WO2020173476A1

WO2020173476A1 - Pharmaceutical composition containing renal outer medullary k channel inhibitor and preparation method therefor

Info

Publication number: WO2020173476A1
Application number: PCT/CN2020/076925
Authority: WO
Inventors: 奚宏磊
Original assignee: 江苏恒瑞医药股份有限公司
Priority date: 2019-02-28
Filing date: 2020-02-27
Publication date: 2020-09-03
Also published as: TW202045170A; CN113226315A; CN113226315B

Abstract

A pharmaceutical composition containing a renal outer medullary K channel inhibitor and a preparation method therefor. The pharmaceutical composition contains (R)-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methoxy pyridine carboxamide or a pharmaceutically acceptable salt thereof. The pharmaceutical composition has a good dissolution rate and excellent stability.

Description

A pharmaceutical composition containing an inhibitor of renal potassium efflux channel and its preparation method This application claims the priority of Chinese patent application CN201910152541.9 whose filing date is February 28, 2019. This application quotes the full text of the aforementioned Chinese patent application. Technical field

This application belongs to the field of medical technology, and relates to a pharmaceutical composition containing a renal potassium efflux channel (ROMK) inhibitor. Background technique

Diuretics are generally recommended as first-line antihypertensive drugs in the latest national hypertension guidelines, and are suitable for mild to moderate hypertension, especially in elderly hypertension or complicated by heart failure. According to statistics, there were nearly 263 million hypertensive patients in China in 2010, and the diuretic use rate of hypertensive population was 10%, and there is a lot of room for growth.

Clinically, traditional diuretics have the risk of causing hypokalemia. ROMK new rake point antihypertensive diuretic development, ROMK for the inward rectifier K ⁺ channels (inwardly rectifying K channels, Kir) a family, belong Kiri type, the maintenance of renal potassium ions play a crucial balance effect. In rat kidney, there are at least three subtypes of ROMK channels: ROMK1, ROMK2 and ROMK3 type. ROMK2 is mostly distributed in the ascending limb of Henle (TALH); ROMK1 and ROMK3 are mainly expressed in the cortical collecting duct (CCD). ROMK expressed in TALH and Na ⁺ /K72Cl_ transporter regulate the secretion and reabsorption of sodium and potassium ions, and ROMK expressed in CCD and Na ⁺ /K ⁺ transporter regulate the secretion of potassium ions together. Therefore, blocking the ROMK site can not only diuresis and lower blood pressure by inhibiting the reabsorption of Na ⁺ , but also does not cause hypokalemia due to excessive reduction of serum potassium, which is a good diuretic research direction.

WO2016091042A1 (publication date 2016-06-16) discloses a class of extrarenal medullary secretory potassium channel (ROMK) inhibitors, chemically named ⑻ -5-cyano-AK1_(2-hydroxy-2-(4-methyl) -1-carbonyl-1,3-dihydro Isobenzofuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide. Compared with other ROMK inhibitors, this compound has added polar groups and maintains ROMK On the basis of inhibitor activity, ClogP is reduced, hERG selectivity is improved, and safety is increased. Its structure is shown in formula (A).

Generally, the active compound must be provided to the patient in the form of a composition in order to use its activity to effectively treat various diseases, and the appropriate components can overcome the stability and dissolution problems. Summary of the invention

This application provides a pharmaceutical composition containing the active substance ⑻ -5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzo Furan-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or its pharmaceutically acceptable salt and at least one pharmaceutical excipient, the content of impurity A in the pharmaceutical composition is less than 0.5% of the total weight of the active material, preferably less than 0.1% of the total weight of the active material, the content of impurity B is less than 1.0% of the total weight of the active material, preferably less than 0.5% of the total weight of the active material, where impurities A and B refer to When the detection method detects impurities with a relative retention time of 0.44 (impurity A) and a relative retention time of 0.62 (impurity B), the detection method is as follows: Chromatographic column: Phenomenex Luna, 4.6 mmx200 mm, 5 (xm; column Temperature: 35 °C; Flow rate: 1.0 mL/min; Detection wavelength: 240 nm; Mobile phase: Use ammonium dihydrogen phosphate buffer solution (take 2.3 g ammonium dihydrogen phosphate, add 1000 mL of water to dissolve, add 1 mL of triethylamine , Mixing): Acetonitrile=95:5 is mobile phase A, acetonitrile is mobile phase B, and gradient elution is performed according to the following table;

Time (minutes) Mobile phase A (%) Mobile phase B (%)

0 90 10 25 50 50

35 15 85

35.1 90 10

45 90 10 This application provides a pharmaceutical composition containing the active substance CR>5-cyano-N-(1-(2-hydroxyl-2-(4-methyl-1-carbonyl-1,3-di Hydroisobenzofuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or a pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient, the pharmaceutical composition does not Contains polyethylene glycol and/or polyvinyl alcohol.

