Pharmaceutical composition containing propranolol and neutral endo-peptidase inhibitor as well as preparation method and application of pharmaceutical composition

Abstract

The invention discloses a pharmaceutical composition containing propranolol and a neutral endo-peptidase inhibitor, the pharmaceutical composition comprises propranolol and a neutral endo-peptidase inhibitor, and the propranolol and the neutral endo-peptidase inhibitor are combined and connected through a non-covalent bond. According to the invention, sacubitril and propranolol are combined into a dual-effect salt, so that the two active pharmaceutical ingredients are synchronously released, the drug effect is favorably improved, the synergistic effect is favorably generated in the treatment process, the side effect of propranolol is effectively reduced, and the clinical use values of sacubitril and propranolol are potentially improved; on the premise of ensuring the antihypertensive effect, the occurrence probability of side effects is effectively reduced, and the medication safety is improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a salt containing propranolol and a neutral endopeptidase inhibitor, its preparation method, and its uses. Background Technology

[0002] Propranolol is a non-selective beta-blocker that acts on both beta1 (cardiac-dominant) and beta2 (peripheral tissue-dominant) receptors. By inhibiting beta1 receptors in cardiomyocytes, it reduces cAMP (cyclic adenosine monophosphate) concentration, weakens calcium ion influx, thereby slowing the heart rate (decreased sinoatrial node automaticity), reducing myocardial contractility, and prolonging atrioventricular node conduction time. This triple action directly reduces myocardial oxygen consumption, making it particularly suitable for patients with angina. Simultaneously, by inhibiting abnormal electrical activity, it can be used to treat supraventricular arrhythmias (such as atrial fibrillation and atrial flutter). Long-term use can also inhibit renin release (blocking beta1 receptors on juxtaglomerular cells in the kidneys), weakening the renin-angiotensin-aldosterone system (RAAS) activity, producing a mild antihypertensive effect, making it suitable for the treatment of hypertension. Meanwhile, blocking β2 receptors in vascular smooth muscle counteracts β2-mediated vasodilation, initially causing peripheral vasoconstriction (e.g., cold extremities), but long-term blockade leads to a sustained decrease in blood pressure due to RAAS inhibition and reduced cardiac output. Blocking β2 receptors in bronchial smooth muscle weakens bronchodilatory function, potentially inducing or exacerbating bronchospasm; therefore, it is contraindicated in asthma patients. Propranolol is highly lipid-soluble (log P = 3.1), readily crossing the blood-brain barrier and blocking β receptors in the central nervous system. This expands its off-label applications in treating anxiety disorders and migraines (possibly related to central nervous system excitability inhibition), but may also cause neurological side effects such as vivid dreams and depression. Propranolol can also inhibit platelet aggregation (the mechanism is not fully understood), potentially having an indirect effect on thrombosis prevention.

[0003] Propranolol's "non-selective" nature gives it a unique advantage in clinical applications. Firstly, it has a wide range of indications and prominent "cross-disciplinary" applications: in addition to classic cardiovascular indications (angina pectoris, hypertension, arrhythmia), due to its effects on β2 receptors and the central nervous system, it is also used for: migraine prevention (reducing cerebral vasodilation, the mechanism of which may be related to β-receptor blockade and inhibition of platelet serotonin release); essential tremor (blocking peripheral β2 receptors to reduce muscle tremors, while central effects inhibit nerve conduction); acute attacks of anxiety disorders (relieving physical symptoms such as palpitations and tremors, especially suitable for performative anxiety); and adjunctive treatment of hyperthyroidism (inhibiting symptoms of hyperadrenocorticism, such as tachycardia and tremor). These uses are mostly "off-label" applications, but the clinical evidence is sufficient, and the price is low (generic drugs cost only a few cents per day), making them extremely valuable in resource-limited areas. Its pharmacokinetic characteristics are suitable for rapid onset of action: it is rapidly absorbed orally (bioavailability of about 30%, strong first-pass effect), reaching peak plasma concentration in 1-2 hours; intravenous injection can have an immediate effect, making it suitable for emergency situations (such as paroxysmal supraventricular tachycardia). Its high lipid solubility allows for wide distribution, especially in central nervous system diseases, where it is more effective, whereas water-soluble beta-blockers (such as atenolol) can hardly cross the blood-brain barrier.

[0004] Propranolol also has significant limitations and drawbacks in clinical use. It may block pancreatic β2 receptors (promoting insulin release) and mask symptoms of hypoglycemia (such as palpitations and tremors), requiring caution in diabetic patients who may experience hypoglycemic coma. It may also increase triglycerides and decrease HDL-C (good cholesterol), which is detrimental to those with dyslipidemia. Propranolol may occasionally exacerbate limb ischemia in patients with Raynaud's syndrome, and long-term use may occasionally cause lower limb arterial spasm. Its relatively good lipid solubility may cause approximately 10%-15% of patients to experience symptoms such as vivid dreams, insomnia, and depression, especially in elderly patients or those with a history of mental illness. The inhibition of the sinoatrial node and atrioventricular node by propranolol may lead to bradycardia (heart rate <50 beats / min) and atrioventricular block (grade II or higher requires discontinuation), making it contraindicated in patients with sick sinus syndrome or severe conduction disorders. Propranolol's blocking of β2 receptors may slightly constrict peripheral blood vessels (especially in the skin and skeletal muscle), leading to reduced local blood flow and obstructed tissue fluid return, resulting in mild lower extremity edema.

[0005] Therefore, it is necessary to modify propranolol to reduce its side effects in clinical applications. Summary of the Invention

[0006] The purpose of this invention is to provide a pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor. This invention also provides a method for preparing the pharmaceutical composition and its uses, which are the second and third objectives of this invention.

[0007] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0008] As a first aspect of the invention, the present invention provides a pharmaceutical composition comprising propranolol and a neutral endopeptidase inhibitor, the pharmaceutical composition comprising propranolol and the neutral endopeptidase inhibitor being linked by a non-covalent bond.

[0009] As a further preferred embodiment of the present invention, the non-covalent bond is an ionic bond.

[0010] As a further preferred embodiment of the present invention, the neutral endopeptidase inhibitor is sacubitril or a pharmaceutically acceptable salt thereof.

[0011] As a further preferred embodiment of the present invention, the molar ratio of propranolol to neutral endopeptidase inhibitor is 1:0.5 to 2, and preferably the molar ratio of propranolol to neutral endopeptidase inhibitor is 1:1.

[0012] As a further preferred embodiment of the present invention, the pharmaceutical composition is propranolol-neutral endopeptidase inhibitor salt, wherein the propranolol-neutral endopeptidase inhibitor salt is [1-isopropylamino-3-(naphth-1-oxy)prop-2-ol][4-{[(1S,3R)-1-([1,1'-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutyric acid].

[0013] As a further preferred embodiment of the present invention, the propranolol-neutral endopeptidase inhibitor salt is in crystalline, partially crystalline, amorphous, and polymorphic forms, preferably in crystalline form; its X-ray diffraction pattern includes crystal form A, wherein crystal form A has characteristic peaks at 2θ values ​​of 6.6°±0.2°, 11.7°±0.2°, 12.4°±0.2°, and 16.4°±0.2°.

[0014] As a second aspect of the invention, the invention also provides a method for preparing the pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor, obtained by any of the following preparation methods (A)-(F):

[0015] Preparation method (A): Add solvent to propranolol and neutral endopeptidase inhibitor, and place the resulting suspension at room temperature and stir magnetically. If a solid is obtained, centrifuge to separate it. If not, treat it at low temperature or stir it in a temperature cycle until a solid is precipitated.

[0016] Preparation method (B): Dissolve propranolol and neutral endopeptidase inhibitor in a solvent at room temperature to obtain a solution, and then slowly evaporate it completely at room temperature before collecting the resulting solid.

