Sacubitril and valsartan sodium controlled-release composition, preparation method and application thereof, and medicine

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a sacubitril and valsartan sodium controlled-release composition, a preparation method and application thereof, and a medicine. The invention provides a double-layer osmotic pump controlled release tablet of sacubitril and valsartan sodium, the tablet can continuously release medicine within 24 hours, and the oral administration of the original developed preparation on the market is changed into the oral administration of the original developed preparation once every two days, so that the medication compliance of a patient is greatly improved. Besides, the drug release of the preparation is characterized by zero-order release, the influence of the pH value of the environment is small, the influence of the complex environment of the gastrointestinal tract in the gastrointestinal tract is small, the safety of the drug is greatly improved, the fluctuation of the blood concentration caused by the peak valley effect of a common quick-release tablet is avoided, the steady-state blood concentration can be achieved after the preparation is taken once, and the preparation is safe and reliable. The effectiveness of the medicine is improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulations, and particularly to controlled-release compositions of sacubitril / valsartan sodium, their preparation methods and applications, as well as pharmaceuticals. Background Technology

[0002] 1. Basic Drug Information

[0003] Sacubitril / valsartan sodium contains two components: valsartan and sacubitril.

[0004] Valsartan is an antihypertensive drug. As an angiotensin receptor inhibitor, it has a certain antihypertensive effect on various types of hypertension. It can also reverse left ventricular hypertrophy caused by hypertension, helping to improve the long-term prognosis of heart failure caused by hypertension.

[0005] Sacubitril is an enkephalinase inhibitor that increases the level of natriuretic peptides in the bloodstream, effectively counteracting the harmful effects of the renin-angiotensin system and sympathetic nerve activation. It promotes sodium and water excretion and dilates blood vessels, thereby slowing left ventricular remodeling. This improves cardiac function and chest tightness symptoms, ultimately delaying the progression of heart failure and improving patients' quality of life.

[0006] Therefore, this compound preparation is particularly suitable for heart failure patients with hypertension, as it lowers blood pressure, improves their long-term prognosis, and enhances their quality of life.

[0007] 2. Drug Background

[0008] Sacubitril / Valsartan Sodium Tablets (LCZ696), developed by Novartis Pharma Schweiz AG of Switzerland and marketed under the brand name Entresto, were approved by the FDA on July 7, 2015. Sacubitril / Valsartan Sodium Tablets are immediate-release film-coated tablets, available in three strengths based on sacubitril: 50mg (sacubitril 24mg / valsartan 26mg), 100mg (sacubitril 49mg / valsartan 51mg), and 200mg (sacubitril 97mg / valsartan 103mg). All three strengths contain the same excipients except for coloring. Sacubitril / valsartan sodium tablets are primarily used in adult patients with chronic heart failure (NYHA class II-IV, LVEF ≤ 40%), reducing the risk of cardiovascular death and hospitalization for heart failure. They can be used as an alternative to angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in combination with other heart failure medications. Sacubitril / valsartan sodium tablets are a sodium salt complex composed of anionic sacubitril and valsartan, sodium cations, and water molecules in a molar ratio of 1:1:3:2.5.

[0009]

[0010] 3. Basic information about the original research

[0011] 3.1 Mechanism of Action

[0012] Sacubitril / valsartan sodium contains the neprilysin inhibitor sacubitril and the angiotensin receptor antagonist valsartan. Sacubitril / valsartan sodium inhibits neprilysin (a neutral endopeptidase; NEP) via LBQ657 (the active metabolite of the prodrug sacubitril) and simultaneously blocks the type 1 receptor (AT1) of angiotensin II via valsartan. By increasing the levels of peptides degraded by neprilysin (e.g., natriuretic peptides) through LBQ657 and simultaneously inhibiting the action of angiotensin II via valsartan, sacubitril / valsartan sodium can produce cardiovascular and renal effects in patients with heart failure. Valsartan inhibits the action of angiotensin II by selectively blocking the AT1 receptor and also inhibits angiotensin II-dependent aldosterone release.

[0013] 3.2 Pharmacokinetics

[0014] 3.2.1 Absorption

[0015] Following oral administration, Norceptul breaks down into sacubitril (which is subsequently metabolized to LBQ657) and valsartan, reaching peak plasma concentrations at 0.5, 2, and 1.5 hours, respectively. The absolute oral bioavailability of sacubitril and valsartan is approximately ≥60% and 23%, respectively. Valsartan in Norceptul exhibits higher bioavailability compared to other marketed tablets of valsartan. Steady-state levels of sacubitril, LBQ657, and valsartan are reached after 3 days of continuous administration. At steady state, with Norceptul administered twice daily and once daily, no significant accumulation of sacubitril and valsartan was observed, while LBQ657 accumulation was approximately 1.6-fold and 1.2-fold, respectively. Co-administration of Norceptul with food had no clinically significant effect on systemic exposure to sacubitril, LBQ657, and valsartan. Although valsartan exposure decreased with co-administration of Norceptul with food, this reduction in exposure did not result in a clinically significant attenuation of therapeutic efficacy. Therefore, Norsent can be taken with food or on an empty stomach.

