以片床温度30℃～35℃进行干燥5分钟～10分钟，出片；然后放置于设定温度45℃的鼓风干燥箱中，进行老化，24小时后，得到包衣片；
步骤4：将步骤3得到的包衣片，进行激光打孔，小孔尺寸0.4～0.7mm得到沙库巴曲缬沙坦钠缓释片。
以上步骤制得的沙库巴曲缬沙坦钠缓释片溶出数据如表1和图1-2所示。
表1 实施例I-1～2制得的沙库巴曲缬沙坦钠缓释片的溶出度
Figure PCTCN2022105144-appb-000006
实施例I-3～4
Figure PCTCN2022105144-appb-000007
制备过程：
将上述沙库巴曲缬沙坦钠通过60目筛网处理；山梨醇过40目去团。
步骤1：将上述处方中的沙库巴曲缬沙坦钠、山梨醇、氯化钠、羟丙甲纤维素置于混合锅中，设置混合速度18r/min，混合20分钟，再加入内加硬脂酸镁，设置混合速度18r/min，混合5分钟；得到含药层混合物；
步骤2：将步骤1得到的含药层混合物置于干法制粒机中，调节设备参数，使之能压制成有一定硬度的大片，再用1.0mm筛网进行整粒；再与硬脂酸镁混合，设置混合速度18r/min，混合5分钟；然后再置于旋转压片机上，压制成浅弧圆形含药片芯；
步骤3：
根据以下步骤配制缓释包衣溶液：将纯化水加入烧杯中，使用磁力搅拌器进行搅拌，在搅拌过程中加入丙酮，全部加入后搅拌5分钟，使之混合均匀；再缓慢加入
Figure PCTCN2022105144-appb-000008
CA，持续搅拌30分钟～120分钟使之完全溶解，得到缓释包衣溶液；
对步骤2得到的含药片芯用上述缓释包衣溶液进行包衣，使用8rpm～15rpm的包衣锅转速进行转动，进风风量控制在30m 3/h～120m 3/h，片床温度控制在25℃～35℃，喷液速度设定在5rpm～20rpm范围进行喷液，持续包衣使之包衣增重分别为7.9％和8.2％停止喷液，再以片床温度30℃～35℃进行干燥5分钟～10分钟，出片；然后放置于设定温度45℃的鼓风干燥箱中，进行老化，24小时后得到包衣片；
步骤4：将步骤3得到的包衣片，进行激光打孔，小孔尺寸0.4～0.7mm得到沙库巴 曲缬沙坦钠缓释片。
以上步骤制得的沙库巴曲缬沙坦钠缓释片溶出数据如表2和图3-4所示。
表2 实施例I-3～4制得的沙库巴曲缬沙坦钠缓释片的溶出度
Figure PCTCN2022105144-appb-000009
实施例I-5～6
Figure PCTCN2022105144-appb-000010
Figure PCTCN2022105144-appb-000011
制备过程：
将上述沙库巴曲缬沙坦钠通过60目筛网处理。
步骤1：将上述处方中含药层的沙库巴曲缬沙坦钠、聚氧乙烯、氯化钠、羟丙甲纤维素置于混合锅中，设置混合速度18r/min，混合20分钟；再加入含药层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到含药层混合物；
步骤2：将上述处方中助推层的聚氧乙烯、氯化钠、红氧化铁置于混合锅中，设置混合速度18r/min，混合10分钟；再加入助推层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到助推层混合物；
步骤3：将步骤1得到的含药层混合物和步骤2得到的助推层混合物置于旋转压片机上，调节设备参数，使含药层的片重为333mg，助推层的片重为167mg，总片重为500mg，硬度100N～180N，压制浅弧圆形含药片芯；
步骤4：
根据以下步骤配制缓释包衣溶液：将纯化水加入烧杯中，使用磁力搅拌器进行搅拌，在搅拌过程中加入丙酮，全部加入后搅拌5分钟，使之混合均匀；再缓慢加入
Figure PCTCN2022105144-appb-000012
CA，持续搅拌30分钟～90分钟使之完全溶解，得到缓释包衣溶液；
对步骤3得到的含药片芯用上述缓释包衣溶液进行包衣，使用8rpm～15rpm的转速进行转动，片床温度控制在25℃～35℃，喷液速度设定在5rpm～20rpm范围进行喷液，持续包衣使之包衣增重8.2％和8.0％停止喷液，再以片床温度30℃～35℃进行干燥5分钟～10分钟，出片；然后放置于设定温度45℃的鼓风干燥箱中，进行老化，24小时后得到包衣片；
步骤5：将步骤4得到的包衣片，进行激光打孔，打孔面应为含药层(白色对应面)小孔尺寸0.4～0.7mm得到沙库巴曲缬沙坦钠缓释片。
以上步骤制得的沙库巴曲缬沙坦钠缓释片溶出数据如表1和图5-6所示。
表3 实施例I-5～6制得的沙库巴曲缬沙坦钠缓释片的溶出度
Figure PCTCN2022105144-appb-000013
Figure PCTCN2022105144-appb-000014