In the pharmaceutical composition provided in the present application, the pharmaceutical excipient can be selected from at least one pharmaceutical excipient selected from fillers, disintegrants, glidants, and lubricants.

In the pharmaceutical composition provided in this application, the filler can be selected from glucose, sucrose, mannitol, sorbitol, lactose, pregelatinized starch, dextrin, silicified microcrystalline cellulose, microcrystalline cellulose, and cellulose -One or more of lactose, preferably one or more of lactose, microcrystalline cellulose, and cellulose-lactose.

In the pharmaceutical composition provided in this application, the content of the filler may be 20%-99% of the total weight of the pharmaceutical composition, preferably 50%-95%.

Disintegrants are substances that can quickly break the tablets into fine particles in the gastrointestinal juice, so that the functional ingredients can be quickly dissolved and absorbed, and play a role. Most of them have good water absorption and swelling properties, so as to realize the disintegration of oral preparations. solution. In the pharmaceutical composition provided in this application, the disintegrant can be selected from one of crospovidone, croscarmellose sodium, carboxymethyl starch sodium, and low-substituted hydroxypropyl cellulose Or more, preferably low-substituted hydroxypropyl cellulose and/or croscarmellose sodium, most preferably low-substituted hydroxypropyl cellulose.

The content of the disintegrant in the pharmaceutical composition provided in the present application can be 0.5%-20% of the total weight of the composition, preferably 1%-10%, specifically 0.5%, 0.6%, 0.7%, 0.8%, 0.9% , 1.0%, 1.2%,

1.5%, 1.8%, 2.0%, 2.3%, 2.5%, 2.7%, 3%, 3.2%, 3.5%, 3.7%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%.

In some embodiments, the pharmaceutical composition provided in the present application optionally contains a binder, and the binder may be selected from the group consisting of hydroxypropyl methylcellulose, starch slurry, mucilage, povidone, methylcellulose, One or more of ethyl cellulose and sodium carboxymethyl cellulose. The content of the binder may account for 0.1%-20% of the total weight of the pharmaceutical composition, preferably 1%-10%, most preferably 2%-5%.

Lubricants are generally used to facilitate processing, prevent the formulation material from adhering to the production equipment, reduce friction between particles, improve the flow rate of the formulation, and help the formulation to be discharged from the production equipment. In the pharmaceutical composition provided in this application, the lubricant can be selected from magnesium stearate, stearic acid, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, palmitic acid, and stearin One or more of calcium acid, talc, silicon dioxide, carnauba wax, sodium stearyl fumarate, preferably magnesium stearate, and the content of the lubricant may be 0.1% of the total weight of the pharmaceutical composition 5%, preferably 0.1%-3%, most preferably 0.1%-1.5%, specifically 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1% , 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%.

In the pharmaceutical composition provided in this application, the glidant may be selected from one or more of silicon dioxide, corn starch, micronized silica gel, and talc, preferably silicon dioxide, and the content of the glidant It can be 0.1%-8% of the total weight of the composition, preferably 0.5%-5%, most preferably 1.0%-3.0%.

In the pharmaceutical composition provided in the present application, the content of the active substance may be 0.1%-25% of the total weight of the pharmaceutical composition, preferably 0.5%-20%.

In a preferred embodiment of this application, the pharmaceutical composition contains an active substance (R>5-cyano-N-(1-(2-hydroxyl-2-(4-methyl-1-carbonyl-1,3-di Hydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient, in the pharmaceutical composition The content of impurity A is less than 0.5% of the total weight of the active material, and the content of impurity B is less than 1.0% of the total weight of the active material. The filler is selected from lactose, microcrystalline cellulose, cellulose-lactose, preferably cellulose-lactose, and the content is 20%-99% of the total weight of the composition, preferably 50%-95% _{; the} disintegrant is selected from low-substituted hydroxypropyl cellulose and/or croscarmellose sodium, preferably low-substituted hydroxypropyl cellulose , The content is the drug group 0.5%-20% of the total weight of the compound, preferably 1%-10% _{; the} lubricant is magnesium stearate, and the content is 0.1%-3% of the total weight of the pharmaceutical composition, most preferably 0.1%-1.5% _; glid The agent is silicon dioxide, and the content is 0.5%-5% of the total weight of the pharmaceutical composition, most preferably 1.0%-3.0%.