[0016] 3.2.2 Distribution

[0017] Nosentol has a high binding rate to plasma proteins (94–97%). Based on a comparison of plasma exposure and cerebrospinal fluid exposure, LBQ657 has limited cross-border penetration across the blood-brain barrier (0.28%). The mean apparent volumes of distribution for valsartan and sacubitril range from 75 L to 103 L, respectively.

[0018] 3.2.3 Metabolism

[0019] Sacubitril is rapidly converted to LBQ657 via esterase; LBQ657 undergoes no significant further metabolism. Valsartan is minimally metabolized, with only about 20% of the administered dose recovered as metabolites. Low concentrations of hydroxy metabolites (<10%) are observed in plasma. Since CYP450 enzymes minimally mediate the metabolism of sacubitril and valsartan, it is not expected that co-administration with drugs that affect CYP450 enzymes will have no impact on their pharmacokinetics.

[0020] 3.2.4 Excretion

[0021] After oral administration, 52–68% of sacubitril (mainly in the form of LBQ657), ~13% of valsartan and its metabolites are excreted in the urine; 37–48% of sacubitril (mainly in the form of LBQ657), 86% of valsartan and its metabolites are excreted in the feces.

[0022] The mean plasma elimination half-life (T1 / 2) of sacubitril, LBQ657 and valsartan were approximately 1.43 hours, 11.48 hours and 9.90 hours, respectively.

[0023] 4. Existing relevant patented technologies

[0024] The original formulation of sacubitril / valsartan sodium tablets has expired its composition patent in China (CN 102091330B). This invention relates to a pharmaceutical composition comprising an AT1-antagonist valsartan or a pharmaceutically acceptable salt thereof and a NEP inhibitor or a pharmaceutically acceptable salt thereof, with or without a pharmaceutically acceptable carrier, for the treatment or prevention of conditions selected from hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina pectoris, and kidney disease. Methods for treating functional impairment, heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria in primary nephropathy, and renal vascular hypertension, conditions or diseases of diabetic retinopathy, and control of other vascular conditions such as migraine, peripheral vascular disease, Raynaud's disease, vascular proliferation, cognitive impairment, glaucoma, and stroke, including administering the commercially available drug composition to mammals in need of treatment.

[0025] In addition to the original formulation composition patent, the domestic patents for sacubitril / valsartan sodium tablets also include: (1) CN118141776A of Disa Pharmaceutical Group Co., Ltd., which specifically relates to a sacubitril / valsartan sodium tablet composition and its preparation method. The invention provides a process for fluidized bed granulation using an aqueous solvent after compounding molten lipid excipients with sacubitril / valsartan sodium raw material; (2) CN116983301A of Tianjin Medical University General Hospital, which provides a sacubitril / valsartan sodium pharmaceutical composition, its preparation method and uses. The composition is composed of sacubitril / valsartan sodium and 2-acetylpyrrole, and is further prepared into oral solid dosage forms such as tablets, capsules, and granules for the treatment of chronic heart failure; (3) CN116850150A of Wujin People's Hospital of Changzhou City, this invention solves the problem of sacubitril / valsartan sodium being hygroscopic by selecting excipients, especially the appropriate addition of sodium succinate and valine, and optimizing the preparation process, especially by using low temperature cold grinding technology, and provides a preparation of sacubitril / valsartan sodium that is not easily hygroscopic and deliquescent and has high stability; (4) CN116850152A of Disha Pharmaceutical Group Co., Ltd., this invention sprays wax material in the form of solution or suspension onto the surface of the raw material, dries it to form a binary complex, and then granulates it with other excipients by dry method. The invention aims to improve the hygroscopicity of the active pharmaceutical ingredient and reduce environmental control costs; (5) CN115444829A of Nanjing Kangchuanji Pharmaceutical Technology Co., Ltd., the invention relates to a sacubitril / valsartan sodium gastric retention sustained-release tablet and its preparation method, the invention relies on hydrophilic gel skeleton material and swelling agent to achieve sustained release effect and gastric retention effect; (6) CN113648284A of Nanjing Hainan Pharmaceutical Technology Co., Ltd., the invention uses xylitol and silicified microcrystalline cellulose as fillers, screens specific excipients and controls the ratio of each excipient, and solves the sticking problem of the tablet in the preparation process; (7) Nan (8) CN113456607A of Jingkang Chuanji Pharmaceutical Technology Co., Ltd. This invention develops a method for preparing a single-layer osmotic pump controlled-release tablet. By controlling the single-layer osmotic pump controlled-release tablet, the drug can be taken orally once a day, with a stable blood concentration and less affected by the gastrointestinal environment; (9) CN114796145A of Nanjing Zhengda Tianqing Pharmaceutical Co., Ltd. This invention provides a sacubitril / valsartan sodium tablet and its preparation process. By adjusting the prescription ratio and adjusting the amount of filler, disintegrant and binder, the granules can be compressed smoothly and are easy to form. Sacubitril / valsartan sodium tablets with better compressibility, better stability and rapid dissolution are obtained.

[0026] 5. Disadvantages of existing technology

[0027] Original reagent:

[0028] The original formulation was an immediate-release tablet, which required twice-daily dosing, resulting in poor patient compliance. The original formulation was a gastric-soluble film-coated immediate-release preparation, and the uniformity of the film coating had a significant impact on the release characteristics of the tablets, leading to large differences in dissolution characteristics between tablets. The blood drug concentration of the immediate-release tablets was not stable enough, exhibiting peak-and-trough phenomena, which was not conducive to reducing the toxic side effects of the drug and improving its efficacy.