实施例II-1
Figure PCTCN2022105144-appb-000015
制备过程：
将上述沙库巴曲缬沙坦钠通过60目筛网处理。
步骤1：将上述处方中含药层的沙库巴曲缬沙坦钠、共聚维酮、羟乙基纤维素、胶态二氧化硅、滑石粉置于混合锅中，设置混合速度18r/min，混合20分钟；再将混合物料进 行干法制粒整粒，最后加入含药层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到含药层混合物；
步骤2：将上述处方中助推层的聚氧乙烯、氯化钠、共聚维酮、红氧化铁置于混合锅中，设置混合速度18r/min，混合10分钟；再加入助推层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到助推层混合物；
步骤3：将步骤1得到的含药层混合物和步骤2得到的助推层混合物置于旋转压片机上，调节设备参数，使含药层的片重为300mg，助推层的片重为100mg，总片重为400mg，硬度100N～180N，压制浅弧圆形含药片芯；
步骤4：
根据以下步骤配制缓释包衣溶液：将纯化水加入烧杯中，使用磁力搅拌器进行搅拌，在搅拌过程中加入丙酮，全部加入后搅拌5分钟，使之混合均匀；再缓慢加入
Figure PCTCN2022105144-appb-000016
CA，持续搅拌30分钟～90分钟使之完全溶解，得到缓释包衣溶液；
对步骤3得到的含药片芯用上述缓释包衣溶液进行包衣，使用8rpm～15rpm的转速进行转动，片床温度控制在25℃～35℃，喷液速度设定在5rpm～20rpm范围进行喷液，持续包衣使之包衣增重在8.0％～11.0％时停止喷液，再以片床温度30℃～35℃进行干燥5分钟～10分钟，出片；然后放置于设定温度45℃的鼓风干燥箱中，进行老化，24小时后得到包衣片；
步骤5：将步骤4得到的包衣片，进行激光打孔，打孔面应为含药层(白色对应面)小孔尺寸0.4～0.7mm得到沙库巴曲缬沙坦钠缓释片。
以上步骤制得的沙库巴曲缬沙坦钠缓释片在pH6.8磷酸盐中的溶出数据如表4和图7所示。
表4 实施例II-1制得的沙库巴曲缬沙坦钠缓释片的溶出度
Figure PCTCN2022105144-appb-000017
实施例II-2
Figure PCTCN2022105144-appb-000018
制备过程：
将上述沙库巴曲缬沙坦钠通过60目筛网处理。
步骤1：将上述处方中含药层除润滑剂硬脂酸镁外的原辅料置于混合锅中，设置混合速度18r/min，混合20分钟；再将混合物料进行干法制粒整粒，最后加入含药层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到含药层混合物；
步骤2：将上述处方中助推层的聚氧乙烯、氯化钠、共聚维酮、红氧化铁置于混合锅中，设置混合速度18r/min，混合10分钟；再加入助推层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到助推层混合物；
步骤3：将步骤1得到的含药层混合物和步骤2得到的助推层混合物置于旋转压片机上，调节设备参数，使含药层的片重为280mg，助推层的片重为120mg，总片重为400mg，硬度100N～180N，压制浅弧圆形含药片芯；
步骤4：
根据以下步骤配制缓释包衣溶液：将纯化水加入烧杯中，使用磁力搅拌器进行搅拌，在搅拌过程中加入丙酮，全部加入后搅拌5分钟，使之混合均匀；再缓慢加入
Figure PCTCN2022105144-appb-000019
CA，持续搅拌30分钟～90分钟使之完全溶解，得到缓释包衣溶液；
对步骤3得到的含药片芯用上述缓释包衣溶液进行包衣，使用8rpm～15rpm的转速进行转动，片床温度控制在25℃～35℃，喷液速度设定在5rpm～20rpm范围进行喷液，持续包衣使之包衣增重在8.0％～11.0％时停止喷液，再以片床温度30℃～35℃进行干燥5分钟～10分钟，出片；然后放置于设定温度45℃的鼓风干燥箱中，进行老化，24小时后得到包衣片；
步骤5：将步骤4得到的包衣片，进行激光打孔，打孔面应为含药层(白色对应面)小孔尺寸0.4～0.7mm得到沙库巴曲缬沙坦钠缓释片。
以上步骤制得的沙库巴曲缬沙坦钠缓释片在pH6.8磷酸盐中的溶出数据如表5和图8所示。
表5 实施例II-2制得的沙库巴曲缬沙坦钠缓释片的溶出度
Figure PCTCN2022105144-appb-000020
实施例II-3
Figure PCTCN2022105144-appb-000021
Figure PCTCN2022105144-appb-000022
制备过程：
