A pharmaceutical composition of a complex and its preparation method

Abstract

This invention belongs to the field of pharmaceutical formulation technology, and relates to a pharmaceutical composition of a complex and its preparation method, particularly to a pharmaceutical composition of a complex of an angiotensin II receptor antagonist metabolite and a NEP inhibitor and its preparation method.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and relates to a pharmaceutical composition of a complex and its preparation method, particularly to a pharmaceutical composition of a complex of an angiotensin II receptor antagonist metabolite and a NEP inhibitor and its preparation method. Background Technology

[0002] Hypertension is a clinical syndrome characterized primarily by elevated systemic arterial pressure and is the most common cardiovascular disease. Hypertension often has a slow onset and lacks specific clinical manifestations, leading to delayed diagnosis. It is usually only discovered when blood pressure is measured or when complications involving the heart, brain, or kidneys occur. A long-term causal relationship exists between hypertension and the risk of morbidity and mortality from cardiovascular and cerebrovascular diseases.

[0003] Statistics show that over one billion people worldwide currently have uncontrolled hypertension, a number projected to increase to 1.5 billion by 2030. In my country, the 2012-2015 China Hypertension Survey (CHS) revealed a prevalence of hypertension among adults aged ≥18 years at 27.9% (weighted average 23.2%), with awareness, treatment, and control rates of 51.6%, 45.8%, and 16.8%, respectively, and a treatment and control rate of 37.5%. The incidence of hypertension is on the rise. Statistics indicate that there are approximately 290 million cardiovascular disease patients in my country (China Cardiovascular Disease Report 2013). Uncontrolled and untreated hypertension can lead to coronary artery disease, coronary heart disease, angina, and potentially serious complications such as hypertensive heart disease and heart failure. Furthermore, long-term hypertension can damage organs such as the kidneys, brain, and cardiovascular system.

[0004] Heart failure is a severe manifestation or late stage of various heart diseases and a crucial aspect of global chronic cardiovascular disease prevention and control, with persistently high mortality and readmission rates. Epidemiological data from Europe and the United States show that the prevalence of heart failure in adults is 1.5%–2.0%, and this prevalence increases with age, reaching ≥10% in individuals aged ≥70 years. A 2003 epidemiological survey in China showed that the prevalence of heart failure in adults aged 35–74 years was 0.9%. The "China Cardiovascular Disease Report 2016" indicates that the prevalence of cardiovascular disease in my country is continuously rising, with cardiovascular disease being the leading cause of death, exceeding that of cancer and other diseases. my country's aging population and the increasing incidence of chronic diseases such as coronary heart disease, hypertension, diabetes, and obesity, coupled with improved medical care leading to longer survival rates for heart disease patients, have resulted in a continued upward trend in the prevalence of heart failure in my country. A survey of 10,714 hospitalized heart failure patients in China showed that the in-hospital mortality rates for heart failure patients in 1980, 1990, and 2000 were 15.4%, 12.3%, and 6.2%, respectively. The leading causes of death were left ventricular failure (59%), arrhythmia (13%), and sudden cardiac death (13%). The China-HF study showed a mortality rate of 4.1% for hospitalized heart failure patients.

[0005] WO2007056546A1 discloses a sodium salt complex of valsartan and sacubitril (AHU377) (LCZ696) and its preparation method, which was approved for marketing in China in 2017. Trade name: (The product name listed overseas) (2015) Used for heart failure. Its molecular structural units are as follows:

[0006]

[0007] Patent WO2009061713 discloses a formulation of sacubitril / valsartan sodium and its preparation method. The formulation is prepared by mixing a therapeutic agent with at least one pharmaceutically acceptable excipient, and then directly compressing the mixture using suitable equipment such as a tablet press or pressing the mixture using suitable equipment such as a roller press.

[0008] Already listed The formulation contains microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, magnesium stearate, talc, and colloidal silica. The film coating composition includes hydroxypropyl methylcellulose, titanium dioxide (E171), polyethylene glycol 4000, talc, and iron oxide red (E172).

[0009] In addition, WO2017125031A1 discloses a series of complexes consisting of angiotensin receptor antagonist metabolites (EXP3174) and NEP inhibitors (Sacubitril), which show certain effects on heart failure with preserved ejection fraction (HFpEF). The molecular structural units are as follows:

[0010]

[0011] However, due to the different compositions of compounds, it is crucial to find formulations that meet clinical requirements, which necessitates further research and development. Summary of the Invention

[0012] In view of the problems existing in the prior art, the present invention provides a novel complex pharmaceutical composition and its preparation method.

[0013] This invention is achieved through the following technical solution: a pharmaceutical composition of a complex, wherein the structural units of the complex are as follows:

[0014] (aEXP3174·bAHU377)·xCa·nA

[0015] Where a:b = 1:0.25-4; x is a value between 0.5 and 3; A refers to water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, methyl tert-butyl ether, acetonitrile, toluene, and dichloromethane; n is a value between 0 and 3.

[0016] The pharmaceutical composition contains one or more of the following: low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, and pregelatinized starch, in any proportion, and is used in the pharmaceutical composition at a rate of 4%-50%; and one or more other excipients.