[0029] Other formulation patents:

[0030] Many other patents focus on the hygroscopicity of the active pharmaceutical ingredient (API) to prevent it from absorbing moisture during formulation production, but they do not help with drug release. Nanjing Kangchuanji Pharmaceutical's sacubitril / valsartan sodium gastric retention sustained-release tablets and monolayer osmotic pump controlled-release tablets, while achieving a sustained-release effect, exhibit first-order release and a relatively short duration of sustained release. Summary of the Invention

[0031] In view of this, the present invention provides a controlled-release composition of sacubitril / valsartan sodium, a preparation method thereof, and its application as a pharmaceutical. The present invention aims to develop a product with a simple manufacturing process, requiring only once-daily oral administration, providing a long duration of action, avoiding the peak-and-trough phenomenon caused by immediate-release tablets, resulting in more stable drug release, and improving the safety and efficacy of the product.

[0032] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0033] In a first aspect, the present invention provides a controlled-release composition of sacubitril / valsartan sodium, comprising a drug layer and a booster layer;

[0034] The drug layer comprises the following components in parts by weight:

[0035]

[0036] The booster layer comprises the following components in parts by weight:

[0037]

[0038] In some specific embodiments of the present invention, the weight ratio of the drug layer to the booster layer includes (311-377):(117-150).

[0039] In some specific embodiments of the present invention, in the drug layer:

[0040] The sacubitril / valsartan sodium is present in parts by weight of 38.18, 39.45, 40.00, 41.27, or 42.19; and / or

[0041] The adhesive is present in parts by weight of 1.18 parts, 1.27 parts, 1.72 parts, 2.00 parts, or 2.12 parts;

[0042] The antagonist is present in parts by weight of 19.72 parts, 20.64 parts, 21.10 parts, 24.00 parts, or 25.45 parts; and / or

[0043] The osmotic pressure regulator is present in parts by weight of 0.59 parts, 0.63 parts, 0.86 parts, 1.00 parts, or 1.06 parts; and / or

[0044] The lubricant is present in parts by weight of 0.34 parts, 0.39 parts, 0.40 parts, or 0.42 parts; and / or

[0045] In the booster layer:

[0046] The antagonist is present in parts by weight of 16.00 parts, 16.88 parts, 16.97 parts, 17.20 parts, or 19.72 parts; and / or

[0047] The osmotic pressure regulator is present in parts by weight of 6.00 parts, 6.33 parts, 6.36 parts, 6.88 parts, or 7.89 parts; and / or

[0048] The adhesive is present in parts by weight of 1.00 parts, 1.05 parts, 1.06 parts, 1.20 parts, or 1.38 parts; and / or

[0049] The colorant is present in parts by weight of 0.20 parts, 0.21 parts, 0.34 parts, or 0.39 parts; and / or

[0050] The lubricant comprises 0.17 parts, 0.20 parts, or 0.21 parts by weight;

[0051] As a preferred option

[0052] The adhesive comprises one or more of povidone, hydroxypropyl methylcellulose, or hydroxypropyl cellulose; and / or

[0053] The blocking agent comprises one or more of hydroxypropyl methylcellulose, polyoxyethylene, or carnauba wax; and / or

[0054] The osmotic pressure regulator comprises one or more of potassium chloride, sodium chloride, or calcium chloride; and / or

[0055] The lubricant comprises one or more of magnesium stearate, talc, or sodium stearate fumarate; and / or

[0056] The colorant includes iron oxide red;

[0057] As a preferred option

[0058] In the drug layer:

[0059] The adhesive comprises polyvinyl ketone K90; and / or

[0060] The blocking agent includes polyethylene oxide; and / or

[0061] The osmotic pressure regulator includes sodium chloride; and / or

[0062] The lubricant includes magnesium stearate; and / or

[0063] In the booster layer:

[0064] The blocking agent includes polyethylene oxide; and / or

[0065] The osmotic pressure regulator includes sodium chloride; and / or

[0066] The adhesive comprises hydroxypropyl methylcellulose; and / or

[0067] The colorant includes iron oxide red; and / or

[0068] The lubricant includes magnesium stearate.

[0069] Secondly, the present invention also provides a method for preparing the sacubitril / valsartan sodium controlled-release composition, comprising the following steps:

[0070] Step 1, Drug layer granulation: Weigh the prescribed amounts of sacubitril / valsartan sodium, binder, blocker, osmotic pressure regulator (passed through a 60-mesh sieve), and lubricant, premix them, sieve them, mix them, and granulate them to obtain drug layer granules.

[0071] Step 2, Propeller layer granulation: Weigh the prescribed amounts of inhibitor, osmotic pressure regulator (passed through a 60-mesh sieve), binder, colorant (passed through a 40-mesh sieve), and lubricant, premix them, sieve them, mix them, and granulate them to obtain the propulsion layer granules.

[0072] Thirdly, the present invention also provides a controlled-release composition of sacubitril / valsartan sodium prepared by the aforementioned preparation method.