In the unit dosage form of the pharmaceutical composition provided in this application, (R)-5 -cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroiso) The content of benzofuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or its pharmaceutically acceptable salt can be 0.5 mg-100 mg, preferably 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg , 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, most preferably 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg.

The pharmaceutical composition provided in this application may be a tablet, granule, powder (including fine granules) or a capsule, preferably a tablet.

In the preferred pharmaceutical combination of this application, the tablet or granule may also contain at least one coating material, and the coating material may be selected from hypromellose, ethylcellulose, methylcellulose, Hydroxypropyl cellulose, povidone, polyvinyl acetate resin polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer dispersion One or more of body, Opadry.

The active substance in the preferred pharmaceutical combination of this application ⑻ -5 -cyano-N- (1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran- 5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or its pharmaceutically acceptable salt. The particle size d0.9 is less than 80 fim, preferably d0.9 is less than 60 fim, most preferably d0 .9 is less than 40 fim.

The CR described in the preferred pharmaceutical composition of the present application:)-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroiso) The pharmaceutically acceptable salt of benzofuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide is selected from hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate Salt, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, right Tosylate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanilla Acid salt, mandelate, succinate, gluconate, citrate, benzene sulfonate, hydrobromide, fumarate, hydrobromide, lactobionate or lauryl sulfonate, etc., L-tartrate or malate is preferred, and L-tartrate is most preferred.

Another aspect of the present application provides a method for preparing the above-mentioned pharmaceutical composition, comprising: 1) (R)-5 -cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl) -1,3-dihydroisobenzofuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or a pharmaceutically acceptable salt thereof and selected from fillers and optionally selected from The step of mixing at least one pharmaceutical excipient among disintegrant, glidant and lubricant; 2) the step of wet granulation, dry granulation, direct compression or capsule filling of the mixture obtained from step 1) , The step 2) is preferably dry granulation or direct compression.

The preparation method of the pharmaceutical composition provided in the present application further includes a coating step after the tableting step, and the coating agent used can be selected from Opadry, hypromellose, and ethyl cellulose One or more, preferably Opadry, which does not contain polyvinyl alcohol and/or polyethylene glycol.

When the pharmaceutical composition described in the present application is a tablet, it can be prepared by compressing the granules obtained as described above, and the shape of the tablet is not particularly limited, preferably lentil, disc, round, oval (such as capsule). Tablets:), teardrop-shaped or polygonal (such as triangles or diamonds)> The prepared tablets can be coated by spraying a suspension/solution of the coating agent with a pan coater (pan coater:).

When granules are used in the pharmaceutical composition of the present application, the granules obtained as described above can be used directly or can be granulated into a desired granular shape by appropriate techniques. In addition, the granules thus prepared can be coated with a coating agent by spraying a suspension/solution of the coating agent.

Use of the pharmaceutical composition provided in this application in the preparation of a medicament for the treatment or prevention of ROMK-mediated diseases, the diseases may be selected from liver cirrhosis, acute and chronic renal insufficiency, nephrotic syndrome, pulmonary hypertension , Cardiovascular disease, myocardial infarction, stroke, heart failure, pulmonary hypertonia, atherosclerosis and kidney stones.

The pharmaceutical composition provided in this application is placed at 60 ^° C. After 30 days, the content of impurity A in the pharmaceutical composition does not exceed 0.5%, preferably not more than 0.1%; the content of impurity B in the composition does not exceed 1.0 %, preferably not more than 0.5%. Put the pharmaceutical composition provided by this application in an aluminum foil bag and place it at 60 ^° C. After 30 days, the content of impurity A in the pharmaceutical composition does not exceed 0.5%, preferably not more than 0.1%; the content of impurity B does not It exceeds 1.0%, preferably not more than 0.5%. detailed description

The application will be explained in more detail below in conjunction with the examples. The examples of the application are only used to illustrate the technical solutions of the application, and do not limit the essence and scope of the application.