[0017] As a preferred embodiment of the present invention, the pharmaceutical composition contains low-substituted hydroxypropyl cellulose and crospovidone, wherein the amount of low-substituted hydroxypropyl cellulose used in the pharmaceutical composition is preferably 17%-30%, and the amount of crospovidone used in the pharmaceutical composition is preferably 8%-20%.

[0018] As a preferred embodiment of the present invention, the ratio of low-substituted hydroxypropyl cellulose to crospovidone is preferably 1:1 to 3:1, and the sum of their weights is preferably used in the pharmaceutical composition at 25% to 40%. More preferably, when the proportion of the complex in the pharmaceutical composition is 25% to 30%, the ratio of low-substituted hydroxypropyl cellulose to crospovidone is 1.75:1 to 2.25:1, and more preferably 2:1.

[0019] As a preferred embodiment of the present invention, the pharmaceutical composition contains sodium carboxymethyl starch, croscarmellose sodium, and croscarmellose, wherein the amount of sodium carboxymethyl starch used in the pharmaceutical composition is 4%-12%, the amount of croscarmellose sodium used in the pharmaceutical composition is 4%-12%, and the amount of croscarmellose used in the pharmaceutical composition is 4%-12%; the sum of the weights of the three is preferably 15%-35% of the amount used in the pharmaceutical composition. More preferably, when the proportion of the complex in the pharmaceutical composition is 40%-50%, the amount of sodium carboxymethyl starch used in the pharmaceutical composition is 8-12%, the amount of croscarmellose sodium used in the pharmaceutical composition is 8-12%, and the amount of croscarmellose used in the pharmaceutical composition is 8-12%.

[0020] In this invention, the aforementioned proportion of low-substituted hydroxypropyl cellulose has a large surface area and porosity, exhibiting strong water absorption and swelling properties, and demonstrating a significant disintegration effect. Furthermore, the aforementioned proportion of crospovidone exhibits good flowability in this invention, rapidly demonstrating capillary activity and excellent hydration capacity in water, and also possesses good disintegration properties. The combined use of low-substituted hydroxypropyl cellulose and crospovidone allows the product to rapidly disintegrate in the dissolution medium, achieving a rapid release effect.

[0021] As a preferred embodiment of the present invention, one or more other excipients include one or more fillers, lubricants, and coating agents, etc.

[0022] As a preferred embodiment of the present invention, the filler comprises one or more of microcrystalline cellulose, lactose, mannitol, and dicalcium phosphate in any proportion, and the amount used is 16%-60% of the weight of the pharmaceutical composition, preferably 17%-45%.

[0023] As a preferred embodiment of the present invention, the filler comprises a mixture of microcrystalline cellulose and lactose, preferably with a mass ratio of microcrystalline cellulose to lactose of 1:1 to 5:1, and preferably with a total mass of microcrystalline cellulose and lactose of 16% to 60% of the weight of the pharmaceutical composition, more preferably 17% to 45%.

[0024] As a preferred embodiment of the present invention, the lactose is preferably anhydrous lactose. The anhydrous lactose and microcrystalline cellulose constitute approximately 40% or more of the total formulation. As a filler in the formulation, it exhibits good flowability and compressibility, and its properties are stable. The resulting tablets have a smooth appearance and good hardness and disintegration. It can also be used in direct compression processes and dry granulation processes.

[0025] As a preferred embodiment of the present invention, when the proportion of the complex in the pharmaceutical composition is 25%-30% (specifically, the complex is calculated as free acid, such as 60 or 120 mg), the mass ratio of the microcrystalline cellulose and lactose is 1.5:1-5:1, and preferably the total mass of the microcrystalline cellulose and lactose is 17%-45% of the weight of the pharmaceutical composition.

[0026] As a preferred embodiment of the present invention, when the proportion of the complex in the pharmaceutical composition is 40%-50% (specifically, the complex is 240 mg based on free acid), the mass ratio of the microcrystalline cellulose to lactose is 1.8:1-2.2:1 (specifically, 1.9:1, 2:1, 2.1:1, etc.), and preferably the total mass of the microcrystalline cellulose and lactose is 17%-45% of the weight of the pharmaceutical composition.

[0027] As a preferred embodiment of the present invention, the complex (using anhydrous free acid C) 46 H 50 The mass of the drug composition (based on ClN7O7) is 20%-50% of the total weight of the drug composition, and the preferred specific dosages are 30mg, 60mg, 90mg, 120mg, 150mg, 180mg, 210mg, 240mg, 270mg, 300mg, etc.

[0028] As a preferred embodiment of the present invention, the lubricant comprises one or a mixture of two or more of silica, stearic acid, magnesium stearate, polyethylene glycol, and hydrogenated castor oil, and the mass of the lubricant is 1%-3% of the weight of the pharmaceutical composition.