[0017] Preparation method (C): Dissolve propranolol and neutral endopeptidase inhibitor in a solvent, add the unsuitable solvent dropwise while stirring, until a solid precipitates out, then separate the precipitated solid;

[0018] Preparation method (D): Dissolve propranolol and neutral endopeptidase inhibitor in a solvent, cool to 5°C at a rate of 0.1°C / min, and maintain at 5°C. Collect the resulting solid.

[0019] Preparation method (E): Add solvent to propranolol and neutral endopeptidase inhibitor, and stir the resulting suspension magnetically at 50°C. If a solid is obtained, centrifuge to separate it. If not, treat it at low temperature or stir it in a temperature cycle until a solid is precipitated.

[0020] Preparation method (F): Add solvent to propranolol and neutral endopeptidase inhibitor, and stir the resulting suspension in a biochemical incubator under temperature cycling for 2 days. Then, determine whether to continue the temperature cycling or maintain magnetic stirring at 5°C based on the solution condition until a large amount of solid is obtained. Then, centrifuge to collect the solid.

[0021] In preparation methods (A), (E) and (F), during the temperature cycling process, the temperature is raised to 30-80℃, the stirring time is 0.5-4 hours, the temperature is lowered to 2-10℃, the temperature is lowered at a rate of 0.05-0.5℃ / min, and the temperature is raised at a rate of 0.1-5℃ / min.

[0022] As a further preferred embodiment of the present invention, the solvent in method (A) is a mixture of n-heptane and 2-methyltetrahydrofuran, or acetone, or ethyl acetate; the solvent in method (B) is isopropyl acetate / n-heptane; the solvent in method (C) is at least one of acetone, tetrahydrofuran, 1,4-dioxane, or acetonitrile; the mixed solvent in method (D) is any combination of isopropanol / water, ethyl acetate / n-heptane, and acetone / n-heptane; the mixed solvent in method (E) is any combination of toluene / n-heptane, 2-methyltetrahydrofuran / n-heptane, methyl ethyl ketone / n-heptane, isopropyl acetate / n-heptane, and cyclopentyl methyl ether / n-heptane; and the solvent in method (F) is any combination of isopropyl acetate / n-heptane, 2-methyltetrahydrofuran / n-hexane, methyl isobutyl ketone / n-hexane, toluene / n-heptane, and chloroform / n-heptane.

[0023] In preparation method (A), the total amount of propranolol and neutral endopeptidase inhibitor is 150-5 mg:1 mL in solvent, and the volume ratio of n-heptane to 2-methyltetrahydrofuran, or acetone, or ethyl acetate is 1-10:1. Low-temperature treatment is carried out by stirring at 2-10℃ for 1-8 days. Temperature cycling treatment is carried out by heating, cooling, heating, and cooling during stirring, which constitutes one temperature cycle treatment. The number of temperature cycles is 1-20.

[0024] In preparation method (B), the total amount of propranolol and neutral endopeptidase inhibitor is 100-2 mg: 1 mL in solvent, and the volume ratio of isopropyl acetate / n-heptane mixed solvent is 1-15:1.

[0025] In preparation method (C), the total amount of propranolol and neutral endopeptidase inhibitor is 150-5 mg / 1 mL in solvent, and the total amount of propranolol and neutral endopeptidase inhibitor is 20-0.5 mg / 1 mL in unsuitable solvent.

[0026] In preparation method (D), the total amount of propranolol and neutral endopeptidase inhibitor is 150-2 mg / 1 mL in solvent. The volume ratio of the mixed solvent isopropanol / water, ethyl acetate / n-heptane, or acetone / n-heptane is 1-15:1. The cooling and stirring treatment is as follows: stir at 30-80℃ for 0.5-4 hours, cool to 2-10℃ at a rate of 0.05-0.5℃ / min, and finally maintain at 2-10℃ for stirring for 1-8 days. After low-temperature stirring, the solid is separated by centrifugation and then vacuum dried at room temperature for 0.5-5 days.

[0027] In preparation method (E), the volume ratio of other solvents to n-heptane in the mixed solvent is 1:1-18; the total amount of propranolol and neutral endopeptidase inhibitor is 100-10 mg:1 mL.

[0028] In preparation method (F), the total amount of propranolol and neutral endopeptidase inhibitor is 150-5 mg:1 mL in solvent; in the mixed solvent, the volume ratio of isopropyl acetate / n-heptane, 2-methyltetrahydrofuran / n-hexane, methyl isobutyl ketone / n-hexane, toluene / n-heptane, and chloroform / n-heptane is 1:1-9.

[0029] In a third aspect, the present invention further discloses the use of the pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor in the preparation of a medicament for treating or preventing diseases or conditions, wherein the diseases or conditions are selected from: myocardial infarction; hypertension; angina pectoris; supraventricular tachyarrhythmia, ventricular arrhythmia; palpitations and syncope; tachycardia; tachycardia caused by hyperthyroidism; thyroid storm; hemangioma; melanoma; esophageal variceal bleeding due to portal hypertension; migraine; cerebrovascular ischemic disease; familial essential tremor; schizophrenia; anxiety disorder; hypoxic episodes of tetralogy of Fallot (F4); epidemic hemorrhagic fever; aplastic anemia; restless legs syndrome; and aortic dissection hematoma.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] 1. This invention combines sacubitril and propranolol into a dual-action salt. Due to the interaction at the microscopic level, the simultaneous release of the two active pharmaceutical ingredients helps to enhance the efficacy and the occurrence of synergistic effects during treatment. It can effectively reduce the side effects of propranolol and thus potentially improve the clinical value of both. While ensuring the antihypertensive effect, it effectively reduces the probability of side effects and improves the safety of medication.

[0032] 2. The salt of the present invention has a good and stable physical shape under storage conditions, which can better avoid the risk of chemical degradation caused by moisture absorption and gelation, and ensure stable and controllable product quality.

[0033] 3. Under the same dosage, the dual-action salt-lowering effect is significantly better than propranolol alone or neutral endopeptidase inhibitor alone. Compared with propranolol alone or neutral endopeptidase inhibitor alone, it demonstrates the synergistic effect of neutral endopeptidase inhibitor on propranolol in terms of antihypertensive effect. Attached Figure Description

[0034] Figure 1 XRPD diagram of sacubitril salt crystal form A;

[0035] Figure 2 TGA / DSC plot of sacubitril salt crystal form A;

[0036] Figure 3 Sacubitril propranolol salt crystal form A 1 H NMR spectrum;

[0037] Figure 4 Sacubitril propranolol salt crystal form A, sacubitril monomer, propranolol monomer 1 H NMR comparison image. Detailed Implementation

[0038] The dual-function salt of this invention can be in the form of a complex or a supramolecular ion complex. The propranolol and the neutral endopeptidase inhibitor are linked by a non-covalent bond, for example, in a salt formed by propranolol and the neutral endopeptidase inhibitor.

[0039] The neutral endopeptidase inhibitor is sacubitril or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts include, for example, metal ion salts such as sodium, potassium, and calcium salts, and organic base salts such as choline salts and meglumine salts.

[0040] The dual-function salt of the present invention is in crystalline, partially crystalline, amorphous, and polymorphic form, preferably in crystalline form, such as a salt or cocrystal formed by propranolol and a neutral endopeptidase inhibitor.

[0041] In the dual-action salt of the present invention, propranolol and a neutral endopeptidase inhibitor are present in a molar ratio of 1:0.5–2, or 1:0.8–1.5, or 1:0.9–1.2, or 1:1.

[0042] The dual-function salt of this invention is a propranolol-neutral endopeptidase inhibitor salt.

[0043] The dual-function salt of this invention is [1-isopropylamino-3-(naphth-1-oxy)prop-2-ol][4-{[(1S,3R)-1-([1,1'-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutyric acid].

[0044] The dual-function salt of this invention can be an amorphous solid.

[0045] The dual-function salt of the present invention can be a crystalline solid, and its X-ray powder diffraction pattern includes crystal form A.

[0046] The X-ray powder diffraction of crystal form A has characteristic peaks at 2θ values ​​of 6.6°±0.2°, 11.7°±0.2°, 12.4°±0.2°, and 16.4°±0.2°.