[0073] Fourthly, the present invention also provides the use of the sacubitril / valsartan sodium controlled-release composition or the sacubitril / valsartan sodium controlled-release composition prepared by the preparation method in any of the following:

[0074] (I) To prepare drugs that reduce the frequency of medication, lower the total dosage and / or increase patient compliance;

[0075] (II) Preparation of drugs to avoid or reduce peak-valley phenomena during drug release;

[0076] (III) Preparing drugs that reduce the toxic side effects of other drugs; and / or

[0077] (IV) Prepare drugs to improve efficacy.

[0078] Fifthly, the present invention also provides a medicament comprising the sacubitril / valsartan sodium controlled-release composition described herein or the sacubitril / valsartan sodium controlled-release composition prepared by the aforementioned method, and pharmaceutically acceptable excipients.

[0079] In some specific embodiments of the present invention, the drug comprises the sacubitril / valsartan sodium controlled-release composition described above or the sacubitril / valsartan sodium controlled-release composition prepared by the preparation method described above, a semi-permeable membrane, and a film coating.

[0080] The semipermeable membrane comprises the following components in parts by weight:

[0081] Semi-permeable membrane material: 3.82–5.16 parts

[0082] 0.32–0.43 parts of pore-forming agent

[0083] The film coating comprises the following components in parts by weight:

[0084] 3.39–3.80 parts of membrane material

[0085] Plasticizer 0.34–0.42 parts;

[0086] As a preferred option

[0087] In the semipermeable membrane:

[0088] The semi-permeable membrane material comprises 3.82 parts, 4.73 parts, 4.80 parts, 5.06 parts, or 5.16 parts by weight; and / or

[0089] The porogen is present in parts by weight of 0.32 parts, 0.39 parts, 0.40 parts, 0.42 parts, or 0.43 parts; and / or

[0090] In the film coating:

[0091] The membrane material comprises 3.39 parts, 3.44 parts, 3.55 parts, 3.60 parts, or 3.80 parts by weight; and / or

[0092] The plasticizer is present in parts by weight of 0.34 parts, 0.39 parts, 0.40 parts, or 0.42 parts;

[0093] As a preferred option

[0094] The semipermeable membrane material comprises one or more of ethyl cellulose, cellulose acetate, or polyvinyl acetate resin; and / or

[0095] The pore-forming agent comprises one or more of propylene glycol, polyethylene glycol, or fatty acid esters; and / or

[0096] The membrane material includes, but is not limited to, one or a combination of two or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone; and / or

[0097] The plasticizer includes, but is not limited to, one or a combination of two or more of polyethylene glycol, propylene glycol or castor oil;

[0098] As a preferred option

[0099] In the semipermeable membrane:

[0100] The semi-permeable membrane material includes cellulose acetate; and / or

[0101] The pore-forming agent includes polyethylene glycol; and / or

[0102] In the film coating:

[0103] The membrane material includes hydroxypropyl methylcellulose; and / or

[0104] The plasticizer includes polyethylene glycol.

[0105] Sixthly, the present invention also provides a method for preparing the aforementioned drug, comprising the following steps:

[0106] Step 1, Drug layer granulation: Weigh the prescribed amounts of sacubitril / valsartan sodium, binder, blocker, osmotic pressure regulator (passed through a 60-mesh sieve) and lubricant, premix and then sieve, mix and granulate to obtain drug layer granules;

[0107] Step 2, granulation of the booster layer: Weigh the prescribed amounts of inhibitor, osmotic pressure regulator (passed through a 60-mesh sieve), binder, colorant (passed through a 40-mesh sieve) and lubricant, premix them, sieve them, mix them, and granulate them to obtain the booster layer granules.

[0108] Step 3, tableting: Granulate the drug layer obtained in Step 1 and the propulsion layer obtained in Step 2 according to the prescription amount, mix them, and then compress them into tablets;

[0109] Step 4, Semi-permeable membrane coating: The semi-permeable membrane material and the pore-forming agent are dissolved in 94% acetone, coated, and dried to constant weight to obtain tablets coated with a semi-permeable membrane.

[0110] Step 5, punching: Punch holes in the tablets coated with the semi-permeable membrane;

[0111] Step 6, film coating: Prepare a film coating solution by mixing the film material and the plasticizer, and then coat the perforated tablets obtained in Step 5 with a film.

[0112] In a seventh aspect, the present invention also provides a drug prepared by the aforementioned method.

[0113] This invention provides a pharmaceutical composition and a method for preparing the same. The composition consists of sacubitril / valsartan sodium and other excipients, and when formulated into a bilayer osmotic pump controlled-release tablet, the tablet can continuously release the drug for 24 hours.

[0114] The beneficial effects of this invention include:

[0115] (1) It can reduce the frequency of medication, make it easier for patients to take medication for a long time, and improve patient compliance;

[0116] (2) The drug is released at zero order, and the blood drug concentration is stable, avoiding or reducing peak and trough phenomena, which helps to reduce the toxic side effects of the drug and improve its efficacy.