将上述沙库巴曲缬沙坦钠通过60目筛网处理。
步骤1：将上述处方中含药层的沙库巴曲缬沙坦钠、共聚维酮、羟乙基纤维素、黄氧化铁、胶态二氧化硅、滑石粉置于混合锅中，设置混合速度18r/min，混合20分钟；再将混合物料进行干法制粒整粒，最后加入含药层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到含药层混合物；
步骤2：将上述处方中助推层的聚氧乙烯、氯化钠、共聚维酮、红氧化铁置于混合锅中，设置混合速度18r/min，混合10分钟；再加入助推层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到助推层混合物；
步骤3：将步骤1得到的含药层混合物和步骤2得到的助推层混合物置于旋转压片机上，调节设备参数，使含药层的片重为300mg，助推层的片重为100mg，总片重为400mg，硬度100N～180N，压制浅弧圆形含药片芯；
步骤4：
根据以下步骤配制缓释包衣溶液：将纯化水加入烧杯中，使用磁力搅拌器进行搅拌，在搅拌过程中加入丙酮，全部加入后搅拌5分钟，使之混合均匀；再缓慢加入
Figure PCTCN2022105144-appb-000023
CA，持续搅拌30分钟～90分钟使之完全溶解，得到缓释包衣溶液；
对步骤3得到的含药片芯用上述缓释包衣溶液进行包衣，使用8rpm～15rpm的转速进行转动，片床温度控制在25℃～35℃，喷液速度设定在5rpm～20rpm范围进行喷液，持 续包衣使之包衣增重在8.0％～14.0％时停止喷液，再以片床温度30℃～35℃进行干燥5分钟～10分钟，出片；然后放置于设定温度45℃的鼓风干燥箱中，进行老化，24小时后得到包衣片；
步骤5：将步骤4得到的包衣片，进行激光打孔，打孔面应为含药层(白色对应面)小孔尺寸0.4～0.7mm得到沙库巴曲缬沙坦钠缓释片。
以上步骤制得的沙库巴曲缬沙坦钠缓释片在pH6.8磷酸盐、水和pH4.5醋酸盐介质中的溶出数据如表6和图9、图11和图10所示。
表6 实施例II-3制得的沙库巴曲缬沙坦钠缓释片的溶出度
Figure PCTCN2022105144-appb-000024
实施例II-4
Figure PCTCN2022105144-appb-000025
Figure PCTCN2022105144-appb-000026
制备过程：
将上述沙库巴曲缬沙坦钠通过60目筛网处理。
步骤1：将上述处方中含药层的沙库巴曲缬沙坦钠、共聚维酮、羟乙基纤维素、胶态二氧化硅、滑石粉置于混合锅中，设置混合速度18r/min，混合20分钟；再将混合物料进行干法制粒整粒，最后加入含药层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到含药层混合物；
步骤2：将上述处方中助推层的聚氧乙烯、氯化钠、共聚维酮、红氧化铁置于混合锅中，设置混合速度18r/min，混合10分钟；再加入助推层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到助推层混合物；
步骤3：将步骤1得到的含药层混合物和步骤2得到的助推层混合物置于旋转压片机上，调节设备参数，使含药层的片重为300mg，助推层的片重为100mg，总片重为400mg，硬度100N～180N，压制浅弧圆形含药片芯；
步骤4：
根据以下步骤配制缓释包衣溶液：将纯化水加入烧杯中，使用磁力搅拌器进行搅拌，在搅拌过程中加入丙酮，全部加入后搅拌5分钟，使之混合均匀；再缓慢加入
Figure PCTCN2022105144-appb-000027
CA，持续搅拌30分钟～90分钟使之完全溶解，得到缓释包衣溶液；
对步骤3得到的含药片芯用上述缓释包衣溶液进行包衣，使用8rpm～15rpm的转速进行转动，片床温度控制在25℃～35℃，喷液速度设定在5rpm～20rpm范围进行喷液，持续包衣使之包衣增重在8.0％～11.0％时停止喷液，再以片床温度30℃～35℃进行干燥5分钟～10分钟，出片；然后放置于设定温度45℃的鼓风干燥箱中，进行老化，24小时后得到包衣片；
步骤5：将步骤4得到的包衣片，进行激光打孔，打孔面应为含药层(白色对应面) 小孔尺寸0.4～0.7mm得到沙库巴曲缬沙坦钠缓释片。
以上步骤制得的沙库巴曲缬沙坦钠缓释片在pH6.8磷酸盐中的溶出数据如表7和图12所示。
表7 实施例II-4制得的沙库巴曲缬沙坦钠缓释片的溶出度
Figure PCTCN2022105144-appb-000028
实施例II-5
Figure PCTCN2022105144-appb-000029