[0047] The X-ray powder diffraction of crystal form A has characteristic peaks at one, two, or three of the following locations with 2θ values: 8.5°±0.2°, 15.0°±0.2°, and 18.1°±0.2°.

[0048] The X-ray powder diffraction of crystal form A has characteristic peaks at 2θ values ​​of 8.5°±0.2°, 15.0°±0.2°, and 18.1°±0.2°.

[0049] The X-ray powder diffraction of crystal form A has characteristic peaks at one, two, or three of the following locations with 2θ values ​​of 15.5°±0.2°, 21.8°±0.2°, and 23.4°±0.2°.

[0050] The X-ray powder diffraction of crystal form A has characteristic peaks at 2θ values ​​of 15.5°±0.2°, 21.8°±0.2°, and 23.4°±0.2°.

[0051] The X-ray powder diffraction of crystal form A has characteristic peaks at any 4, 5, 6, 7, 8, 9, or 10 locations with 2θ values ​​of 6.6°±0.2°, 8.5°±0.2°, 11.7°±0.2°, 12.4°±0.2°, 15.0°±0.2°, 15.5°±0.2°, 16.4°±0.2°, 18.1°±0.2°, 21.8°±0.2°, or 23.4°±0.2°.

[0052] The X-ray powder diffraction of crystal form A shows characteristic peaks at 2θ values ​​of 6.6°±0.2°, 8.5°±0.2°, 11.7°±0.2°, 12.4°±0.2°, 15.0°±0.2°, 15.5°±0.2°, 16.4°±0.2°, 18.1°±0.2°, 21.8°±0.2°, and 23.4°±0.2°.

[0053] The dual-function salt of the present invention can be obtained by the following preparation methods (A), (B), (C), (D), (E), and (F).

[0054] Preparation method (A): Add solvent to propranolol and neutral endopeptidase inhibitor, and stir magnetically at room temperature. If a suspension is obtained, centrifuge to separate it. If a gel is formed, transfer to temperature cycling treatment (50℃~5℃, 0.1℃ / min) or stir at 5℃ until a solid is obtained, for example, 1-8 days, 1.5-6 days, 2-4 days, or 3 days.

[0055] In some embodiments of the present invention, in preparation method (A), the molar ratio of propranolol to neutral endopeptidase inhibitor is 1:0.5-2, or 1:0.8-1.5, or 1:0.9-1.2, or 1:1.

[0056] In some embodiments of the present invention, in preparation method (A), the amount of solvent added, for example, the total amount (mass) of propranolol and neutral endopeptidase inhibitor: solvent (volume) is 150-5:1, 100-10:1, 50-20:1, or 30:1.

[0057] In some embodiments of the present invention, in preparation method (A), the solvent is a mixture of n-heptane and 2-methyltetrahydrofuran, or acetone, or ethyl acetate. The volume ratio of n-heptane to 2-methyltetrahydrofuran, or acetone, or ethyl acetate is 1-10:1, or 2-7:1, or 3-5, or 4:1.

[0058] In some embodiments of the present invention, in preparation method (A), the low-temperature treatment is carried out by stirring at 2-10°C, 3-8°C, 4-6°C, or 5°C. The stirring time can be 1-8 days, 1.5-6 days, 2-4 days, or 3 days.

[0059] In some embodiments of the present invention, in the method (A) for preparing the dual-function salt, the temperature cycling process involves heating, cooling, heating, and cooling during stirring, thus constituting one temperature cycle. The number of temperature cycles is not particularly limited, for example, an upper limit of 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, or 6 cycles, and a lower limit of 1, 2, 3, 4, or 5 cycles.

[0060] During the temperature cycling process, the temperature is increased to 30-80℃, 35-70℃, 40-60℃, or 50℃. The stirring time is 0.5-4 hours, 1-3 hours, or 2 hours, followed by cooling to 2-10℃, 3-8℃, 4-7℃, or 5℃. The cooling rate is 0.05-0.5℃ / min, 0.08-0.3℃ / min, or 0.1℃ / min. The heating rate is 0.1-5℃ / min, 0.5-3℃ / min, or 1℃ / min.

[0061] In some embodiments of the present invention, in preparation method (A), the temperature cycling process is as follows: magnetic stirring at 50°C for 2 hours, cooling to 5°C at a rate of 0.1°C / min over 450 minutes, then stirring at 5°C for 2 hours, heating to 50°C at a rate of 1.0°C / min over 45 minutes, magnetic stirring at 50°C for 2 hours, cooling to 5°C at a rate of 0.1°C / min over 450 minutes, and maintaining stirring at 5°C. This constitutes one temperature cycling process.

[0062] As a specific embodiment of the method (A) for preparing the salt with dual functions of the present invention, see, for example, the method described in Examples 1-16.

[0063] As a specific embodiment of the dual-function salt preparation method (A) of the present invention, it is used to prepare sacubitril salt crystal form A.

[0064] Preparation method (B): Propranolol and a neutral endopeptidase inhibitor are dissolved in a solvent and then slowly evaporated at room temperature to obtain a dual-function salt. The evaporation time is not particularly limited, and can be continued until a solid is obtained, for example, 1-18 days, 2-12 days, 6-8 days, or 7 days.

[0065] In some embodiments of the present invention, in preparation method (B), the molar ratio of propranolol to neutral endopeptidase inhibitor is 1:0.5-2, or 1:0.8-1.5, or 1:0.9-1.2, or 1:1.

[0066] In some embodiments of the present invention, in preparation method (B), the amount of solvent added, for example, the total amount (mass) of propranolol and neutral endopeptidase inhibitor: solvent (volume) is 100-2 mg: 1 mL, 50-5 mg: 1 mL, 20-8 mg: 1 mL, or 10 mg: 1 mL.

[0067] In the preparation method (B) of the dual-function salt of the present invention, the solvent is at least one of ethanol, isopropyl acetate, acetone, acetonitrile, or a mixed solvent of isopropyl acetate / n-heptane.

[0068] The volume ratio of the isopropyl acetate / n-heptane mixed solvent is 1-15:1, or 3-12:1, 1-3:1, or 2:1.

[0069] As a specific embodiment of the method (B) for preparing the salt with dual functions of the present invention, see, for example, the method described in Examples 17-21.

[0070] As a specific embodiment of the dual-function salt preparation method (B) of the present invention, it is used to prepare sacubitril salt crystal form A.

[0071] Preparation method of dual-action salt (C): dissolve propranolol and neutral endopeptidase inhibitor in a good solvent, and then add a poor solvent dropwise while stirring until a solid precipitates out. Separate the precipitated solid.

[0072] In some embodiments of the present invention, in the method (C) for preparing the dual-action salt, the molar ratio of propranolol to the neutral endopeptidase inhibitor is 1:0.5-2, or 1:0.8-1.5, or 1:0.9-1.2, or 1:1.

[0073] In some embodiments of the present invention, in the method (C) for preparing the dual-action salt, the amount of good solvent added, such as the total amount (mass) of propranolol and neutral endopeptidase inhibitor: solvent (volume) is 150-5 mg: 1 mL, 100-10 mg: 1 mL, 50-15 mg: 1 mL, or 25 mg: 1 mL.

[0074] In some embodiments of the present invention, in the method (C) for preparing the dual-action salt, the amount of undesirable solvent added, such as the total amount (mass) of propranolol and neutral endopeptidase inhibitor: undesirable solvent (volume) is 20-0.5 mg: 1 mL, 10-0.8 mg: 1 mL, 5-1 mg: 1 mL, or 1.5 mg: 1 mL.

[0075] In the preparation method (C) of the dual-purpose salt of the present invention, the solvent is at least one selected from acetone, acetonitrile, 1,4-dioxane, or tetrahydrofuran. The unsuitable solvent is at least one selected from n-heptane or water.

[0076] As a specific embodiment of the method (C) for preparing the salt with dual functions of the present invention, see, for example, the method described in Examples 22-25.