[0117] (3) It can reduce the total dosage of medication;

[0118] (4) The drug release is not affected by the environment, which greatly increases the effectiveness of the drug. Attached Figure Description

[0119] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0120] Figure 1 Show the in vitro dissolution curve of commercially available sacubitril / valsartan sodium tablets;

[0121] Figure 2 Showing the in vitro dissolution curve of the single-layer osmotic pump sustained-release tablet;

[0122] Figure 3 The in vitro dissolution curve of Example 1 is shown;

[0123] Figure 4 The in vitro dissolution curve of Example 2 is shown;

[0124] Figure 5 Example 3 shows the in vitro dissolution curve;

[0125] Figure 6 Example 4 shows the in vitro dissolution curve;

[0126] Figure 7 The in vitro dissolution curve of Example 5 is shown. Detailed Implementation

[0127] This invention discloses a controlled-release composition of sacubitril / valsartan sodium, its preparation method, and its applications. Those skilled in the art can refer to the content of this document and appropriately modify the process parameters to achieve the desired pharmaceutical results. It is particularly important to note that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments. Those skilled in the art will clearly be able to modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0128] The present invention provides a sacubitril / valsartan sodium tablet, the main formulation of which is shown in Table 1:

[0129] Table 1

[0130]

[0131]

[0132] in:

[0133] The adhesive is at least one of polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hydroxypropyl cellulose;

[0134] The blocking agent is at least one of hydroxypropyl methylcellulose, polyoxyethylene, and carnauba wax;

[0135] The osmotic pressure regulator is at least one of potassium chloride, sodium chloride, and calcium chloride;

[0136] The lubricant is at least one of magnesium stearate, talc, and sodium stearate fumarate.

[0137] The colorant includes, but is not limited to, iron oxide red;

[0138] The semipermeable membrane material is at least one of ethyl cellulose, cellulose acetate, and polyvinyl alcohol resin;

[0139] The pore-forming agent is at least one of propylene glycol, polyethylene glycol, and fatty acid esters;

[0140] The membrane material comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone; and / or

[0141] The plasticizer includes one or more of polyethylene glycol, propylene glycol, or castor oil;

[0142] further:

[0143] The drug layer binder is polyvinylpyrrolidone K90; the drug layer inhibitor is polyethylene oxide; the drug layer osmotic pressure regulator is sodium chloride; and the drug layer lubricant is magnesium stearate.

[0144] The booster layer inhibitor is polyethylene oxide; the booster layer osmotic pressure regulator is sodium chloride; the booster layer binder is hydroxypropyl methylcellulose; the booster layer colorant is iron oxide red; and the booster layer lubricant is magnesium stearate.

[0145] The semi-permeable membrane material is cellulose acetate; the pore-forming agent is polyethylene glycol.

[0146] The membrane material is hydroxypropyl methylcellulose; the plasticizer is polyethylene glycol.

[0147] This invention develops a bilayer osmotic pump controlled-release tablet for sacubitril / valsartan sodium. This tablet can continuously release the drug over 24 hours, changing the twice-daily oral administration of the original formulation to once every two days, greatly increasing patient compliance. Furthermore, the formulation of this invention is characterized by zero-order release, which is less affected by environmental pH and the complex gastrointestinal environment, significantly increasing drug safety. It avoids the peak-and-trough effect of conventional immediate-release tablets, achieving steady-state blood drug concentrations with a single dose, thus increasing drug efficacy.

[0148] The sacubitril / valsartan sodium controlled-release composition, preparation method and application provided by this invention are all commercially available.

[0149] The present invention will be further illustrated below with reference to the embodiments:

[0150] Example 1

[0151] This embodiment provides a sacubitril / valsartan sodium tablet, the formulation of which is shown in Table 2.

[0152] Table 2

[0153]

[0154]

[0155] The process steps for preparing the above-mentioned sacubitril / valsartan sodium tablets are as follows:

[0156] 1) Drug layer granulation: Weigh the prescribed amounts of sacubitril / valsartan sodium, povidone, polyoxyethylene, sodium chloride (passed through a 60-mesh sieve), and magnesium stearate. Premix and pass through a 40-mesh sieve. After sieving, mix again at a speed of 15 rpm for 10 rpm. After uniform mixing, granulate using a dry granulator with the following settings: vertical speed 10 rpm, horizontal speed 60 rpm, pressure roller speed 6 rpm, granulation speed 60 rpm, and extrusion pressure 5 MPa.

[0157] 2) Propeller Layer Granulation: Weigh the prescribed amounts of polyethylene oxide, sodium chloride (passed through a 60-mesh sieve), hydroxypropyl methylcellulose, iron oxide red (passed through a 40-mesh sieve), and magnesium stearate. Premix and pass through a 40-mesh sieve. Mix again at a speed of 15 rpm for 10 rpm. After uniform mixing, granulate using a dry granulator. Set the vertical speed to 10 rpm, the horizontal speed to 60 rpm, and the pressure roller speed to 6 rpm. Set the granulation speed to 60 rpm and the extrusion pressure to 5 MPa.

[0158] 3) Tableting: Compress the tablets into double-layer tablets according to the prescription ratio. The tableting speed is 20 rpm, and the tablet hardness is controlled at 60-100 N.

[0159] 4) Semi-permeable membrane coating: Dissolve cellulose acetate and polyethylene glycol in 94% acetone until clear and transparent, then coat the product. Control the material temperature within the range of 25.0-35.0°C. Stop coating when the coating weight gain is 6.0%-80%. After coating, dry the product until it reaches constant weight.