Figure PCTCN2022105144-appb-000030
制备过程：
将上述沙库巴曲缬沙坦钠通过60目筛网处理。
步骤1：将上述处方中含药层除润滑剂硬脂酸镁外的原辅料置于混合锅中，设置混合速度18r/min，混合20分钟；再将混合物料进行干法制粒整粒，最后加入含药层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到含药层混合物；
步骤2：将上述处方中助推层的聚氧乙烯、氯化钠、共聚维酮、红氧化铁置于混合锅中，设置混合速度18r/min，混合10分钟；再加入助推层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到助推层混合物；
步骤3：将步骤1得到的含药层混合物和步骤2得到的助推层混合物置于旋转压片机上，调节设备参数，按含药层和助推层的目标重量进行压片，得到总片重为400mg，硬度100N～180N，压制浅弧圆形含药片芯；
步骤4：
根据以下步骤配制缓释包衣溶液：将纯化水加入烧杯中，使用磁力搅拌器进行搅拌，在搅拌过程中加入丙酮，全部加入后搅拌5分钟，使之混合均匀；再缓慢加入
Figure PCTCN2022105144-appb-000031
CA，持续搅拌30分钟～90分钟使之完全溶解，得到缓释包衣溶液；
对步骤3得到的含药片芯用上述缓释包衣溶液进行包衣，使用8rpm～15rpm的转速进行转动，片床温度控制在25℃～35℃，喷液速度设定在5rpm～20rpm范围进行喷液，持续包衣使之包衣增重在8.0％～11.0％时停止喷液，再以片床温度30℃～35℃进行干燥5分钟～10分钟，出片；然后放置于设定温度45℃的鼓风干燥箱中，进行老化，24小时后得到包衣片；
步骤5：将步骤4得到的包衣片，进行激光打孔，打孔面应为含药层(白色对应面)小孔尺寸0.4～0.7mm得到沙库巴曲缬沙坦钠缓释片。
以上步骤制得的沙库巴曲缬沙坦钠缓释片在pH6.8磷酸盐中的溶出数据如表8和图13所示。
表8 实施例II-5制得的沙库巴曲缬沙坦钠缓释片的溶出度
Figure PCTCN2022105144-appb-000032
Figure PCTCN2022105144-appb-000033
实施例II-6
Figure PCTCN2022105144-appb-000034
制备过程：
将上述沙库巴曲缬沙坦钠通过60目筛网处理。
步骤1：将上述处方中含药层的沙库巴曲缬沙坦钠、共聚维酮、羟乙基纤维素、黄氧化铁、胶态二氧化硅、滑石粉置于混合锅中，设置混合速度18r/min，混合20分钟；再将混合物料进行干法制粒整粒，最后加入含药层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到含药层混合物；
步骤2：将上述处方中助推层的聚氧乙烯、氯化钠、共聚维酮、红氧化铁置于混合锅中，设置混合速度18r/min，混合10分钟；再加入助推层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到助推层混合物；
步骤3：将步骤1得到的含药层混合物和步骤2得到的助推层混合物置于旋转压片机上，调节设备参数，使含药层的片重为300mg，助推层的片重为100mg，总片重为400mg，硬度100N～180N，压制浅弧圆形含药片芯；
步骤4：
根据以下步骤配制缓释包衣溶液：将纯化水加入烧杯中，使用磁力搅拌器进行搅拌，在搅拌过程中加入丙酮，全部加入后搅拌5分钟，使之混合均匀；再缓慢加入
Figure PCTCN2022105144-appb-000035
CA，持续搅拌30分钟～90分钟使之完全溶解，得到缓释包衣溶液；
对步骤3得到的含药片芯用上述缓释包衣溶液进行包衣，使用8rpm～15rpm的转速进行转动，片床温度控制在25℃～35℃，喷液速度设定在5rpm～20rpm范围进行喷液，持续包衣使之包衣增重在8.0％～14.0％时停止喷液，再以片床温度30℃～35℃进行干燥5分钟～10分钟，出片；然后放置于设定温度45℃的鼓风干燥箱中，进行老化，24小时后得到包衣片；
步骤5：将步骤4得到的包衣片，进行激光打孔，打孔面应为含药层(白色对应面)小孔尺寸0.4～0.7mm得到沙库巴曲缬沙坦钠缓释片。
以上步骤制得的沙库巴曲缬沙坦钠缓释片在pH6.8磷酸盐缓冲液、水和pH4.5醋酸盐介质中的溶出数据如表9和图14、图16和图15所示。说明该缓释片在正常的生理条件中释放不受环境介质影响。
表9 实施例II-6制得的沙库巴曲缬沙坦钠缓释片的溶出度
Figure PCTCN2022105144-appb-000036
Figure PCTCN2022105144-appb-000037