[0077] As a specific embodiment of the method (C) for preparing the salt with dual functions of the present invention, it is used to prepare amorphous salt of sacubitril propranolol.

[0078] Preparation method of dual-action salt (D): Add solvent to propranolol and neutral endopeptidase inhibitor, cool and stir to obtain a salt with dual action.

[0079] In some embodiments of the present invention, in preparation method (D), the molar ratio of propranolol to neutral endopeptidase inhibitor is 1:0.5-2, or 1:0.8-1.5, or 1:0.9-1.2, or 1:1.

[0080] In some embodiments of the present invention, in the method (D) for preparing the dual-action salt, the amount of solvent added, for example, the total amount (mass) of propranolol and neutral endopeptidase inhibitor: solvent (volume) is 150-2 mg: 1 mL, 100-5 mg: 1 mL, 50-10 mg: 1 mL, or 12.5 mg: 1 mL.

[0081] In some embodiments of the present invention, in the method (D) for preparing the dual-action salt, the mixed solvent is isopropanol / water, ethyl acetate / n-heptane, or acetone / n-heptane.

[0082] The volume ratio of the mixed solvent isopropanol / water, or ethyl acetate / n-heptane, or acetone / n-heptane is 1-15:1, or 3-12:1, 1-3:1, or 2:1.

[0083] In some embodiments of the present invention, in preparation method (D), the cooling and stirring treatment is performed as follows: stirring at 30-80°C, 35-70°C, 40-60°C, or 50°C. The stirring time can be 0.5-4 hours, 1-3 hours, or 2 hours. Then, the temperature is lowered to 2-10°C, 3-8°C, 4-7°C, or 5°C at a rate of 0.05-0.5°C / min, 0.08-0.3°C / min, or 0.1°C / min. Finally, the temperature is maintained at 2-10°C, 3-8°C, 4-7°C, or 5°C while stirring. The stirring time can be 1-8 days, 1.5-6 days, 2-4 days, or 3 days.

[0084] In some embodiments of the present invention, in preparation method (D), after low-temperature stirring, the solid is separated by centrifugation and then vacuum dried at room temperature for 0.5-5 days, 0.5-3 days, 1-2 days, or 1 day.

[0085] As a specific embodiment of the method (D) for preparing the salt with dual functions of the present invention, see, for example, the method described in Examples 26-28.

[0086] As a specific embodiment of the dual-function salt preparation method (D) of the present invention, it is used to prepare amorphous salt of sacubitril propranolol.

[0087] Preparation method of dual-action salt (E): Add solvent to propranolol and neutral endopeptidase inhibitor, and stir the resulting suspension magnetically at 50°C. If a solid is obtained, centrifuge it; if not, treat it at low temperature or circulate it at temperature until a solid precipitates.

[0088] In some embodiments of the present invention, the suspension stirring time in the method (E) for preparing the dual-effect salt can be 1-10 days, 1-6 days, 2-4 days, 3 days, or 2 days.

[0089] In some embodiments of the present invention, the solvent in the method (E) for preparing the dual-function salt is any one of toluene / n-heptane, 2-methyltetrahydrofuran / n-heptane, methyl ethyl ketone / n-heptane, isopropyl acetate / n-heptane, and cyclopentyl methyl ether / n-heptane.

[0090] In the mixed solvent, the volume ratio of toluene / n-heptane is 1:1-18, 1:3-15, 1:6-12, or 1:9; the volume ratio of 2-methyltetrahydrofuran / n-heptane is 1:1-18, 1:3-15, 1:6-12, or 1:9; the volume ratio of methyl ethyl ketone / n-heptane is 1:1-18, 1:3-15, 1:6-12, or 1:9; the volume ratio of isopropyl acetate / n-heptane is 1:1-18, 1:3-15, 1:6-12, or 1:9; and the volume ratio of methyl ethyl ketone / n-heptane is 1:1-9, 1:2-6, 1:3-5, or 1:4.

[0091] In some embodiments of the present invention, in the preparation method (E), the amount of solvent added, for example, the total amount (mass) of propranolol and neutral endopeptidase inhibitor: solvent (volume) is 100-10 mg: 1 mL, 80-20 mg: 1 mL, 60-40 mg: 1 mL, or 30 mg: 1 mL.

[0092] In some embodiments of the present invention, in preparation method (E), after suspension stirring at 50°C for 0.5-10 days, 0.5-5 days, 1-4 days, 2 days, or 3 days, the mixture is switched to temperature cycling stirring (the sample is heated to 50°C and equilibrated for 2 hours, then cooled to 5°C at a rate of 0.1°C / min, and then heated to 50°C at a rate of 1.0°C / min and equilibrated for 2 hours, and then this cycle is repeated) for 0.5-10 days, 0.5-7 days, 0.5-4 days, 1 day, or 3 days, and then the solid is collected by centrifugation.

[0093] As a specific embodiment of the method (E) for preparing the salt with dual functions of the present invention, see, for example, the method described in Examples 29-37.

[0094] As a specific embodiment of the method (E) for preparing the salt with dual functions of the present invention, it is used to prepare either sacubitril salt crystal form A or amorphous form.

[0095] Preparation method of dual-action salt (F): Add solvent to propranolol and neutral endopeptidase inhibitor, and stir the resulting suspension in a biochemical incubator under temperature cycling (heat the sample to 50°C and equilibrate for 2 hours, cool down to 5°C at a rate of 0.1°C / min, and heat up to 50°C at a rate of 1.0°C / min and equilibrate for 2 hours, and then repeat this cycle) for 2 days. Determine whether to continue the temperature cycling or keep it at 5°C with magnetic stirring based on the solution condition. If a large amount of solid is obtained, collect the solid by centrifugation.

[0096] In some embodiments of the present invention, in the method (F) for preparing the dual-action salt, the molar ratio of propranolol to the neutral endopeptidase inhibitor is 1:0.5-2, or 1:0.8-1.5, or 1:0.9-1.2, or 1:1.

[0097] In some embodiments of the present invention, in the method (F) for preparing the dual-action salt, the amount of solvent added, for example, the total amount (mass) of propranolol and neutral endopeptidase inhibitor: solvent (volume) is 150-5 mg: 1 mL, 100-10 mg: 1 mL, 50-20 mg: 1 mL, or 30 mg: 1 mL.

[0098] In the method (F) for preparing the dual-function salt of the present invention, the solvent is any combination of isopropyl acetate / n-heptane, 2-methyltetrahydrofuran / n-hexane, methyl isobutyl ketone / n-hexane, toluene / n-heptane, and chloroform / n-heptane.

[0099] In the mixed solvent, the volume ratio of isopropyl acetate / n-heptane is 1:1-9, 1:2-8, 1:3-6, or 1:4; the volume ratio of 2-methyltetrahydrofuran / n-hexane is 1:1-9, 1:2-7, 1:4-6, or 1:4; the volume ratio of methyl isobutyl ketone / n-hexane is 1:1-9, 1:2-8, 1:3-6, or 1:4; the volume ratio of toluene / n-heptane is 1:1-9, 1:2-7, 1:4-6, or 1:4; and the volume ratio of chloroform / n-heptane is 1:1-9, 1:2-8, 1:3-6, or 1:4.

[0100] In some embodiments of the present invention, in the method (F) for preparing the dual-effect salt, the temperature cycling process involves heating, cooling, heating, and cooling during stirring, thus constituting one temperature cycle. The number of temperature cycles is not particularly limited, and the duration is 0.5-30 days, 1-15 days, 1-10 days, 2 days, or 9 days. After 2 days of temperature cycling, the magnetic stirring time at 5°C is 0.5-10 days, 1-7 days, 2-4 days, or 3 days.

[0101] During the temperature cycling process, the temperature is increased to 30-80℃, 35-70℃, 40-60℃, or 50℃. The stirring time is 0.5-4 hours, 1-3 hours, or 2 hours, followed by cooling to 2-10℃, 3-8℃, 4-7℃, or 5℃. The cooling rate is 0.05-0.5℃ / min, 0.08-0.3℃ / min, or 0.1℃ / min. The heating rate is 0.1-5℃ / min, 0.5-3℃ / min, or 1℃ / min.