[0029] As a preferred embodiment of the present invention, the lubricant is a combination of silica and magnesium stearate. Silica mainly acts as a flow aid and also has a lubricating effect, while magnesium stearate is a hydrophobic material that easily mixes with the particles and adheres to the particle surface in the present invention, thereby reducing the friction between the particles and the die. When the two are used together in the aforementioned proportion in the pharmaceutical composition of the present invention, the flowability of the material is significantly increased, resulting in smooth and aesthetically pleasing tablets after compression.

[0030] Unless otherwise stated, the sum of the percentages of the aforementioned raw materials and excipients in the pharmaceutical composition is 95%-100%, and all amounts used are by weight.

[0031] As a preferred embodiment of the present invention, the coating agent comprises any gastric-soluble coating. Specifically, for example, the gastric-soluble coating comprises 85G640059-CN, wherein the gastric-soluble coating is performed using a solvent mixture such as water (preferably, the gastric-soluble coating agent and purified water are mixed at a mass ratio of 1:5 to 1:8 before coating), and the weight gain after coating is approximately 0.1% to 4%.

[0032] In the composition of the complex of the present invention, the molecular formula of EXP3174 is C 22 H 21 ClN6O2 has a molecular weight of approximately 436.9; AHU377 has the molecular formula C 24 H 29 NO5 has a molecular weight of approximately 411.5.

[0033] The complex of the drug can be obtained by methods known in the prior art, wherein the complex and its preparation method disclosed in WO2017125031A1 are incorporated herein by reference.

[0034] As a more preferred technical solution of the present invention, the value of a:b includes 1:0.25, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, and 1:4.

[0035] As a more preferred embodiment of the present invention, the structural units of the complex are as follows:

[0036] (EXP3174·AHU377)·xCa·nH2O

[0037] or

[0038]

[0039] Where x is a value between 0.5 and 2; and n is a value between 0 and 3.

[0040] As a more preferred technical solution of the present invention, x includes 0.5, 1, 1.5, and 2.

[0041] As a more preferred embodiment of the present invention, the structural units of the complex are as follows:

[0042] (EXP3174·AHU377)·1.5Ca·nH2O

[0043] or

[0044] (EXP3174·AHU377)·2Ca·nH2O

[0045] Where n is any value between 1 and 3.

[0046] As a more preferred technical solution of the present invention, n includes 0.5, 1, 1.5, 2, 2.5, and 3.

[0047] As a more preferred embodiment of the present invention, the composite comprises:

[0048] (EXP3174·AHU377)·1.5Ca·1H2O;

[0049] (EXP3174·AHU377)·1.5Ca·1.5H2O;

[0050] (EXP3174·AHU377)·1.5Ca·2H2O;

[0051] (EXP3174·AHU377)·1.5Ca·2.5H2O;

[0052] (EXP3174·AHU377)·1.5Ca·3H2O;

[0053] (EXP3174·AHU377)·2Ca·1H2O;

[0054] (EXP3174·AHU377)·2Ca·1.5H2O;

[0055] (EXP3174·AHU377)·2Ca·2H2O;

[0056] (EXP3174·AHU377)·2Ca·2.5H2O;

[0057] (EXP3174·AHU377)·2Ca·3H2O.

[0058] Those skilled in the art will understand that, within the unit cell of the supramolecular complex, the alisartan ester metabolite (EXP3174), AHU377, and calcium ions (Ca) are present. 2+ Solvent molecules and other molecules will fill it in the form of several structural units.

[0059] The supramolecular complex (complex) described in this invention differs from a mixture obtained by simply mixing two active ingredients physically. In the complex molecule, EXP3174 and AHU377, along with a pharmaceutically acceptable calcium cation, are bound together by non-covalent bonds to form a supramolecular complex (complex). These non-covalent bonds are well-known to those skilled in the art and include, but are not limited to, hydrogen bonds, coordination bonds, ionic bonds, etc. The XRD pattern of the resulting supramolecular complex (complex) is significantly different from that of the calcium salts of EXP3174 and AHU377. Its solubility in various solvents (such as water, ethanol, ethanol-water, etc.) also shows significant differences, as do its other physicochemical properties, such as hygroscopicity, melting point, and infrared spectrum.

[0060] The pharmaceutical composition is a solid dosage form suitable for oral administration, preferably an oral tablet or capsule.

[0061] The present invention further provides a method for preparing the pharmaceutical composition, wherein the raw and excipient materials are prepared by direct compression or dry granulation and then tableted, and then coated with a coating agent to obtain a coated pharmaceutical composition.

[0062] The present invention further provides that the pharmaceutical composition can be used in the prevention and / or treatment of hypertension, heart failure, and hypertension and heart failure.

[0063] The advantages of this invention over the prior art include:

[0064] (1) The implementation scheme of the present invention can effectively ensure the disintegration and dissolution of the drug and has good granulation flowability and other effects.

[0065] (2) The pharmaceutical composition obtained by the present invention, through clinical verification, can effectively achieve the in vivo drug concentration and can be used in the prevention and / or treatment of hypertension, heart failure, and hypertension and heart failure.

[0066] (3) The present invention greatly reduces the composition of raw and auxiliary materials in the prescription, and is not only simple in process, but also environmentally friendly and economical, which is conducive to large-scale industrial application.