WO2017211271A discloses (R)-5-cyano-N-( 1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) ethyl (Yl) piperidin-4-yl)-4-methoxypyridine carboxamide and its L-tartrate salt preparation method. The pharmaceutical excipients used in this application can all be purchased through commercial channels. Example 1

The active pharmaceutical ingredient ⑻ -5 -cyano-N- (1- (2-hydroxy-2-( 4 -methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) ethyl Yl)piperidin-4-yl)-4 -methoxypyridinecarboxamide L (+) -tartrate is mixed with lactose, microcrystalline cellulose, croscarmellose sodium, and the binder is polyvinylpyrrolidone The K30 aqueous solution is prepared by high-speed shear granulation process to prepare granules, and then the granules are dried with a water content of less than 3%, sieved, and then mixed with magnesium stearate to be uniformly compressed into tablets, and the composition 1 is obtained.

The active pharmaceutical ingredient ⑻ -5 -cyano-N- (1- (2 -hydroxy-2-(4 -methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl) (Ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide L (+) -tartrate with lactose, microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone K30, stearin Magnesium acid was mixed and uniformly compressed into tablets to obtain composition 2.

The active pharmaceutical ingredient ⑻ -5 -cyano-N- (1- (2-hydroxy-2-( 4 -methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) ethyl Yl)piperidin-4-yl)-4-methoxypyridinecarboxamide L (+) -tartrate and cellulose-lactose, croscarmellose sodium, silicon dioxide, and magnesium stearate are mixed uniformly Compressed into tablets, the composition 3 was obtained.

Table 2.

Put the tablets prepared from the composition 1-3 into an aluminum foil bag and place them at 60 ^° C. Samples will be taken at 0, 5, 10, and 30 days to determine the content of impurity A and impurity B in the composition, and to investigate the tablet stability. The results are shown in Table 3.

table 3.

The above results indicate that composition 2 has better stability during the stability test. Show The water added in the wet granulation process will have a significant impact on the levels of impurities A and B, and the powder direct pressing process is better. Example 2

The active pharmaceutical ingredient ⑻ -5-cyano-N- (1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) ethyl Yl) piperidine-4-yl) -4-methoxypyridinecarboxamide L( +) -tartrate and cellulose-lactose, croscarmellose sodium or low-substituted hydroxypropyl cellulose, dioxide The silicon and magnesium stearate were mixed and uniformly compressed into tablets to obtain compositions 4 and 5.

Table 4.

Put the tablets prepared from compositions 4 and 5 into an aluminum foil bag and place them at 60 ^° C. Samples were taken at 0, 5, 10, and 30 days to determine the content of impurity A and impurity B in the composition, and to examine the tablet stability. The results are shown in Table 5.

table 5.

The above results show that during the stability test, the stability of compositions 4 and 5 are equivalent, and basically consistent with composition 3, and both are better than composition 1. Example 3

On the basis of composition 5, coating was prepared to prepare compositions 6-8, the composition of which is shown in Table 6.

Table 6.

Put the tablets prepared from compositions 6 to 8 into an aluminum foil bag and place them at 60 ^° C. Samples will be taken at 0, 5, 10, and 30 days to determine the contents of impurity A and impurity B in the composition, and investigate the tablet’s stability. The results are shown in Table 7.

Table 7.

The above results indicate that during the stability test, the pharmaceutical composition 6 that does not contain polyethylene glycol and polyvinyl alcohol has better stability. Example 4

Put the composition 6 into a thermostat at 40 ^° C, 60 ^° C, 25 ^° C±2 ^° C/RH75%±5% and 25 ^° C±2 ^° C/RH90%±5%, light (total) The illuminance is greater than 1.2*10 ⁶ Lux-hr) and placed without packaging. Samples were taken at 5 days, 10 days, and 30 days to detect the impurity content and dissolution. The measurement results are shown in Table 8.

Table 8. Results of stability test

The above results show that during the stability test, without any packaging, the composition 6 without polyethylene glycol and polyvinyl alcohol has better stability for impurity A and impurity B under various conditions; only at 25 ^° The dissolution rate decreases under the condition of C±2 ^° C/RH90%±5%, and the dissolution rate also has better stability under other conditions. Example 5

The composition 7 was packaged in a polyester/aluminum/polyethylene medicinal composite bag, and placed at 40 ^° C ± 2 ^° C/RH75% ± 5% for 6 months and 25 ^° 0 ± 2 ^° 0/111160% ± The stability of the impurity content and dissolution rate of composition 7 was investigated under the condition of 5% for 12 months. The measurement results are shown in Table 9 and Table 10.