[0102] In some embodiments of the present invention, in the method (F) for preparing the dual-effect salt, the temperature cycling process is as follows: the sample is heated to 50°C and equilibrated for 2 hours, then cooled to 5°C at a rate of 0.1°C / min, and then heated to 50°C at a rate of 1.0°C / min and equilibrated for 2 hours, thereby constituting one temperature cycling process.

[0103] As a specific embodiment of the method (F) for preparing the salt with dual functions of the present invention, see, for example, the method described in Examples 38-52.

[0104] As a specific embodiment of the method (F) for preparing the salt with dual functions of the present invention, it is used to prepare sacubitril propranolol salt crystal form A.

[0105]

[0106] According to the present invention, the compound of formula (I) used as a raw material refers to its solid (crystalline or amorphous), semi-solid, wax, or oil form. Preferably, the compound of formula (I) used as a raw material is in solid powder form. The "stirring" is performed by conventional methods in the art, such as magnetic stirring or mechanical stirring, at a stirring speed of 50-1800 rpm, wherein magnetic stirring is 200-1500 rpm, preferably 250-1200 rpm, more preferably 300-1100 rpm, and mechanical stirring is preferably 100-300 rpm.

[0107] In some embodiments of the present invention, the temperature cycling process is heating, stirring, cooling, stirring, heating, stirring, cooling, and stirring, thus constituting one temperature cycle. The number of temperature cycles is not particularly limited, for example, an upper limit of 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, and 6, and a lower limit of 1, 2, 3, 4, and 5.

[0108] During the temperature cycling process, the temperature is increased to 30-80℃, 35-70℃, 40-60℃, or 50℃. The stirring time is 0.5-4 hours, 1-3 hours, or 2 hours, followed by cooling to 2-10℃, 3-8℃, 4-7℃, or 5℃. The cooling rate is 0.05-0.5℃ / min, 0.08-0.3℃ / min, or 0.1℃ / min. The heating rate is 0.1-5℃ / min, 0.5-3℃ / min, or 1℃ / min.

[0109] In some embodiments of the present invention, the temperature cycling process is as follows: magnetic stirring at 50°C for 2 hours, cooling to 5°C at a rate of 0.1°C / min over 450 minutes, then stirring at 5°C for 2 hours, heating to 50°C at a rate of 1°C / min over 45 minutes, magnetic stirring at 50°C for 2 hours, cooling to 5°C at a rate of 0.1°C / min over 450 minutes, and maintaining stirring at 5°C. This constitutes one temperature cycling process.

[0110] In this invention, "undesirable solvent" is sometimes also referred to as "anti-solvent".

[0111] In this invention, "crystal" or "polymorph" refers to that confirmed by the X-ray diffraction pattern shown. Those skilled in the art will understand that the physicochemical properties discussed herein can be characterized, and the experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is known to those skilled in the art that X-ray diffraction patterns typically change with instrument conditions. It is particularly important to note that the relative intensities of X-ray diffraction patterns can also vary with experimental conditions, so the order of peak intensities cannot be considered the sole or decisive factor. In fact, the relative intensities of diffraction peaks in an X-ray diffraction pattern are related to the preferred orientation of the crystal, and the peak intensities shown herein are illustrative rather than for absolute comparison. Furthermore, experimental errors in peak angles are typically 5% or less, and these angular errors should also be taken into account, generally allowing for ±0.2° errors. Additionally, due to the influence of experimental factors such as sample thickness, an overall shift in peak angles may occur, and a certain degree of shift is generally permissible. Therefore, those skilled in the art will understand that the X-ray diffraction pattern of a crystal form in this invention need not be completely identical to the X-ray diffraction pattern in the examples referred to herein. The phrase "same X-ray diffraction pattern" does not mean absolutely identical; the positions of the same peaks may differ by ±0.2°, and the peak intensities are allowed to have some variability. Any crystal form with a pattern having the same or similar characteristic peaks as those in these spectra falls within the scope of this invention. Those skilled in the art can compare the spectra listed in this invention with a spectra of an unknown crystal form to verify whether the two sets of spectra reflect the same or different crystal forms.

[0112] In some embodiments, the crystal form of the present invention is pure and singular, substantially free of any other crystal form. In this invention, "substantially free" when referring to a new crystal form means that the crystal form contains less than 20% (by weight) of other crystal forms, particularly less than 10% (by weight), more specifically less than 5% (by weight), and even more specifically less than 1% (by weight). It should be noted that the numerical values ​​and ranges mentioned in this invention should not be narrowly interpreted as numerical values ​​or ranges themselves. Those skilled in the art should understand that they may fluctuate around specific numerical values ​​depending on the specific technical environment, without departing from the spirit and principles of the present invention. In this invention, such fluctuation ranges, foreseeable by those skilled in the art, are often expressed using the term "about".

[0113] The upper and lower limits of the numerical range described in this invention specification can be combined arbitrarily.

[0114] Example

[0115] The present invention will be further illustrated by specific embodiments below, but these are not intended to limit the scope of protection of the present invention. Those skilled in the art can make improvements to the preparation method and the instruments used within the scope of the claims, and these improvements should also be considered within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

[0116] Unless otherwise specified, "room temperature" in this invention usually refers to 20°C to 30°C.

[0117] The abbreviations used in this invention are explained as follows:

[0118] XRPD: X-ray powder diffraction

[0119] DSC: Differential Scanning Calorimetry

[0120] TGA: Thermogravimetric Analysis

[0121] MeOH: Methanol

[0122] EtOH: Ethanol

[0123] IPA: Isopropyl alcohol

[0124] Acetone: Acetone

[0125] THF: Tetrahydrofuran

[0126] 2-MeTHF: 2-Methyltetrahydrofuran

[0127] EtOAc: Ethyl acetate

[0128] IPAc: Isopropyl acetate

[0129] H2O: water

[0130] MTBE: Methyl tert-butyl ether

[0131] 1,4-Dioxane: 1,4-Dioxane

[0132] ACN: Acetonitrile

[0133] n-Heptane: n-Heptane

[0134] n-Hexane: n-Hexane

[0135] Toluene

[0136] MEK: Methyl Ethyl Ketone

[0137] CPME: Cyclopentyl methyl ether

[0138] MIBK: Methyl isobutyl ketone

[0139] CHCl3: Chloroform

[0140] SGF: Gastric juice containing pepsin

[0141] Instruments and methods used for data collection:

[0142] The X-ray powder diffraction pattern described in this invention was obtained using a PANalytical Empyrean type X-ray powder diffractometer and a PANalytical X'Pert. 3 Collected using a type X-ray powder diffractometer.

[0143] PANalytical X'Pert 3 The method parameters for Type I and Empyrean X-ray powder diffraction are as follows:

[0144] X-ray type: Cu, Kα

[0145] 1.540598; 1.544426

[0146] Kα2 / Kα1 intensity ratio: 0.50

[0147] Voltage: 45 kV

[0148] Current: 40 milliamperes (mA)

[0149] Diverging slit: 1 / 8 degree

[0150] Scanning mode: Continuous

[0151] Scan range: from 3.0 to 40.0 degrees

[0152] Scanning time per step: 46.7 seconds

[0153] Step size: 0.0263 degrees

[0154] The differential scanning calorimetry (DSC) data described in this invention were acquired using a TA Instruments DiscoveryDSC 2500 / DSC 250 differential scanning calorimeter. The instrument control software was TRIOS, and the analysis software was UniversalAnalysis. Typically, 1–5 mg of sample was placed in a covered (unless otherwise specified) aluminum crucible, and the sample was heated from room temperature to the desired temperature at a rate of 10 °C / min under the protection of dry N2 at a rate of 50 mL / min. Simultaneously, the TA software recorded the heat change of the sample during the heating process.