[0067] (4) The present invention effectively controls the tablet weight when the proportion of active ingredients in the drug composition is high, thus ensuring the dissolution and efficacy of the drug and facilitating its clinical use. Detailed Implementation

[0068] The present invention will be further described in detail below with reference to embodiments, but the implementation of the invention is not limited thereto.

[0069] Example 1

[0070] Preparation of AHU377 free acid:

[0071] Add 2.1 g of AHU377 calcium salt and 40 mL of isopropyl acetate to a 250 mL single-necked flask, and add 4.5 mL of 2 mol / L hydrochloric acid at room temperature, stirring until dissolved. Separate the layers, collect the organic layer, and wash the organic layer twice with 20 mL of water; remove the solvent under reduced pressure at 35 °C to obtain free AHU377 acid.

[0072] Example 2

[0073] Preparation of the complex: (Prepared according to Example 2 of patent WO2017125031A1)

[0074]

[0075] At room temperature, 2.36 g of AHU377 free acid obtained according to the method in Example 1, 2 g of EXP3174, and 40 mL of acetone were added to a 250 mL three-necked flask and dissolved. At room temperature, 1.3 equivalents of calcium hydroxide solid relative to AHU377 and 1 mL of water were added, and the mixture was stirred at room temperature for 10 h. Another 40 mL of acetone was added, and the reaction was continued for 8 h. The mixture was filtered through a Buchner funnel under nitrogen protection. The solid was washed with acetone to obtain a white solid, which was then dried under vacuum at 35 °C for 8 h to obtain 3.5 g of solid (EXP3174·AHU377). 3- ·1.5Ca 2+ • 2.5H2O, HPLC purity was 99%. Repeat the experiment to obtain a sufficient amount for efficacy testing.

[0076] Example 3

[0077] Preparation of the complex: (Prepared according to Example 3 of patent WO2017125031A1)

[0078]

[0079] At room temperature, 2.36 g of AHU377 free acid obtained according to the method in Example 1, 2 g of EXP3174, and 40 mL of acetone were added to a 250 mL three-necked flask and dissolved. At room temperature, 1.6 equivalents of calcium hydroxide solid relative to AHU377 and 0.6 mL of water were added, and the mixture was stirred at 35°C for 6 h. Another 40 mL of acetone was added, and the reaction was continued for 8 h. The mixture was filtered through a Buchner funnel under nitrogen protection. The solid was washed with acetone to obtain a white solid, which was then dried under vacuum at 50°C for 8 h to obtain 3.1 g of solid (EXP3174·AHU377). 3- ·1.5Ca 2+ • 2H₂O. Repeat the experiment to obtain a sufficient dosage for the efficacy test.

[0080] Example 4

[0081] Following the preparation methods of Examples 2 and 3, the following complexes were prepared respectively:

[0082] (EXP3174·AHU377)·1.5Ca·1H2O;

[0083] (EXP3174·AHU377)·1.5Ca·1.5H2O;

[0084] (EXP3174·AHU377)·1.5Ca·3H2O;

[0085] (EXP3174·AHU377)·2Ca·1H2O;

[0086] (EXP3174·AHU377)·2Ca·1.5H2O;

[0087] (EXP3174·AHU377)·2Ca·2H2O;

[0088] (EXP3174·AHU377)·2Ca·2.5H2O;

[0089] (EXP3174·AHU377)·2Ca·3H2O.

[0090] Example 5: Selection of Disintegrant and its Dosage

[0091] Dissolution curves were measured in a pH 6.8 medium to investigate different types of disintegrants and screen for the optimal disintegrant dosage. The formulation design details are shown in Table 1, and the dissolution curve results are shown in Table 2.

[0092] Table 1 Experimental formulations with different disintegrants and dosages

[0093]

[0094] Table 2. Results of dissolution curve studies for different disintegrants and dosages.

[0095]

[0096] The results of the disintegrant selection show that using low-substituted hydroxypropyl cellulose and crospovidone can promote dissolution more effectively than using low-substituted hydroxypropyl cellulose alone. When the amount of low-substituted hydroxypropyl cellulose and crospovidone used reaches 17.8% and 8.9% respectively, the dissolution rate can reach more than 85% within 15 minutes.

[0097] Therefore, it is preferred that low-substituted hydroxypropyl cellulose is used in the pharmaceutical composition at an amount of 17%-30%, and crospovidone is used in the pharmaceutical composition at an amount of 8%-20%, and preferably both are used in the pharmaceutical composition at an amount of 25%-40%.

[0098] Example 6: Selection of Filler and its Dosage

[0099] Based on Example 5, the fillers selected for this product formulation are crystalline cellulose (Type 102) and anhydrous lactose (DTHV). Experimental results showed that different filler ratios may affect the disintegration and dissolution of the tablet core. A suitable formulation ratio was selected by combining disintegration time and dissolution curves in a pH 6.8 medium, as detailed in Table 3. The combined use of these two fillers ensures that the appearance, weight variation, and friability of the tablet core meet the requirements.