Table 9.40 °C ±2 ^° C/RH75%±5% stability test results

Table 1 Stability test results under 0.25 ^° C±2 ^° C/RH60%±5% conditions

The above results show that during the stability test, the composition 7 has good stability of impurity A, impurity B and dissolution under various conditions; it is only placed under the conditions of 40 ^° C ±2 ^° C/RH75% ± 5%. The content of impurity A increased slightly every month. Example 6

The active pharmaceutical ingredient ⑻ -5-cyano-N- (1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) ethyl Yl) piperidine-4-yl) -4-methoxypyridinecarboxamide L( +) -tartrate and cellulose-lactose, croscarmellose sodium or low-substituted hydroxypropyl cellulose, dioxide Silicon and magnesium stearate are uniformly mixed and compressed into tablets, and then coated with a film coating premix to obtain composition 9.

Table 11.

Pack the composition 9 in a polyester/aluminum/polyethylene medicinal composite bag, and place it at 40 ^° C ±2 ^° C/RH75%±5% for 6 months and 25 ^° C±2 ^° C/RH60%± The stability of the impurity content and dissolution rate of Composition 9 was examined for 12 months under the condition of 5%. The measurement results are shown in Table 12 and Table 13.

Table 12. Results of stability test under 40 ^° C±2 ^° C/RH75%±5% conditions

Table 13. Results of stability test at 25 ^° C±2 ^° C/RH60%±5%

The above results indicate that during the stability test, the composition 9 has good stability of impurity A, impurity B and dissolution under various conditions. Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present invention. modify. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims

Rights request

1. A pharmaceutical composition containing the active substance ⑻ -5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzene) Parafuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or its pharmaceutically acceptable salt and at least one pharmaceutical excipient, the content of impurity A in the pharmaceutical composition Less than 0.5% of the total weight of the active material, and the content of impurity B is less than 1.0% of the total weight of the active material. Impurities A and B refer to the relative retention time of 0.44 (impurity A) when tested according to the following detection method, and relative retention For impurities with a time of 0.62 (impurity B), the detection method is as follows: Chromatographic column: Phenomenex Luna, 4.6 mm><200 mm, 5 (im; column temperature: 35...; flow rate: 1.0 mL/min; detection wavelength: 240 nm; mobile phase: ammonium dihydrogen phosphate buffer solution: acetonitrile=95:5 as mobile phase A, acetonitrile as mobile phase B, gradient elution according to the following table;

Time (minutes) Mobile phase A (%) Mobile phase B (%)

0 90 10

25 50 50

35 15 85

35.1 90 10

45 90 10

2. A pharmaceutical composition containing the active substance ⑻ -5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzene) And furan-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridine carboxamide or a pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient, wherein the pharmaceutical composition does not contain polyethylene Diol and/or polyvinyl alcohol.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical excipient is selected from at least one pharmaceutical excipient selected from fillers, disintegrants, glidants, and lubricants.

4. The pharmaceutical composition according to claim 3, wherein the filler is selected from glucose, sucrose, mannitol, sorbitol, lactose, pregelatinized starch, dextrin, silicified microcrystalline cellulose, microcrystalline cellulose , One or more of cellulose-lactose, preferably one or more of lactose, microcrystalline cellulose, and cellulose-lactose.

5. The pharmaceutical composition according to claim 4, wherein the content of the filler is 20%-99% of the total weight of the pharmaceutical composition, preferably 50%-95%.

6. The pharmaceutical composition according to claim 3, wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose One or more of, preferably low-substituted hydroxypropyl cellulose and/or croscarmellose sodium, most preferably low-substituted hydroxypropyl cellulose.

7. The pharmaceutical composition according to claim 6, wherein the content of the disintegrant is 0.5%-20% of the total weight of the pharmaceutical composition, preferably 1%-10%.

8. The pharmaceutical composition according to claim 3, wherein the lubricant is selected from magnesium stearate, stearic acid, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, palmitic acid One or more of calcium stearate, talc, silicon dioxide, carnauba wax, sodium stearyl fumarate, preferably magnesium stearate, and the content of the lubricant may be the total weight of the pharmaceutical composition 0.1%-5%, preferably 0.1%-3%, most preferably 0.1%-1.5%.

9. The pharmaceutical composition according to claim 3, wherein the glidant is selected from one or more of silicon dioxide, corn starch, micronized silica gel, and talc, preferably silicon dioxide, the glidant The content of the agent may be 0.1%-8% of the total weight of the pharmaceutical composition, preferably 0.5%-5%, most preferably 1.0%-3.0%.