[0155] The thermogravimetric analysis (TGA) data described in this invention were acquired using a Discovery TGA 5500 / TGA 550 thermogravimetric analyzer. The instrument control software was TRIOS, and the analysis software was Universal Analysis. Typically, 1–5 mg of sample was placed in a platinum crucible. Using a segmented high-resolution detection method, the sample was heated from room temperature to 350°C at a heating rate of 10°C / min under the protection of dry N2 at a rate of 50 mL / min. Simultaneously, the TA software recorded the weight change of the sample during the heating process.

[0156] The liquid hydrogen NMR spectrum of this invention 1 H NMR was acquired on a Bruker 400M NMR spectrometer, with DMSO-d6 as the solvent.

[0157] Unless otherwise specified, all the following examples are performed at room temperature.

[0158] Examples 1-16: Preparation of sacubitril propranolol salt by room temperature suspension stirring

[0159] Sixteen room-temperature suspension-stirring experiments were conducted using different solvent systems and molar ratios. Approximately 15 mg of sacubitril per dose and propranolol in the corresponding molar ratio were weighed into HPLC vials, and 0.5 mL of the solvents listed in Table 1 were added. The resulting suspensions were magnetically stirred at room temperature. If a solid was obtained, it was centrifuged and XRPD was measured. If no solid was obtained, it was subjected to low-temperature treatment or temperature-cycle stirring until a solid precipitated. The experimental results are shown in Table 1, yielding sacubitril propranolol salt crystal form A, amorphous, propranolol, gel-like substances, and sacubitril propranolol crystal form A+ propranolol samples.

[0160] Table 1: Summary of Room Temperature Suspension Stirring Test

[0161]

[0162] *: The sample was stirred at room temperature for 1 day to form a gel, and then subjected to temperature cycling treatment (50℃~5℃, 0.1℃ / min, 3 days) to form a gel.

[0163] **: The sample was stirred at room temperature for 1 day to form a gel, and then subjected to temperature cycling treatment (50℃~5℃, 0.1℃ / min, 3 days) to precipitate solids.

[0164] ***: The sample was stirred at room temperature for 2 days and then became a suspension.

[0165] #: The sample was stirred at room temperature for 3 days and then slightly gelled. It was then subjected to temperature cycling treatment (50℃~5℃, 0.1℃ / min, 1 day) and gelled. The temperature cycling was continued for 5 days until gelled.

[0166] ##: The sample was stirred at room temperature for 2 days and then slightly gelled. After being stirred at 5°C for 3 days, it partially gelled and partially became a suspension.

[0167] Examples 17-21: Preparation of sacubitril propranolol salt by slow evaporation

[0168] Five slow evaporation tests were conducted using different solvent systems. Approximately 15 mg of sacubitril per dose and the corresponding molar ratio of propranolol were weighed into 3-mL glass vials, and dissolved in 1.5–2.0 mL of the solvent listed in Table 2 (unresolved samples were filtered through a 0.45 μm PTFE membrane). The vial was sealed with sealing film, and four pinholes were punched in it. It was then left to evaporate slowly at room temperature. The resulting solid was collected and subjected to XRPD testing. The results are shown in Table 2.

[0169] Table 2: Summary of Slow Evaporation Test

[0170]

[0171] Examples 22-25: Preparation of sacubitril propranolol salt by adding antisolvent

[0172] Four antisolvent addition experiments were conducted using different solvents. Approximately 15 mg of sacubitril per dose and propranolol in the corresponding molar ratio were added to 20 mL vials. The solids were completely dissolved using 0.6 mL of solvent (see Table 3) (undissolved samples were filtered through a 0.45 μm PTFE membrane to obtain a clear solution). The antisolvents listed in Tables 7-8 were added dropwise to this clear solution while stirring until solids precipitated, or until the total volume of antisolvent reached 10 mL. Samples without solid precipitation underwent low-temperature treatment. The precipitated solids were separated and XRPD tests were performed. The results are shown in Table 3. The antisolvent addition experiments yielded amorphous samples.

[0173] Table 3: Summary of Antisolvent Addition Experiments

[0174]

[0175] *: When the sample was added to the antisolvent at room temperature, a solid precipitated out. After stirring, it became a gel. After being transferred to -20℃ and stirred for 1 day, a solid precipitated out, but some of it still became a gel.

[0176] **: After adding the antisolvent to the sample at room temperature, a solid precipitated. After stirring for 1 day, it formed a gel. After being transferred to 5°C and stirred for 3 days, it formed a gel.

[0177] Examples 26-28: Preparation of sacubitril propranolol salt by slow cooling

[0178] Three slow evaporation tests were conducted using different solvent systems. Approximately 15 mg of sacubitril and the corresponding molar ratio of propranolol were weighed into 3-mL glass vials. 1.2 mL of the solvent listed in Table 4 was added, and the mixture was stirred at 50°C to dissolve the sample (undissolved samples were filtered through a 0.45 μm PTFE membrane). The temperature was lowered to 5°C at a rate of 0.1°C / min and maintained at 5°C. The resulting solid was collected and subjected to XRPD testing. The results are shown in Table 4, yielding an amorphous sample.

[0179] Table 4: Summary of the Slow Cooling Experiment

[0180]

[0181] Examples 29-37: 50 ℃ Preparation of Sacubitril Propranolol Salt by Suspension Stirring

[0182] Nine suspension stirring experiments were conducted at 50°C using different solvent systems. Approximately 15 mg of sacubitril per dose and propranolol in the corresponding molar ratio were weighed into HPLC glass vials, and 0.5 mL of the solvents listed in Table 5 were added. The resulting suspensions were magnetically stirred at 50°C. If a solid was obtained, it was centrifuged to determine XRPD; otherwise, it was subjected to low-temperature treatment or temperature-cycle stirring until a solid precipitated. The experimental results are shown in Table 5.

[0183] Table 5: Summary of the 50℃ Suspension Stirring Test

[0184]

[0185] *: The sample was stirred at 50℃ for 3 days and then slightly gelled. It was then transferred to temperature circulation stirring (50℃~5℃, 0.1℃ / min) for about 1 day and gelled. The temperature circulation stirring was continued for 7 days until gelled.

[0186] #: After stirring the sample at 50℃ for 3 days, it slightly gelled. Then, it was stirred in a temperature-cycled manner (50℃~5℃, 0.1℃ / min) for about 1 day, after which a solid was precipitated as a suspension.

[0187] ##: The sample was stirred at 50℃ for 2 days and then slightly gelled. After about 3 days of temperature circulation stirring (50℃~5℃, 0.1℃ / min), it became a suspension.

[0188] Examples 38-52: Preparation of Sacubitril Propranolol Salt by Temperature Cyclic Stirring

[0189] Fifteen temperature-cycle stirring experiments were conducted using different solvent systems. Approximately 15 mg of sacubitril and the corresponding molar ratio of propranolol were weighed into HPLC glass vials, and 0.5 mL of the solvents listed in Table 6 were added to each. The resulting suspensions were magnetically stirred in a biochemical incubator under temperature cycling conditions (heating the sample to 50°C and equilibrating for 2 hours, then cooling to 5°C at a rate of 0.1°C / min, then heating back to 50°C at a rate of 1.0°C / min and equilibrating for 2 hours, then repeating this cycle, finally maintaining the sample at 5°C). If a solid was obtained, it was collected by centrifugation and subjected to XRPD analysis. The experimental results are shown in Table 6.

[0190] Table 6: Summary of Temperature Cyclic Stirring Test

[0191]

[0192]

[0193] *: The sample was gelled at 5℃ and continued to be stirred for 7 days to form a gel.

[0194] **: The sample was stirred under temperature cycling for 2 days and became a suspension with little solids. After being transferred to 5℃ for about 3 days, it became a suspension with more solids.

[0195] #: The sample was stirred under temperature cycling for 2 days and then turned into a gel. After about 3 days at 5℃, it became a suspension with more solids.