[0100] Table 3. Formulation designs with different ratios of microcrystalline cellulose / lactose

[0101]

[0102] Table 4. Results of studies on disintegration time at different ratios of microcrystalline cellulose / lactose.

[0103]

[0104] Table 5. Results of the study on dissolution curves of different ratios of microcrystalline cellulose / lactose.

[0105]

[0106] In addition, the results of the flowability test of the mixed powder showed that the microcrystalline cellulose / lactose ratio of 2:1 and the angle of repose of about 40° could meet the flowability requirements.

[0107] When the microcrystalline cellulose / lactose ratio is 6:1, the tablet is thicker, which may affect swallowing and compliance.

[0108] Based on the above results, it can be seen that the optimal mass ratio of microcrystalline cellulose to anhydrous lactose is 1:1-5:1, and the optimal total mass of microcrystalline cellulose and lactose is 18%-60% of the weight of the pharmaceutical composition. This not only results in rapid disintegration but also rapid dissolution. More preferably, the mass ratio of microcrystalline cellulose to lactose is 1.5:1-5:1, with a dissolution rate of ≥85% after 30 minutes.

[0109] Example 7 investigated the pharmacokinetic properties of samples that were dissolved in vitro in animals.

[0110] Using the preferred technical solutions in Examples 5 and 6, three samples with different characteristics were prepared and subjected to canine PK tests. The specific formulation composition is shown in Table 6, and the dissolution curve results are shown in Table 7.

[0111] Table 6 Composition of Different Prescriptions

[0112]

[0113] *The enteric coating formula contains Eudragit L30D-55, talc, triethyl citrate, and purified water, mixed in a mass ratio of 1:6 before coating. The weight gain after coating is approximately 3%.

[0114] Table 7. In vitro dissolution results of different formulations

[0115]

[0116] Results: Since the 3C batch was coated with enteric coating, the enteric coating film will not be destroyed in acidic media below pH 5.5. Therefore, the dissolution curves of the 3C batch tablets at pH 1.2 and pH 5.0 were not tested.

[0117] Using the suspension of the active pharmaceutical ingredient as a control, three batches of samples (3A, 3B, and 3C) were used in a canine pharmacokinetic study to investigate the pharmacokinetic behavior of formulations with different in vitro dissolution behaviors in beagle dogs. The results are shown in Table 8.

[0118] Table 8. Pharmacokinetic results of different formulations in beagle dogs.

[0119]

[0120]

[0121] Note: LBQ657 is an active metabolite of sacubitril.

[0122] The results above show that, compared with the suspension, the F values ​​of all three sacubitril formulation tablets were over 90%, indicating that sacubitril is mainly absorbed in the distal small intestine. In contrast, the bioavailability of EXP3174 enteric-coated tablets was only about 60% of that of the suspension. The F values ​​of the other two groups without enteric coating were both over 90%, indicating that EXP3174 is absorbed in both the proximal and distal small intestine.

[0123] The above experiments showed that enteric-coated samples had reduced absorption compared to suspensions; therefore, we chose gastric-coated samples. Specifically, for example, gastric-coated samples include 85G640059-CN, which uses a mixture of solvents such as water, resulting in a weight gain of approximately 0.1%-4% after coating.

[0124] Based on the technical solutions of the aforementioned experimental examples 5-7, the present invention further yields the following preferred embodiments.

[0125] Example 8

[0126] Using the complex obtained in Example 3 as the active pharmaceutical ingredient, a complex pharmaceutical composition and its preparation method are described, comprising:

[0127]

[0128]

[0129] The preparation method is as follows: the aforementioned raw and auxiliary materials are mixed and directly pressed.

[0130] The coating material, film coating premix (gastric-soluble type 295F640025-CN), and purified water are mixed at a mass ratio of 1:7. The mixture is then coated and directly compressed into tablets (the purified water used for coating is removed after drying). The resulting tablets have a weight gain of approximately 3% after coating.

[0131] Example 9

[0132] Using the complex obtained in Example 3 as the active pharmaceutical ingredient, a complex pharmaceutical composition and its preparation method are described, comprising:

[0133]

[0134] Production process: The preparation method is as follows: the aforementioned raw and auxiliary materials are dry granulated and then compressed into tablets;

[0135] The coating material, film coating premix (gastric soluble type 295F640025-CN), and purified water are mixed at a mass ratio of 1:7. The resulting tablets are coated, granulated, and compressed (the purified water used for coating is removed after drying). The resulting tablets have a weight gain of approximately 3% after coating.

[0136] Example 10

[0137] Using the complex obtained in Example 3 as the active pharmaceutical ingredient, a complex pharmaceutical composition and its preparation method are described, comprising:

[0138]

[0139] Production process: The preparation method is as follows: the aforementioned raw and auxiliary materials are mixed and directly pressed;

[0140] The coating material, film coating premix (gastric-soluble type 295F640025-CN), and purified water are mixed at a mass ratio of 1:6. The mixture is then coated and directly compressed into tablets (the purified water used for coating is removed after drying). The resulting tablets have a weight gain of approximately 3% after coating.