[0160] 5) Perforation: After the tablets are coated with the semi-permeable membrane, a perforation machine is used to make a hole in the center of one side of the drug layer, with a hole diameter of 0.6 mm;

[0161] 6) Film Coating: Prepare a film coating solution of appropriate concentration using hydroxypropyl methylcellulose and polyethylene glycol with purified water. Coat the perforated tablets with the film, controlling the material temperature within the range of 38.0–42.0℃. Stop coating when the coating weight gain reaches 4.0%–60%. After coating, dry until the product reaches constant weight.

[0162] Example 2

[0163] This embodiment provides a sacubitril / valsartan sodium tablet, the formulation of which is shown in Table 3.

[0164] Table 3

[0165]

[0166]

[0167] The process steps for preparing the above-mentioned sacubitril / valsartan sodium tablets are the same as those in Example 1.

[0168] Example 3

[0169] This embodiment provides a sacubitril / valsartan sodium tablet, the formulation of which is shown in Table 4.

[0170] Table 4

[0171]

[0172] The process steps for preparing the above-mentioned sacubitril / valsartan sodium tablets are the same as those in Example 1.

[0173] Example 4

[0174] This embodiment provides a sacubitril / valsartan sodium tablet, the formulation of which is shown in Table 5.

[0175] Table 5

[0176]

[0177] The process steps for preparing the above-mentioned sacubitril / valsartan sodium tablets are the same as those in Example 1.

[0178] Example 5

[0179] This embodiment provides a sacubitril / valsartan sodium bilayer tablet, the formulation of which is shown in Table 6.

[0180] Table 6

[0181]

[0182] The process steps for preparing the above-mentioned sacubitril / valsartan sodium tablets are the same as those in Example 1.

[0183] Comparative Example

[0184] This comparative example provides a single-layer osmotic pump sustained-release tablet prepared according to patent CN113456607A, and the formulation composition is shown in Table 7.

[0185] Table 7

[0186]

[0187] The process steps for preparing the above-mentioned single-layer osmotic pump sustained-release tablets are as follows:

[0188] Weigh the prescribed amounts of drug and excipients (except magnesium stearate), mix them evenly using an equal-incremental method, add an appropriate amount of wetting agent and anhydrous ethanol to prepare a soft mass, and granulate it wet through a 20-mesh sieve. Dry in a 40℃ oven for 0.5 hours, and then dry through a 20-mesh sieve. Add the prescribed amount of magnesium stearate to the total mixture. Compress into tablets using a 10mm diameter circular die, achieving a hardness of 6-8kg. Weigh the prescribed amounts of cellulose acetate and polyethylene glycol 3350, heat them in a 35℃ constant temperature water bath, and add them to an acetone-water solution (94:6) with magnetic stirring until completely dissolved. The coating solution should be clear and transparent. Place the tablet cores in a coating pan, control the tablet bed temperature at 22-29℃, and achieve a 5% weight gain after coating. After coating, age the tablets in a 40℃ oven for 12 hours to remove the acetone. Use a laser drilling machine to drill a 0.6mm diameter release hole on the semi-permeable membrane at the center of one side of the osmotic pump.

[0189] Example of effect

[0190] 1. Dissolution curves of commercially available sacubitril / valsartan sodium tablets (Noxinto) in four in vitro media.

[0191] 1.1 Detection of dissolution curve

[0192] The dissolution curve detection method is shown in Table 8.

[0193] Table 8

[0194]

[0195]

[0196] 1.2 Experimental Results

[0197] Dissolution data are shown in Table 9, and the corresponding curves are shown in Table 9. Figure 1 As shown.

[0198] Table 9

[0199]

[0200]

[0201] 1.3 Results Analysis

[0202] The in vitro dissolution curves of Norceptul in four media show that Norceptul is an immediate-release formulation. According to the Norceptul package insert, it is released completely within half an hour. The peak times for Sacubitril, LBQ657, and Valsartan are 0.5 h, 2.0 h, and 1.5 h, respectively, while their half-lives are 1.43 h, 11.48 h, and 9.90 h, respectively. Therefore, Norceptul needs to be administered twice daily. Sacubitril, LBQ657, and Valsartan take up to 3 days to reach steady-state levels. In pH 2.0, the release rate of Norceptul is significantly slowed, showing a greater influence from pH, and its release in vivo varies among individuals.

[0203] 2. Dissolution curves of the comparative examples in four in vitro media.

[0204] 2.1 Detection of dissolution curve

[0205] The detection method for the dissolution curve is shown in Table 8. The sampling time points are 1h, 2h, 4h, 6h, 8h, 10h, and 12h. Six sacubitril / valsartan sodium tablets prepared according to the comparative formula are taken during the preparation of the test solution.

[0206] 2.2 Experimental Results

[0207] Dissolution data are shown in Table 10, and the corresponding curves are shown in... Figure 2 As shown.

[0208] Table 10

[0209]

[0210]

[0211] 2.3 Results Analysis

[0212] The monolayer osmotic pump sustained-release tablets prepared according to patent CN113456607A show, based on their in vitro dissolution curves in four media, that drug release is completed in about 10 hours. However, the dissolution endpoint of this dosage form is only about 80%, meaning the drug cannot be completely released. Furthermore, its dissolution rate is also relatively slow in pH 2.0 medium, making it susceptible to individual variability in vivo.