[0196] Example 53: Preparation of crystal form A of 300mg batch sacubitril propranolol salt

[0197] Approximately 150.6 mg of sacubitril and 95.0 mg of propranolol were weighed into a 5 mL bottle, and 4 mL of IPAc / n-Heptane (1:4, v / v) was added. The mixture was suspended and stirred at room temperature for 1 day to form a suspension. Then, 50 mg of sacubitril and 30 mg of propranolol were added to the system, and the mixture was circulated and stirred at 50°C–5°C, 0.1°C / min, for 1 day. After temperature cycling, part of the mixture became gel-like, and part became a suspension. The sample was then suspended and stirred at 5°C for 1 day. The sample was centrifuged and washed three times with IPAc / n-Heptane (1:4, v / v) solvent. The solid was vacuum dried at room temperature for approximately 18 hours, yielding approximately 263.0 mg of solid, with a yield of approximately 81%.

[0198] Example 54: Preparation of 2g batch of sacubitril propranolol salt crystal form A

[0199] Approximately 1409.7 mg of sacubitril and 884.8 mg of propranolol were weighed into a 20 mL flask, and 20 mL of IPAc / n-Heptane (1:4, v / v) was added. The mixture was suspended and stirred at room temperature for approximately 5 minutes, and then approximately 22.8 mg of crystal form A seed crystals were added. The sample was then subjected to temperature cycling (50℃~5℃, 0.1℃ / min) for approximately 2 days. After temperature cycling, a small portion formed a gel, and a portion remained a suspension. The sample was then suspended and stirred at 5℃ for 1 day. The sample was filtered and washed three times with 20 mL of IPAc / n-Heptane (1:4, v / v) solvent. The solid was vacuum dried at room temperature for approximately 7 hours, yielding 1980.0 mg of sample, with a yield of approximately 85.4%.

[0200] Example 55: Preparation of crystal form A of 15g batch of sacubitril propranolol salt

[0201] Approximately 6519.1 mg of propranolol and 11381.5 mg of sacubitril were weighed into a 100 mL Easymax reactor, and 100 mL of IPAc / n-Heptane (1:4, v / v) was added to the reactor. The sample was suspended and stirred at 5 °C, and approximately 10 mg of crystal form A seed crystals were added. After 1 day of suspension and stirring at 5 °C, the sample partially gelled and partially became a suspension, at which point 30 mL of IPAc / n-Heptane (1:4, v / v) was added. The sample was stirred at 5 °C for another 2 days until it became a mostly suspension, at which point 10 mL of IPAc / n-Heptane (1:4, v / v) was added, and the sample was suspended and stirred for 7 hours. The sample was filtered and washed three times with 60 mL of n-Heptane solvent. The solid was dried under vacuum at room temperature for approximately 19 hours, yielding 17800.0 mg of solid, with a yield of approximately 99.0%.

[0202] Example 56: Preparation of 20g batch of sacubitril propranolol salt crystal form A

[0203] Approximately 13.08 g of sacubitril and 8.24 g of propranolol were weighed into a 500 mL reactor, and 150 mL of IPAc / n-Heptane (1:4, v / v) was added. The mixture was stirred at 50 °C for 30 min, then cooled to 5 °C at a rate of 1 °C / min and stirred at this temperature. After suspending and stirring at 5 °C for 2 days, part of the mixture formed a suspension, and the rest formed a gel. 50 mL of IPAc / n-Heptane (1:4, v / v) was added, and stirring continued. The mixture was then suspended and stirred at 5 °C for 3 days. The sample was filtered and washed three times with 40 mL of IPAc / n-Heptane (1:4, v / v) solvent. The solid was vacuum dried overnight at room temperature, and approximately 19.9 g of solid was collected, with a yield of approximately 93.3%.

[0204] Using Cu-Kα radiation, the X-ray powder diffraction pattern of sacubitril propranolol salt crystal form A exhibits characteristic peaks at the diffraction angle 2θ positions listed in Table 7. The X-ray powder diffraction pattern of sacubitril propranolol salt crystal form A provided by this invention is attached. Figure 1 As shown. Its TGA and DSC diagrams are shown in Appendix 2. (Through...) 1 ¹H NMR analysis showed that the molar ratio of sacubitril to propranolol in sacubitril-propranolol salt crystal form A was 1.0. (The remaining text appears to be incomplete and requires further context.) Figure 4 A comparison of the three-molecule NMR spectra shows that the active hydrogen at the carboxyl group of sacubitril disappears in the sacubitril propranolol spectrum, indicating that a salt-forming reaction has occurred.

[0205] Table 7: Characteristic peaks, d-values, and relative intensities at the 2θ position of crystal form A.

[0206]

[0207]

[0208] Example 57: Solubility Comparison Test

[0209] Approximately 40 mg of a mixture of sacubitril and propranolol (molar ratio 1:1) and approximately 40 mg of sacubitril-propranolol salt crystal form A were weighed into separate 5 mL glass bottles. 4 mL of SGF (simulated gastric juice containing pepsin) was added sequentially, and the mixture was rotated and mixed at room temperature for 0, 1, 2, 4, and 24 hours (25 rpm). Approximately 0.9 mL of the mixture was then centrifuged and filtered, and the filtrate was tested for HPLC concentration. The results are shown in Table 8.

[0210] Table 8: Comparison of dynamic solubility of sacubitril and propranolol physical mixture with sacubitril-propranolol salt crystal form A in SGF (based on propranolol, solubility unit: mg / mL)

[0211]

[0212] Table 8 shows that the solubility of propranolol in the physical mixture in SGF was 3.2-3.4 mg / mL. However, in the prepared sacubitril propranolol salt crystal form A, the solubility of propranolol in SGF was 2.4-4.9 mg / mL. This indicates that the formation of the eutectic or salt significantly improved the solubility of propranolol compared to the physical mixture (by nearly 50%).

[0213] Example 58: Stability Comparison Test

[0214] Approximately 100 mg of a mixture of sacubitril and propranolol (molar ratio 1:1) and 100 mg of sacubitril-propranolol salt crystal form A of this invention were weighed and stored at 40°C for 6 days. The change in purity of the resulting solids was then measured. The results are shown in Table 9.

[0215] Table 9: Summary of HPLC content of solid stability samples of physical mixtures of sacubitril and propranolol and sacubitril propranolol salt (crystal form A)

[0216]

[0217] As shown in Table 9, the sacubitril propranolol salt crystal form A of the present invention has better chemical and physical stability than the mixture of sacubitril and propranolol.

[0218] Example 59: Pharmacodynamic Comparison Test

[0219] This study examines the antihypertensive effect of sacubitril propranolol salt crystal form A on SHR hypertensive rats to demonstrate the superior efficacy of this invention compared to existing drugs.

[0220] Fifteen spontaneously hypertensive rats were selected and, after acclimatization, divided into three groups: a model group, a 44.1 mg / kg propranolol hydrochloride (equivalent to 40 mg / kg propranolol), and a 100 mg / kg sacubitril propranolol salt crystal form A (equivalent to 40 mg / kg propranolol). Each group received a single dose via gastric cannulation. The rats were anesthetized with a mixture of acetaminophen and sedative, with respiratory maintenance anesthesia. Blood pressure was measured via femoral artery cannulation. Blood pressure was recorded at 0 h before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 3 h, and 4 h after administration. Heart rate and various blood pressure parameters were statistically analyzed, and the rate of change in blood pressure was calculated and compared. The Mean value (mean arterial pressure, mean arterial pressure = (systolic pressure + 2 × diastolic pressure) / 3) was then used as the comparative data for measuring blood pressure among the groups. The obtained blood pressure values ​​are shown in the table below.

[0221] Table 10: Comparison of mean arterial pressure (Mean) at the same time point in different drug administration groups

[0222]

[0223] The results showed that 1 hour after intervention, blood pressure in all treatment groups decreased compared to the model group. 2 hours after intervention, compared to the model group, the rate of change in mean blood pressure, systolic blood pressure, and diastolic blood pressure in all treatment groups decreased significantly (p<0.05). The positive control drug, 44.1 mg / kg propranolol hydrochloride (equivalent to 40 mg / kg propranolol), achieved its maximum antihypertensive effect at 2 hours (p<0.05, vs. model group), after which blood pressure began to rise again. The antihypertensive effect of sacubitril propranolol crystal form A 100 mg / kg (equivalent to 40 mg / kg propranolol) lasted until 4 hours.