实施例II-7
将沙库巴曲缬沙坦钠制备成胃滞留缓释片剂，处方设计如下：
Figure PCTCN2022105144-appb-000038
制备过程：
将上述沙库巴曲缬沙坦钠通过60目筛网处理。
步骤1：将上述处方中除润滑剂以外的原辅料置于混合锅中，设置混合速度18r/min，混合20分钟；再加入处方量的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到物料混合物；
步骤2：将步骤1得到的混合物置于旋转压片机上，调节设备参数，调节片重为1000mg，硬度为140～220N进行压片。
以上步骤制得的沙库巴曲缬沙坦钠缓释片在pH6.8磷酸盐缓冲液中的溶出数据如表10和图17所示。
表10 实施例II-7制得的沙库巴曲缬沙坦钠缓释片的溶出度
Figure PCTCN2022105144-appb-000039
Figure PCTCN2022105144-appb-000040
实施例II-8
将沙库巴曲缬沙坦钠制备成普通凝胶骨架缓释片，处方设计如下：
Figure PCTCN2022105144-appb-000041
制备过程：
将上述沙库巴曲缬沙坦钠通过60目筛网处理。
步骤1：将上述处方中除润滑剂以外的原辅料置于混合锅中，设置混合速度18r/min，混合20分钟；再加入处方量的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到物料混合物；
步骤2：将步骤1得到的混合物置于旋转压片机上，调节设备参数，调节片重为500mg，硬度为100～180N进行压片。
以上步骤制得的沙库巴曲缬沙坦钠缓释片在pH6.8磷酸盐缓冲液中的溶出数据如表11和图18所示。
表11 实施例II-8制得的沙库巴曲缬沙坦钠缓释片的溶出度
Figure PCTCN2022105144-appb-000042
Figure PCTCN2022105144-appb-000043
由实施例II-7～实施例II-8结果可见，胃滞留缓释片和普通凝胶骨架缓释片，在体外溶出中，沙库巴曲和缬沙坦释放速度差异较大，不能达到同步释放。
由实施例I-1～实施例I-6和实施例II-1～实施例II-6结果可见，在体外溶出中，本发明开发的渗透泵剂型中，沙库巴曲缬沙坦钠缓释片中的沙库巴曲和缬沙坦可达到长效同步释放，满足一日一次的给药需求；且释药行为不受介质环境pH的影响。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种沙库巴曲缬沙坦钠缓释组合物，其为24小时缓慢释放药物，其特征在于，沙库巴曲和缬沙坦的溶出同时满足以下三个特征：
    A)在1小时内溶出不超过40％的药物活性成分；
    B)在6小时内溶出10％～70％的药物活性成分；
    C)在24小时内溶出不低于65％的药物活性成分；
    所述的药物活性成分可以选自沙库巴曲缬沙坦钠、或其药学上可接受的其他盐型、溶剂合物及水合物中的一种、两种或更多种；
    优选地，所述的沙库巴曲缬沙坦钠缓释组合物，沙库巴曲溶出同时满足以下三个特征：
    A)在1小时内溶出不超过35％的药物活性成分；
    B)在6小时内溶出10％～70％的药物活性成分；
    C)在24小时内溶出不低于70％的药物活性成分；
    缬沙坦溶出同时满足以下三个特征：
    A)在1小时内溶出不超过35％的药物活性成分；
    B)在6小时内溶出15％～70％的药物活性成分；
    C)在24小时内溶出不低于75％的药物活性成分；
    优选地，所述的沙库巴曲缬沙坦钠缓释组合物，沙库巴曲溶出同时满足以下三个特征：
    A)在1小时内溶出不超过25％的药物活性成分；
    B)在6小时内溶出10％～65％的药物活性成分；
    C)在24小时内溶出不低于75％的药物活性成分；
    缬沙坦溶出同时满足以下三个特征：
    A)在1小时内溶出不超过30％的药物活性成分；
    B)在6小时内溶出10％～65％的药物活性成分；
    C)在24小时内溶出不低于75％的药物活性成分；
    优选地，所述的沙库巴曲缬沙坦钠缓释组合物，沙库巴曲溶出同时满足以下三个特征：
    A)在1小时内溶出不超过25％的药物活性成分；
    B)在6小时内溶出10％～65％的药物活性成分；
    C)在24小时内溶出不低于80％的药物活性成分；
    缬沙坦溶出同时满足以下三个特征：：
    A)在1小时内溶出不超过25％的药物活性成分；
    B)在6小时内溶出15％～65％的药物活性成分；
    C)在24小时内溶出不低于80％的药物活性成分；