[0213] 3. Dissolution curves of sacubitril / valsartan sodium tablets prepared in Examples 1-5 in four in vitro media.

[0214] 3.1 Detection of dissolution curve

[0215] Examples 1 to 5 all used the detection method of dissolution curves as shown in Table 8. The sampling time points were 1h, 2h, 4h, 6h, 8h, 10h, 12h, 16h, 20h, and 24h. During the preparation of the test solution, 12 sacubitril / valsartan sodium tablets prepared according to the formulations of Examples 1 to 5 were taken respectively.

[0216] 3.2 Experimental Results

[0217] (1) The dissolution data of Example 1 are shown in Table 11, and the corresponding curves are shown in Table 11. Figure 3 As shown.

[0218] Table 11

[0219]

[0220]

[0221] (2) The dissolution data of Example 2 are shown in Table 12, and the corresponding curves are shown in Table 12. Figure 4 As shown.

[0222] Table 12

[0223]

[0224]

[0225] (3) The dissolution data of Example 3 are shown in Table 13, and the corresponding curves are shown in Table 13. Figure 5 As shown.

[0226] Table 13

[0227]

[0228] (4) The dissolution data of Example 4 are shown in Table 14, and the corresponding curves are shown in Table 14. Figure 6 As shown.

[0229] Table 14

[0230]

[0231] (5) The dissolution data of Example 5 are shown in Table 15, and the corresponding curves are shown in Table 15. Figure 7 As shown.

[0232] Table 15

[0233]

[0234]

[0235] 3.3 Results Analysis

[0236] As can be seen from the in vitro dissolution curves of Examples 1-5 in four media, the formulation of the present invention releases the drug at a constant rate with zero-order release characteristics within 24 hours, and the release curves under different pH conditions are similar, indicating that pH has no effect on drug release.

[0237] 4. Discussion

[0238] The results above indicate that commercially available tablets are conventional immediate-release formulations, administered twice daily. Patients often forget to take them, leading to poor compliance and reduced therapeutic effectiveness. In contrast, the formulation of this invention extends drug release from 1 hour to 24 hours, and considering the drug's half-life, allows for administration once every two days, significantly improving patient compliance.

[0239] The disintegration and drug release of conventional immediate-release tablets are affected by the complex gastrointestinal environment, such as food residue, individual differences in gastrointestinal motility, and individual differences in pH value. However, the formulation described in this invention is a bilayer osmotic pump controlled-release formulation, whose drug release is not affected by the environment, greatly increasing the effectiveness of the drug.

[0240] Conventional immediate-release tablets release the drug into the body and are absorbed, requiring multiple doses to bring the blood drug concentration within the effective range. However, the peak-and-trough effect remains a significant risk to drug safety. In contrast, the formulation described in this invention releases the drug with zero-order release characteristics, eliminating peak-and-trough effects in blood drug concentration and greatly increasing drug safety.

[0241] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A controlled release composition of sacubitril / valsartan sodium characterized in that, comprising a drug layer and a booster layer; the drug layer comprises, by weight parts, the following components: the booster layer comprises, by weight parts, the following components:

2. The controlled release combination of sacubitril / valsartan sodium composition according to claim 1, wherein, the weight ratio of the drug layer to the booster layer comprises (311-377):(117-150).

3. The controlled release combination of sacubitril / valsartan sodium composition according to claim 1 or 2, wherein in the drug layer: the weight parts of the sacubitril valsartan sodium comprise 38.18 parts, 39.45 parts, 40.00 parts, 41.27 parts or 42.19 parts; and / or the weight parts of the binder comprise 1.18 parts, 1.27 parts, 1.72 parts, 2.00 parts or 2.12 parts; and / or the weight parts of the retarder comprise 19.72 parts, 20.64 parts, 21.10 parts, 24.00 parts or 25.45 parts; and / or the weight parts of the osmotic pressure regulator comprise 0.59 parts, 0.63 parts, 0.86 parts, 1.00 parts or 1.06 parts; and / or the weight parts of the lubricant comprise 0.34 parts, 0.39 parts, 0.40 parts or 0.42 parts; and / or in the booster layer: the weight parts of the retarder comprise 16.00 parts, 16.88 parts, 16.97 parts, 17.20 parts or 19.72 parts; and / or the weight parts of the osmotic pressure regulator comprise 6.00 parts, 6.33 parts, 6.36 parts, 6.88 parts or 7.89 parts; and / or the weight parts of the binder comprise 1.00 parts, 1.05 parts, 1.06 parts, 1.20 parts or 1.38 parts; and / or the weight parts of the colorant comprise 0.20 parts, 0.21 parts, 0.34 parts or 0.39 parts; and / or the weight parts of the lubricant comprise 0.17 parts, 0.20 parts or 0.21 parts; as preferred, the binder comprises one or a combination of more than one of povidone, hypromellose or hydroxypropyl cellulose; and / or the retarder comprises one or a combination of more than one of hypromellose, polyoxyethylene or carnauba wax; and / or the osmotic pressure regulator comprises one or a combination of more than one of potassium chloride, sodium chloride or calcium chloride; and / or the lubricant comprises one or a combination of more than one of magnesium stearate, talc or sodium stearyl fumarate; and / or the colorant comprises iron oxide red; as preferred, in the drug layer: the binder comprises povidone K90; and / or the retarder comprises polyoxyethylene; and / or the osmotic pressure regulator comprises sodium chloride; and / or the lubricant comprises magnesium stearate; and / or in the booster layer: the retarder comprises polyoxyethylene; and / or the osmotic pressure regulator comprises sodium chloride; and / or the binder comprises hypromellose; and / or the colorant comprises iron oxide red; and / or the lubricant comprises magnesium stearate.