[0224] Overall, in terms of the duration of blood pressure reduction, the sacubitril propranolol of this invention is significantly superior to propranolol hydrochloride, extending the duration of action by more than double. Regarding the magnitude of blood pressure reduction, the sacubitril propranolol of this invention reduced blood pressure to a minimum of 104.8 mmHg, which is 10 mmHg lower than the minimum reduction of 114.4 mmHg achieved by propranolol hydrochloride. Under the same dosage of propranolol, this invention shows a significantly greater increase in the magnitude of blood pressure reduction compared to commercially available products. This indicates that the sacubitril propranolol of this invention has a significant advantage over existing commercially available equivalent products.

[0225] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor, characterized in that, The pharmaceutical composition comprises propranolol and a neutral endopeptidase inhibitor, which are linked by a non-covalent bond.

2. The pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor according to claim 1, characterized in that, The non-covalent bond is an ionic bond.

3. The pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor according to claim 2, characterized in that, The neutral endopeptidase inhibitor is sacubitril or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor according to claim 3, characterized in that, The molar ratio of propranolol to neutral endopeptidase inhibitor is 1:0.5 to 2, preferably 1:

1.

5. The pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor according to any one of claims 1-4, characterized in that, The pharmaceutical composition is propranolol-neutral endopeptidase inhibitor salt, which is [1-isopropylamino-3-(naphth-1-oxy)prop-2-ol][4-{[(1S,3R)-1-([1,1'-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutyric acid].

6. The pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor according to claim 5, characterized in that, The propranolol-neutral endopeptidase inhibitor salt is available in crystalline, partially crystalline, amorphous, and polymorphic forms, with the crystalline form being preferred. Its X-ray diffraction pattern includes crystal form A, where crystal form A has characteristic peaks at 2θ values ​​of 6.6°±0.2°, 11.7°±0.2°, 12.4°±0.2°, and 16.4°±0.2°.

7. The method for preparing the pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor as described in claim 1, characterized in that, Obtained by any of the following preparation methods (A)-(F): Preparation method (A): Add solvent to propranolol and neutral endopeptidase inhibitor, and place the resulting suspension at room temperature and stir magnetically. If a solid is obtained, centrifuge to separate it. If not, treat it at low temperature or stir it in a temperature cycle until a solid is precipitated. Preparation method (B): Dissolve propranolol and neutral endopeptidase inhibitor in a solvent at room temperature to obtain a solution, and then slowly evaporate it completely at room temperature before collecting the resulting solid. Preparation method (C): Dissolve propranolol and neutral endopeptidase inhibitor in a solvent, add the unsuitable solvent dropwise while stirring, until a solid precipitates out, then separate the precipitated solid; Preparation method (D): Dissolve propranolol and neutral endopeptidase inhibitor in a solvent, cool to 5°C at a rate of 0.1°C / min, and maintain at 5°C. Collect the resulting solid. Preparation method (E): Add solvent to propranolol and neutral endopeptidase inhibitor, and stir the resulting suspension magnetically at 50°C. If a solid is obtained, centrifuge to separate it. If not, treat it at low temperature or stir it in a temperature cycle until a solid is precipitated. Preparation method (F): Add solvent to propranolol and neutral endopeptidase inhibitor, and stir the resulting suspension in a biochemical incubator under temperature cycling for 1-10 days. Then, depending on the solution condition, determine whether to continue the temperature cycling or maintain magnetic stirring at 5°C until a large amount of solid is obtained. Then, centrifuge to collect the solid. In preparation methods (A), (E) and (F), during the temperature cycling process, the temperature is raised to 30-80℃, the stirring time is 0.5-4 hours, the temperature is lowered to 2-10℃, the temperature is lowered at a rate of 0.05-0.5℃ / min, and the temperature is raised at a rate of 0.1-5℃ / min.

8. The method for preparing the pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor according to claim 7, characterized in that, In method (A), the solvent is a mixture of n-heptane and 2-methyltetrahydrofuran, or acetone, or ethyl acetate; in method (B), the solvent is isopropyl acetate / n-heptane; in method (C), the solvent is at least one of acetone, tetrahydrofuran, 1,4-dioxane, or acetonitrile; in method (D), the mixed solvent is any combination of isopropanol / water, ethyl acetate / n-heptane, or acetone / n-heptane; in method (E), the mixed solvent is any combination of toluene / n-heptane, 2-methyltetrahydrofuran / n-heptane, methyl ethyl ketone / n-heptane, isopropyl acetate / n-heptane, or cyclopentyl methyl ether / n-heptane; in method (F), the solvent is any combination of isopropyl acetate / n-heptane, 2-methyltetrahydrofuran / n-hexane, methyl isobutyl ketone / n-hexane, toluene / n-heptane, or chloroform / n-heptane.

9. The method for preparing the pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor according to claim 8, characterized in that, In preparation method (A), the total amount of propranolol and neutral endopeptidase inhibitor is 150-5 mg:1 mL in solvent, and the volume ratio of n-heptane to 2-methyltetrahydrofuran, or acetone, or ethyl acetate is 1-10:

1. Low-temperature treatment is carried out by stirring at 2-10℃ for 1-8 days. Temperature cycling treatment is carried out by heating, cooling, heating, and cooling during stirring, which constitutes one temperature cycle treatment. The number of temperature cycles is 1-20. In preparation method (B), the total amount of propranolol and neutral endopeptidase inhibitor is 100-2 mg: 1 mL in solvent, and the volume ratio of isopropyl acetate / n-heptane mixed solvent is 1-15:

1. In preparation method (C), the total amount of propranolol and neutral endopeptidase inhibitor is 150-5 mg / 1 mL in solvent, and the total amount of propranolol and neutral endopeptidase inhibitor is 20-0.5 mg / 1 mL in unsuitable solvent. In preparation method (D), the total amount of propranolol and neutral endopeptidase inhibitor is 150-2 mg:1 mL in solvent, and the volume ratio of the mixed solvent isopropanol / water, or ethyl acetate / n-heptane, or acetone / n-heptane is 1-15:

1. The cooling and stirring treatment is as follows: stir at 30-80℃ for 0.5-4 hours, cool to 2-10℃ at a rate of 0.05-0.5℃ / min, and finally maintain at 2-10℃ and stir for 1-8 days. After stirring at low temperature, the solid was separated by centrifugation and then vacuum dried at room temperature for 0.5-5 days. In preparation method (E), the volume ratio of other solvents to n-heptane in the mixed solvent is 1:1-18; the total amount of propranolol and neutral endopeptidase inhibitor is 100-10 mg:1 mL. In preparation method (F), the total amount of propranolol and neutral endopeptidase inhibitor is 150-5 mg:1 mL in solvent; in the mixed solvent, the volume ratio of isopropyl acetate / n-heptane, 2-methyltetrahydrofuran / n-hexane, methyl isobutyl ketone / n-hexane, toluene / n-heptane, and chloroform / n-heptane is 1:1-9.

10. The use of the pharmaceutical composition containing propranolol and a neutral endopeptidase inhibitor as described in claim 1 in the preparation of a medicament for treating or preventing a disease or condition, characterized in that, The diseases or conditions described are selected from: myocardial infarction; hypertension; angina pectoris; supraventricular tachyarrhythmia, ventricular arrhythmia; palpitations and syncope; tachycardia; tachycardia caused by hyperthyroidism; thyroid storm; hemangioma; melanoma; esophageal and gastric variceal bleeding due to portal hypertension; migraine; cerebrovascular ischemic disease; familial essential tremor; schizophrenia; anxiety disorder; tetralogy of Fallot (F4) hypoxic attack; epidemic hemorrhagic fever; Any one of the following: aplastic anemia; restless legs syndrome; aortic dissection hematoma.

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