    优选地，所述沙库巴曲和缬沙坦的溶出为同步释放。
  2. 一种沙库巴曲缬沙坦钠缓释组合物，其特征在于，所述缓释组合物为24小时缓慢释放药物，沙库巴曲和缬沙坦的溶出同时满足以下三个特征：
    A)在2小时内溶出不超过40％的药物活性成分；
    B)在8小时内溶出20％～75％的药物活性成分；
    C)在24小时内溶出不低于65％的药物活性成分；
    所述的药物活性成分可以选自沙库巴曲缬沙坦钠、或其药学上可接受的其他盐型、溶剂合物及水合物中的一种、两种或更多种；
    优选地，所述的沙库巴曲缬沙坦钠缓释组合物，沙库巴曲的溶出同时满足以下三个特征：
    A)在2小时内溶出不超过35％的药物活性成分；
    B)在8小时内溶出20％～70％的药物活性成分；
    C)在24小时内溶出不低于75％的药物活性成分；
    缬沙坦的溶出同时满足以下三个特征：
    A)在2小时内溶出不超过35％的药物活性成分；
    B)在8小时内溶出20％～70％的药物活性成分；
    C)在24小时内溶出不低于75％的药物活性成分；
    优选地，所述的沙库巴曲缬沙坦钠缓释组合物，沙库巴曲的溶出同时满足以下三个特征：
    A)在2小时内溶出不超过25％的药物活性成分；
    B)在8小时内溶出25％～65％的药物活性成分；
    C)在24小时内溶出不低于75％的药物活性成分；
    缬沙坦的溶出同时满足以下三个特征：
    A)在2小时内溶出不超过25％的药物活性成分；
    B)在8小时内溶出25％～65％的药物活性成分；
    C)在24小时内溶出不低于75％的药物活性成分；
    优选地，所述的沙库巴曲缬沙坦钠缓释组合物，沙库巴曲的溶出同时满足以下三个特征：
    A)在2小时内溶出不超过25％的药物活性成分；
    B)在8小时内溶出30％～65％的药物活性成分；
    C)在24小时内溶出不低于80％的药物活性成分；
    缬沙坦的溶出同时满足以下三个特征：
    A)在2小时内溶出不超过25％的药物活性成分；
    B)在8小时内溶出30％～65％的药物活性成分；
    C)在24小时内溶出不低于80％的药物活性成分；
    优选地，所述沙库巴曲和缬沙坦的溶出为同步释放。
  3. 一种沙库巴曲缬沙坦钠缓释组合物，其特征在于，所述组合物包括含药层片芯以及包衣膜，并在含药层一侧打孔；所述的含药层片芯包含药物活性成分以及载体；所述的药物活性成分选自沙库巴曲缬沙坦钠、或其药学上可接受的其他盐型、溶剂合物及水合物中的一种、两种或更多种；所述的载体为渗透压调节剂、溶胀剂、增稠剂、助流剂和润滑剂中的一种或多种；
    所述缓释组合物还任选包括或不包括助推层片芯，所述的助推层片芯包括渗透压调节剂、溶胀剂、着色剂和润滑剂中的一种或多种；所述的包衣膜为半渗透膜；
    优选地，所述沙库巴曲缬沙坦钠缓释组合物为权利要求1或2所述的缓释组合物；
    优选地，所述的含药层片芯还含有着色剂。
  4. 如权利要求3所述的沙库巴曲缬沙坦钠缓释组合物，其特征在于：
    所述的含药层片芯中，所述的药物活性成分为沙库巴曲缬沙坦钠；
    和/或，
    所述的含药层片芯中，所述的渗透压调节剂为氯化钠、氯化钾、甘露醇、山梨醇、硫酸钠、硫酸镁、葡萄糖、果糖、蔗糖和乳糖中的一种或多种；
    和/或，
    所述的含药层片芯中，所述的增稠剂为羟丙甲基纤维素、羟丙纤维素、羟乙基纤维素、乙基纤维素、共聚维酮、阿拉伯胶、预胶化淀粉和聚乙烯吡咯烷酮中的一种或多种；
    和/或，
    所述的含药层片芯中，所述的溶胀剂为聚氧乙烯、卡波姆、羧甲淀粉钠、交联聚维酮和海藻酸钠中的一种或多种；
    和/或，
    所述的含药层片芯中，所述着色剂选自氧化铁红、氧化铁黄和氧化铁黑中的一种或多种；
    和/或，
    所述的含药层片芯中，所述的助流剂为滑石粉、微粉硅胶、胶态二氧化硅中的一种或多种；
    和/或，
    所述的含药层片芯中，所述的润滑剂为硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯、硬酯酰富马酸盐和微粉硅胶中的一种或多种；
    和/或，
    所述的助推层片芯中，所述的渗透压调节剂为氯化钠、氯化钾、甘露醇、山梨醇、硫酸钠、硫酸镁、葡萄糖、果糖、蔗糖和乳糖中的一种或多种；
    和/或，
    所述的助推层片芯中，所述的溶胀剂为聚乙烯吡咯烷酮、羟乙基纤维素、共聚维酮、羟丙甲基纤维素、阿拉伯胶、卡波姆、羧甲淀粉钠、海藻酸钠和聚氧乙烯中的一种或多种；
    和/或，