[0141] Example 11

[0142] Using the complex obtained in Example 3 as the active pharmaceutical ingredient, a complex pharmaceutical composition and its preparation method are described, comprising:

[0143]

[0144] Production process: The preparation method is as follows: the aforementioned raw and auxiliary materials are dry granulated and then compressed into tablets;

[0145] The coating material, film coating premix (gastric-soluble type 295F640025-CN), and purified water are mixed at a mass ratio of 1:6. The resulting tablets are coated, granulated, and compressed (the purified water used for coating is removed after drying). The resulting tablets have a weight gain of approximately 3% after coating.

[0146] Example 12

[0147] Using the complex obtained in Example 3 as the active pharmaceutical ingredient, a complex pharmaceutical composition and its preparation method are described, comprising:

[0148]

[0149] Production process: The preparation method is as follows: the aforementioned raw and auxiliary materials are mixed and directly pressed;

[0150] The coating material, film coating premix (gastric-soluble type 295F640025-CN), and purified water are mixed at a mass ratio of 1:6. The mixture is then coated and directly compressed into tablets (the purified water used for coating is removed after drying). The resulting tablets have a weight gain of approximately 3% after coating.

[0151] Example 13

[0152] Using the complex obtained in Example 3 as the active pharmaceutical ingredient, a complex pharmaceutical composition and its preparation method are described, comprising:

[0153]

[0154]

[0155] Production process: The preparation method is as follows: the aforementioned raw and auxiliary materials are dry granulated and then compressed into tablets;

[0156] The coating material, film coating premix (gastric-soluble type 295F640025-CN), and purified water are mixed at a mass ratio of 1:6. The resulting tablets are coated, granulated, and compressed (the purified water used for coating is removed after drying). The resulting tablets have a weight gain of approximately 3% after coating.

[0157] Example 14

[0158] Using the complex obtained in Example 3 as the active pharmaceutical ingredient, a complex pharmaceutical composition and its preparation method are described, comprising:

[0159]

[0160] Production process: The preparation method is as follows: the aforementioned raw and auxiliary materials are dry granulated and then compressed into tablets;

[0161] The coating material, film coating premix (gastric-soluble type 295F640025-CN), and purified water are mixed at a mass ratio of 1:6. The resulting tablets are coated, granulated, and compressed (the purified water used for coating is removed after drying). The resulting tablets have a weight gain of approximately 3% after coating.

[0162] Example 15

[0163] Using the complex obtained in Example 3 as the active pharmaceutical ingredient, a complex pharmaceutical composition and its preparation method are described, comprising:

[0164]

[0165] Production process: The preparation method is as follows: the aforementioned raw and auxiliary materials are dry granulated and then compressed into tablets;

[0166] The coating material, film coating premix (gastric-soluble type 295F640025-CN), and purified water are mixed at a mass ratio of 1:6. The resulting tablets are coated, granulated, and compressed (the purified water used for coating is removed after drying). The resulting tablets have a weight gain of approximately 3% after coating.

[0167] Note: a The amount of the complexes described in Examples 8-15 is expressed as anhydrous free acid C. 46 H 50 ClN7O7 is used as a metric.

[0168] The dissolution effects of the aforementioned embodiments are as follows:

[0169]

[0170] The dissolution of each embodiment meets the standard requirements and demonstrates sufficient drug exposure in animal experiments.

[0171] Examples 16-23

[0172] Examples 16-23 are identical to the formulations of Examples 8-15, except that the active pharmaceutical ingredient used is the complex from Example 2. a .

[0173] Note: a The amount of the complex is expressed as anhydrous free acid C 46 H 50 ClN7O7 is used as a metric.

[0174] Example 24 uses the pharmaceutical composition of Example 8 for a Phase I clinical trial.

[0175] The complex tablet of this invention has completed a single-center, randomized, double-blind, placebo-controlled Phase I clinical trial in healthy subjects to evaluate its tolerability and pharmacokinetics under multiple doses, single administration, and repeated administration. The single administration included seven dose groups: 60 mg, 180 mg, 360 mg, 540 mg, 720 mg, 960 mg, and 1080 mg. The repeated administration included four dose groups: 180 mg, 360 mg, 540 mg, and 720 mg. A food effect study was conducted at the 480 mg dose group, with urine and fecal samples collected during the first cycle of the food effect study for recovery and drug metabolism studies. The aim was to evaluate the tolerability, pharmacokinetics, drug metabolism and recovery, and the effect of food on the pharmacokinetics of the complex tablet under single and repeated administration in healthy subjects, and to preliminarily evaluate its pharmacodynamics.

[0176] Based on the pharmacokinetic (PK) results of single-dose and multiple-dose administration, it is estimated that after oral administration of 240 mg of the complex of the present invention, the exposure of EXP3174 in the human body is not less than the exposure of the total active ingredient in the human body after oral administration of 100 mg of losartan, and the exposure of LBQ657 in the human body is not less than the exposure of LBQ657 in the human body after oral administration of 200 mg of LCZ696; after oral administration of 480 mg of the complex of the present invention, the exposure of EXP3174 in the human body is not less than the exposure of the total active ingredient in the human body after oral administration of 200 mg of losartan, and the exposure of LBQ657 in the human body is not less than the exposure of LBQ657 in the human body after oral administration of 400 mg of LCZ696.