4. A process for the preparation of the controlled release combination of sacubitril / valsartat sodium according to any one of claims 1 to 3, characterized in that, comprising the following steps: Step 1, drug layer granulation: weigh the prescribed amount of sacubitril valsartan sodium, binder, retarder, osmotic pressure regulator and lubricant, pre-mix, sieve, mix, granulate, and obtain drug layer granulation; Step 2, booster layer granulation: the prescription amount of retarder, osmotic pressure regulator, binder, colorant and lubricant are weighed, premixed, sieved, mixed and granulated to obtain the booster layer granulation.

5. The controlled release sartan composition of sacubitril / valsartan sodium prepared by the method of claim 4.

6. Use of the controlled release sartan composition of sacubitril / valsartan sodium of any one of claims 1-3 or the controlled release sartan composition of sacubitril / valsartan sodium of claim 5 in any one of: (I) preparing a drug for reducing the number of dosing, reducing the total dose and / or increasing the patient's compliance; (II) preparing a drug for avoiding or reducing the peak-trough phenomenon in the release process; (III) preparing a drug for reducing the side effects of the drug; and / or (IV) preparing a drug for improving the effectiveness.

7. A medicament, characterized by, The controlled release sartan composition of sacubitril / valsartan sodium of any one of claims 1-3 or the controlled release sartan composition of sacubitril / valsartan sodium of claim 5, and pharmaceutically acceptable excipients.

8. The medicament according to claim 7, wherein The drug comprises the controlled release sartan composition of sacubitril / valsartan sodium of any one of claims 1-3 or the controlled release sartan composition of sacubitril / valsartan sodium of claim 5, a semi-permeable membrane and a film coating; The semi-permeable membrane comprises the following components by weight: Semi-permeable membrane material 3.82-5.16 parts Pore former 0.32-0.43 parts The film coating comprises the following components by weight: Film material 3.39-3.80 parts Plasticizer 0.34-0.42 parts; As a preferred, In the semi-permeable membrane: The weight parts of the semi-permeable membrane material include 3.82 parts, 4.73 parts, 4.80 parts, 5.06 parts or 5.16 parts; and / or The weight parts of the pore former include 0.32 parts, 0.39 parts, 0.40 parts, 0.42 parts or 0.43 parts; and / or In the film coating: The weight parts of the film material include 3.39 parts, 3.44 parts, 3.55 parts, 3.60 parts or 3.80 parts; and / or The weight parts of the plasticizer include 0.34 parts, 0.39 parts, 0.40 parts or 0.42 parts; As a preferred, The semi-permeable membrane material includes one or a combination of more than two of ethyl cellulose, cellulose acetate or polyvinyl acid resin; and / or The pore former includes one or a combination of more than two of propylene glycol, polyethylene glycol or fatty acid ester; and / or The film material includes one or a combination of more than two of hydroxypropyl methyl cellulose, hydroxypropyl cellulose or polyvinyl pyrrolidone; and / or The plasticizer includes but is not limited to one or a combination of more than two of polyethylene glycol, propylene glycol or castor oil; As a preferred, In the semi-permeable membrane: The semi-permeable membrane material includes cellulose acetate; and / or The pore former includes polyethylene glycol; and / or In the film coating: The film material includes hydroxypropyl methyl cellulose; and / or The plasticizer includes polyethylene glycol.

9. The method of claim 7 or 8, wherein the pharmaceutical preparation is prepared by a method comprising the steps of: The method comprises the following steps: Step 1, drug layer granulation: the prescription amount of sacubitril / valsartan sodium, binder, retarder, osmotic pressure regulator and lubricant are weighed, premixed, sieved, mixed and granulated to obtain the drug layer granulation; Step 2, prilling of the booster layer: the retarding agent, the osmotic pressure regulator, the binder, the colorant and the lubricant are weighed according to the prescription, pre-mixed, sieved, mixed and prilled to obtain the prilling of the booster layer; Step 3, tabletting: the prilling of the drug layer obtained in Step 1 and the prilling of the booster layer obtained in Step 2 are mixed according to the prescription and then tabletted; Step 4, semi-permeable membrane coating: the semi-permeable membrane material and the pore-forming agent are dissolved in 94% acetone, coated and dried to constant weight to obtain the semi-permeable membrane coated tablet; Step 5, punching: the semi-permeable membrane coated tablet is punched; Step 6, film coating: the film material and the plasticizer are configured to obtain a film coating liquid, and the punched tablet obtained in Step 5 is film coated.

10. The drug prepared by the preparation method of claim 9.

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