    所述的助推层片芯中，所述的着色剂为氧化铁红、氧化铁黄和氧化铁黑中的一种或多种；
    和/或，
    所述的助推层片芯中，所述的润滑剂选自硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯、硬酯酰富马酸盐和微粉硅胶中的一种或多种；
    优选地，所述的硬脂酸金属盐为硬脂酸镁和/或硬脂酸钙；
    和/或，
    所述的硬脂酸酯为硬脂酸甘油酯。
  5. 如权利要求3-4任一项所述的沙库巴曲缬沙坦钠缓释组合物，其特征在于：
    所述的含药层片芯中，所述的药物活性成分的含量为10.00％～80.00％，所述的含量是指药物活性成分的质量占含药层片芯总质量的百分比；
    和/或，
    所述的含药层片芯中，所述的渗透压调节剂的含量为1.00％～60.00％，所述的含量是指渗透压调节剂的质量占含药层片芯总质量的百分比；
    和/或，
    所述的含药层片芯中，所述的增稠剂的含量为10.00％～70.00％，所述的含量是指增稠剂的质量占含药层片芯总质量的百分比；
    和/或，
    所述的含药层片芯中，所述的溶胀剂的含量为0.00％～70.00％，所述的含量是指溶胀剂的质量占含药层片芯总质量的百分比；
    和/或，
    所述的含药层片芯中，所述的助流剂的含量为0～5.00％，例如0％～1.00％，所述的含量是指助流剂的质量占含药层片芯总质量的百分比；
    和/或，
    所述的含药层片芯中，所述的润滑剂的含量为0.50％～60.00％，所述的含量是指润滑剂的质量占含药层片芯总质量的百分比；
    和/或，
    所述的含药层片芯中，所述的着色剂的含量为0％～5.00％，所述的含量是指润滑剂的质量占含药层片芯总质量的百分比。
  6. 如权利要求3-5任一项所述的沙库巴曲缬沙坦钠缓释组合物，其特征在于：
    所述的助推层片芯中，所述的渗透压调节剂的含量为1.00％～60.00％，所述的含量 是指渗透压调节剂的质量占助推层片芯总质量的百分比；
    和/或，
    所述的助推层片芯中，所述的溶胀剂的含量为0％～90.00％，例如0％～80.00％，所述的含量是指溶胀剂的质量占助推层片芯总质量的百分比；
    和/或，
    所述的助推层片芯中，所述的着色剂的含量为0.10％～10.00％，所述的含量是指着色剂的质量占助推层片芯总质量的百分比；
    和/或，
    所述的助推层片芯中，所述的润滑剂的含量为0.10％～10.00％，所述的含量是指润滑剂的质量占助推层片芯总质量的百分比。
  7. 如权利要求3-6任一项所述的沙库巴曲缬沙坦钠缓释组合物，其特征在于：所述的半渗透膜包含成膜材料、致孔剂和增塑剂中的一种或多种；优选地，所述的包衣膜中，所述的成膜材料为醋酸纤维素、乙基纤维素、邻苯二甲酸醋酸纤维素、聚醋酸乙烯酯、丙烯酸树脂和甲基丙烯酸树脂中的一种或多种；
    和/或，
    所述的包衣膜中，所述的致孔剂为聚乙二醇、羟丙基纤维素、聚维酮和聚乙烯醇中的一种或多种；
    和/或，
    所述的包衣膜中，所述的增塑剂为三醋酸甘油酯、柠檬酸甘油酯、甘油酯、邻苯二甲酸二丁酯和邻苯二甲酸二乙酯中的一种或多种；
    优选地，所述的包衣膜为卡乐康提供的醋酸纤维素全配方包衣预混剂。
  8. 如权利要求3-7任一项所述的沙库巴曲缬沙坦钠缓释组合物，其特征在于：所述的含药层片芯选自以下任一配方：
    配方一：28.25％沙库巴曲缬沙坦钠、25.00％山梨醇、21.25％一水乳糖、2.50％氯化钠、21.50％羟丙甲纤维素、0.50％胶态二氧化硅、1.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
    配方二：56.50％沙库巴曲缬沙坦钠、20.00％山梨醇、10.00％一水乳糖、1.50％氯化钠、10.50％羟丙甲纤维素、0.50％胶态二氧化硅、1.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
    配方三：37.67％沙库巴曲缬沙坦钠、36.66％山梨醇、3.67％氯化钠、21.00％羟丙甲纤维素、1.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
    配方四：56.50％沙库巴曲缬沙坦钠、25.00％山梨醇、2.50％氯化钠、15.00％羟丙甲纤维素、1.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