[0177] Therefore, when the compound of the present invention is applied to patients with heart failure and hypertension, it shows the expected clinical therapeutic effects in terms of pharmacokinetics and efficacy.

[0178] Comparative Example 1

[0179]

[0180]

[0181] Granulation process: Dry granulation.

[0182] The dissolution results for this formulation at pH 1.2 were slow, as shown in the table below:

[0183]

[0184] Comparative Example 2

[0185]

[0186] Granulation process: The complex of Example 3 and poloxamer 188 were dissolved in dichloromethane. Cross-linked polyvinylpyrrolidone XL and microcrystalline cellulose were placed in a fluidized bed and spray-dried with the air inlet temperature controlled at 50-70°C and the material temperature at 40-50°C. Then, the mixture was mixed with magnesium stearate and compressed into tablets.

[0187] The resulting tablets were stored at 40℃±2℃ and 75%±5%RH for 2 months. Impurities were detected by HPLC. The results show that the product produced by this formulation process has poor stability.

[0188]

[0189]

[0190] Comparative Example 3

[0191] The following formulations were compared with those of the examples. Using the formulations of this invention, the dissolution at pH 1.2 was significantly better than that of the comparative examples 301-305. Furthermore, the dissolution properties of Examples 9 and 11 were similar. A canine pK assay revealed that the in vivo efficacy AUC of the metabolites was [data missing]. last Proximity can effectively ensure the efficacy of the medicine.

[0192] The experimental prescription and results are as follows:

[0193]

[0194]

[0195]

[0196] Beagle internal PK data

[0197] PK parameters Example 9*2 305 Example 11 EXP3174 Unit Mean Mean Mean <![CDATA[AUC last ]]> h*ng / mL 4644.9 3729.2 4271.1 LBQ657 Unit Mean Mean Mean <![CDATA[AUC last ]]> h*ng / mL 4002.5 3473.5 3827.8

[0198] Note: LBQ657 is an active metabolite of sacubitril; *2 indicates 2 tablets.

[0199] As can be seen from the above experimental results, in the formulation of this invention, when the complex a When the dosage in the pharmaceutical composition is 60 mg or 120 mg, and microcrystalline cellulose and lactose are selected as support agents, the combination of low-substituted hydroxypropyl cellulose and crospovidone is preferred, as its dissolution effect is better than that of crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch alone or in other ratios; and based on the comparative results of batches 305, 306 and Examples 9 and 11, the preferred mass ratio of low-substituted hydroxypropyl cellulose to crospovidone is 1.75-2.25:1, more preferably 2:1.

[0200] a The amount of the complex is expressed as anhydrous free acid C 46 H 50 ClN7O7

[0201] Comparative Example 4

[0202] Using the following formulation and Example 9, a monkey pK experiment was conducted to find the AUC of the metabolites in vivo. last Proximity can effectively guarantee the efficacy of the medicine.

[0203] The experimental prescription and results are as follows:

[0204]

[0205] Animal (monkey) internal PK data

[0206]

[0207] Note: LBQ657 is an active metabolite of sacubitril; *4 indicates 4 tablets.

[0208] In vivo PK data in animals showed that the exposure levels of EXP3174 in batch 401 were closer to those in 4 tablets of the 60mg sample from Example 9.

[0209] Comparative Example 5

[0210] The experimental prescription and results are as follows:

[0211] 402 Proportion% 403 Proportion% Example 3 Complex 266.4 52.35 266.4 52.35 microcrystalline cellulose 83 16.31 83 16.31 Anhydrous lactose 53 10.41 53 10.41 Sodium carboxymethyl starch 27 5.31 / / Cross-linked carboxymethyl cellulose sodium 33 6.48 / / Cross-linked polyvinylpyrrolidone 33 6.48 33 6.48 Low-substituted hydroxypropyl cellulose / / 60 11.79 silicon dioxide 8 1.57 8 1.57 magnesium stearate 5.5 1.08 5.5 1.08

[0212]

[0213] Comparing the effects of Examples 4 and 5, and based on the formulations of Examples 14 and 15 (batch 401), and 402 and 403, the applicant of this invention has found that when the complex a When the pharmaceutical composition contains 240 mg of microcrystalline cellulose and lactose in a ratio of 1.8:1 to 2.2:1 (specifically 1.9:1, 2:1, 2.1:1), it preferably contains sodium carboxymethyl starch, croscarmellose sodium, and crospovidone. The amount of sodium carboxymethyl starch used in the pharmaceutical composition is 8-12%, the amount of croscarmellose sodium used in the pharmaceutical composition is preferably 8-12%, and the amount of crospovidone used in the pharmaceutical composition is 8-12%. Compared with other combinations of sodium carboxymethyl starch, croscarmellose sodium, and crospovidone in different ratios, or combinations of crospovidone and low-substituted hydroxypropyl cellulose, and other ratios of microcrystalline cellulose and lactose, it is difficult to achieve the corresponding dissolution, and it is expected that the corresponding in vivo dissolution effect will be difficult to achieve.