10. The pharmaceutical composition according to any one of claims 1-9, wherein the content of the active substance in the pharmaceutical composition is 0.1%-25% of the total weight of the composition, preferably 0.5%-20%.

11. A pharmaceutical composition containing the active substance CR>5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzene) Parafuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient, the content of impurity A in the composition Less than 0.5% of the total weight of the active material, and the content of impurity B is less than 1.0% of the total weight of the active material;

The filler is selected from one or more of lactose, microcrystalline cellulose, and cellulose-lactose, and the content is 20%-99% of the total weight of the composition, preferably 50%-95%; The disintegrant is selected from low-substituted hydroxypropyl cellulose and/or croscarmellose sodium, preferably low-substituted hydroxypropyl cellulose, and the content is 0.5%-20% of the total weight of the pharmaceutical composition, preferably 1% -10%;

The lubricant is magnesium stearate, and the content is 0.1%-3% of the total weight of the pharmaceutical composition, preferably 0.1%-1.5%; the glidant is silicon dioxide, and the content is 0.5%-5% of the total weight of the pharmaceutical composition , Preferably 1.0%-3.0%.

12. The pharmaceutical composition according to any one of claims 1-11, wherein (R)-5-cyano_N-(1-(2-hydroxy-2-(4-methyl-1) in unit dosage form -Carbonyl-1,3-dihydroisobenzofuran-5-yl) ethyl) piperidine-4-yl)-4-methoxy-P than carboxamide or its pharmaceutically acceptable salt content is 0.5 mg -100 mg, preferably 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg,

11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg,

21 mg, 22 mg, 23 mg, 24 mg, 25 mg, most preferably 0.5 mg, 1 mg, 2 mg, 3 mg,

4 mg.

13. The pharmaceutical composition according to claim 12, which is a tablet, powder, granule or capsule, preferably a tablet.

14. The pharmaceutical composition according to claim 13, wherein the tablet or granule further contains at least one coating material, and the coating material can be selected from the group consisting of hypromellose, ethyl cellulose, and methylcellulose. Base cellulose, hydroxypropyl cellulose, povidone, polyvinyl acetate resin, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methacrylic acid One or more of methyl ester copolymer dispersion and Opadry.

15. The pharmaceutical composition according to claim 12, wherein the (R)-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3) -Dihydroisobenzofuran-5-yl) ethyl) piperidin-4-yl) -4-methoxyf ¹ than carboxamide or its pharmaceutically acceptable salt particle size d0.9 is less than 80 |im , Preferably d0.9 is less than 60 |im, most preferably d0.9 is less than 40 fim.

16. The pharmaceutical composition according to any one of claims 1-15, wherein the ⑻-5 -cyano-N-(1-(2-hydroxyl-2-(4-methyl-1-carbonyl) The pharmaceutically acceptable salt of -1,3-dihydroisobenzofuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide is selected from tartrate, hydrochloride, and sulfuric acid Salt, methanesulfonate, phosphate, citrate, maleate, fumarate, malate, besylate, p- Tosylate or hydrobromide, preferably L-tartrate or malate, most preferably L-tartrate.

17. A method for preparing the pharmaceutical composition of any one of claims 1-16, which comprises: 1) (R)-5-cyano-N-(1-(2-hydroxy-2-( 4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or a pharmaceutically acceptable salt thereof The step of mixing at least one pharmaceutical excipient selected from the group consisting of fillers and disintegrants, glidants and lubricants, 2) Wet granulation, dry granulation, and direct compression of the mixture obtained in step 1) In the step of tablet or capsule filling, the step 2) is preferably dry granulation or direct compression.

18. The preparation method of the pharmaceutical composition according to claim 17, which further comprises a coating step, and the coating agent used can be selected from one or more of Opadry, hypromellose, and ethylcellulose , Opadry is preferred, and the Opadry does not contain polyvinyl alcohol and/or polyethylene glycol.

19. Use of the pharmaceutical composition according to any one of claims 1-16 in the preparation of a medicament for the treatment or prevention of ROMK-mediated diseases, the diseases selected from liver cirrhosis, acute and chronic renal function One or more of insufficiency, nephrotic syndrome, pulmonary hypertension, cardiovascular disease, myocardial infarction, stroke, cardiac insufficiency, pulmonary hypertonia, atherosclerosis, and kidney stones.