    配方五：33.93％沙库巴曲缬沙坦钠、48.06％聚氧乙烯、3.00％氯化钠、13.81％羟丙甲纤维素、1.20％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
    配方六：67.87％沙库巴曲缬沙坦钠、24.02％聚氧乙烯、1.5％氯化钠、5.41％羟丙甲纤维素、1.20％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
    配方七：37.70％沙库巴曲缬沙坦钠、38.63％共聚维酮、18.67％羟乙基纤维素、2.33％滑石粉、0.67％胶态二氧化硅、2.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
    配方八：75.40％沙库巴曲缬沙坦钠、11.60％共聚维酮、8.33％羟乙基纤维素、1.00％滑石粉、0.67％胶态二氧化硅、3.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
    配方九：40.39％沙库巴曲缬沙坦钠、26.90％共聚维酮、27.00％羟乙基纤维素、2.86％滑石粉、0.71％胶态二氧化硅、2.14％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
    配方十：75.40％沙库巴曲缬沙坦钠、19.93％聚氧乙烯、1.00％滑石粉、0.67％胶态二氧化硅、3.00％硬脂酸镁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
    配方十一：37.70％沙库巴曲缬沙坦钠、28.20％共聚维酮、28.66％羟乙基纤维素、2.67％滑石粉、0.67％胶态二氧化硅、2.00％硬脂酸镁、0.10％黄氧化铁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比；
    配方十二：75.40％沙库巴曲缬沙坦钠、6.83％共聚维酮、12.00％羟乙基纤维素、2.67％滑石粉、0.67％胶态二氧化硅、2.33％硬脂酸镁、0.10％黄氧化铁，所述的百分比是指各组分的质量占含药层片芯总质量的百分比
    和/或，所述的助推层片芯选自以下配方中的任意一种：
    配方1：65.86％聚氧乙烯、31.74％氯化钠、1.2％红氧化铁、1.20％硬脂酸镁，所述的百分比是指各组分的质量占助推层片芯总质量的百分比；
    配方2：73.00％聚氧乙烯、20.00％共聚维酮、1.00％红氧化铁、5.00％氯化钠、1.00％硬脂酸镁，所述的百分比是指各组分的质量占助推层片芯总质量的百分比；
    配方3：60.83％聚氧乙烯、8.33％共聚维酮、29.17％氯化钠、0.83％红氧化铁、0.84％硬脂酸镁，所述的百分比是指各组分的质量占助推层片芯总质量的百分比；
    配方4：82.00％聚氧乙烯、10.00％共聚维酮、5.00％氯化钠、1.00％红氧化铁、2.00％硬脂酸镁，所述的百分比是指各组分的质量占助推层片芯总质量的百分比；
    配方5：63.00％聚氧乙烯、10.00％共聚维酮、25.00％氯化钠、1.00％红氧化铁、1.00％硬脂酸镁，所述的百分比是指各组分的质量占助推层片芯总质量的百分比；
    和/或，所述的包衣为以下任一组成：
    包衣一：9.00％醋酸纤维素和1.00％聚乙二醇4000，所述的百分比是指各组分的质量占药片片芯总质量的百分比；
    包衣二：7.20％醋酸纤维素和0.80％聚乙二醇4000，所述的百分比是指各组分的质量占药片片芯总质量的百分比；
    包衣三：6％醋酸纤维素和3％聚乙二醇4000，所述的百分比是指各组分的质量占药片片芯总质量的百分比；
    所述药片片芯由含药层片芯和助推层片芯组成；当不含有助推层片芯时，药片片芯即为含药层片芯。
  9. 一种沙库巴曲缬沙坦钠缓释制剂，其特征在于其包含权利要求1～8任一项所述的沙库巴曲缬沙坦缓释组合物；
    优选地，所述的沙库巴曲缬沙坦钠缓释制剂的剂型为缓释片、缓释微丸或缓释胶囊。
  10. 如权利要求1～8任一项所述的沙库巴曲缬沙坦缓释组合物或者如权利要求9所述的沙库巴曲缬沙坦缓释制剂在制备治疗和/或预防射血分数降低的慢性心力衰竭的药物中的应用。
PCT/CN2022/105144 2021-07-12 2022-07-12 沙库巴曲缬沙坦钠缓释组合物、其制备方法及应用 WO2023284724A1 (zh)

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