[0214] a The amount of the complex is expressed as anhydrous free acid C 46 H 50 ClN7O7

[0215] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A composite pharmaceutical composition, characterized by, The structure unit of the complex is as follows: x is 1.5; n is a number between 0 and 3; The proportion of the complex in the pharmaceutical composition is 25%-30%, the pharmaceutical composition contains low-substituted hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone, and the proportion of low-substituted hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone is 1.75:1-2.25:1; and one or more than one other auxiliary material. The low-substituted hydroxypropyl cellulose is used in the pharmaceutical composition in an amount of 17%-30%, and the cross-linked polyvinylpyrrolidone is used in the pharmaceutical composition in an amount of 8%-20%.

2. The pharmaceutical composition of claim 1, wherein The total amount of low-substituted hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone used in the pharmaceutical composition is 25%-40%.

3. The pharmaceutical composition of claim 1, wherein The proportion of low-substituted hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone in the pharmaceutical composition is 2:

1.

4. The pharmaceutical composition of claim 1, wherein The structure unit of the complex is as follows:

5. A pharmaceutical composition of a complex, characterized in that, The proportion of the complex in the pharmaceutical composition is 40%-50%, the pharmaceutical composition contains sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, the total amount of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone used in the pharmaceutical composition is 15%-35%, and one or more than one other auxiliary material. x is 1.5; n is a number between 0 and 3; The pharmaceutical composition contains sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, the amount of sodium carboxymethyl starch used in the pharmaceutical composition is 4%-12%, the amount of cross-linked sodium carboxymethyl cellulose used in the pharmaceutical composition is 4%-12%, and the amount of cross-linked polyvinylpyrrolidone used in the pharmaceutical composition is 4%-12%.

6. The pharmaceutical composition of claim 5, wherein The amount of sodium carboxymethyl starch used in the pharmaceutical composition is 8-12%, the amount of cross-linked sodium carboxymethyl cellulose used in the pharmaceutical composition is 8-12%, and the amount of cross-linked polyvinylpyrrolidone used in the pharmaceutical composition is 8-12%.

7. The pharmaceutical composition of claim 5, wherein the compound is of formula (I) ###00002### (I) or a pharmaceutically acceptable salt thereof. The one or more than one other auxiliary material includes one or more than one filler, lubricant and coating agent; 8. The pharmaceutical composition of any one of claims 1 or 5, wherein the composition is a complex. The filler includes microcrystalline cellulose, lactose, mannitol, calcium hydrogen phosphate, or a mixture of one or more than one thereof in any proportion, and the amount used is 16%-60% of the weight of the pharmaceutical composition. The lubricant includes one or more than one of silicon dioxide, stearic acid, magnesium stearate, polyethylene glycol, hydrogenated castor oil, and the amount of the lubricant is 1%-3% of the weight of the pharmaceutical composition. The coating agent includes a gastric soluble coating agent. The filler includes a mixture of microcrystalline cellulose and lactose, the mass ratio of microcrystalline cellulose to lactose is 1:1-5:1, and the total amount of microcrystalline cellulose and lactose is 16%-60% of the weight of the pharmaceutical composition.

9. The pharmaceutical composition of claim 8, wherein the compound is of formula (I): ###0002### (I) or a pharmaceutically acceptable salt thereof. When the proportion of the complex in the pharmaceutical composition is 25%-30%, the mass ratio of microcrystalline cellulose to lactose is 1.5:1-5:1, and the total amount of microcrystalline cellulose and lactose is 17%-45% of the weight of the pharmaceutical composition.

10. The pharmaceutical composition of claim 8, wherein the compound is of formula (I): ###0002### (I) or a pharmaceutically acceptable salt thereof. When the proportion of the complex in the pharmaceutical composition is 40%-50%, the mass ratio of microcrystalline cellulose to lactose is 1.8:1-2.2:1, and the total amount of microcrystalline cellulose and lactose is 17%-45% of the weight of the pharmaceutical composition.

11. The pharmaceutical composition of claim 8, wherein the compound is of formula (I): ###0002### (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition is a solid preparation suitable for oral administration, selected from oral tablets or capsules.

12. A pharmaceutical composition of a complex according to any one of claims 1 or 5, characterized in that, The complex is in anhydrous free acid form C 46 H 50 ClN7O7.

13. A pharmaceutical composition of a complex according to any one of claims 1 or 5, characterized in that, The complex is in anhydrous free acid C 46 H 50 The amount used is 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, 210 mg, 240 mg, 270 mg, 300 mg, calculated as CIN7O7.

14. A complex pharmaceutical composition according to any one of claims 1 or 5, characterized in that, ​ 15. The pharmaceutical composition of any one of claims 1 or 5, wherein the composition is a complex. The pharmaceutical composition is prepared by a direct compression process or a dry granulation process.

16. Use of a pharmaceutical composition, characterized in that, Use of the pharmaceutical composition according to any one of claims 1-14 in the preparation of a medicament for the prevention and / or treatment of hypertension or heart failure.

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