TW202045170A - Pharmaceutical composition containing inhibitor of renal potassium ion efflux channel and manufacturing method thereof - Google Patents

Abstract

The present application relates to a pharmaceutical composition containing an inhibitor of renal potassium ion efflux channel and a manufacturing method thereof. Specifically, 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-methoxypyridinecarboxamide or a pharmaceutically acceptable salt thereof. The pharmaceutical composition has good dissolution and superior stability.

Description

Pharmaceutical composition containing kidney potassium ion efflux channel inhibitor and preparation method thereof

The application belongs to the technical field of medicine, and relates to a pharmaceutical composition containing a renal potassium efflux channel (ROMK) inhibitor.

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.

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 antihypertensive diuretic development of new targets, ROMK for the inward rectifier K ⁺ channels (inwardly rectifying K channels, Kir) a family, belong Kir1 type, the maintenance of renal potassium ion balance plays a crucial role . In rat kidney, there are at least three subtypes of ROMK channels: ROMK1, ROMK2 and ROMK3. ROMK2 is mostly distributed in the ascending limb of Henle (TALH); ROMK1 and ROMK3 are mainly expressed in cortical collecting duct (CCD). ROMK expressed in TALH and Na ⁺ /K ⁺ /2Cl ^- transporter together regulate the secretion and reabsorption of sodium and potassium ions, and ROMK expressed in CCD and Na ⁺ /K ⁺ transporter together regulate the secretion of potassium ions. 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 potassium, which is a good research direction of diuretics.

（A）WO2016091042A1 (publication date 2016-06-16) discloses a class of extrarenal medullary secretory potassium channel (ROMK) inhibitors, chemically named ( R )-5-cyano- N -(1-(2-hydroxy-2- (4-Methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide, relative to For other ROMK inhibitors, this compound adds polar groups, reduces ClogP, improves hERG selectivity, and increases safety while maintaining the activity of ROMK inhibitors. Its structure is shown in formula (A).

(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 problems of stability and dissolution.

The application provides a pharmaceutical composition containing the active substance ( R )-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, 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 The following 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, 4.6mm×200mm, 5μm; column Temperature: 35℃; Flow rate: 1.0mL/min; Detection wavelength: 240nm; Mobile phase: ammonium dihydrogen phosphate buffer solution (take 2.3g ammonium dihydrogen phosphate, add 1000mL water to dissolve, add 1mL triethylamine, and mix well) ：Acetonitrile=95:5 is mobile phase A, acetonitrile is mobile phase B, gradient elution is performed according to the following table; Table 1 Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 90 10 25 50 50 35 15 85 35.1 90 10 45 90 10 .

The application provides a pharmaceutical composition containing the active substance ( R )-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzene) And furan-5-yl)ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide or its pharmaceutically acceptable salt and at least one pharmaceutical excipient, the pharmaceutical composition does not contain polyethylene Diol and/or polyvinyl alcohol.

In the pharmaceutical composition provided in this 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, cellulose -One or more of lactose, preferably one or more of lactose, microcrystalline cellulose, and cellulose-lactose.

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

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. . In the pharmaceutical composition provided in this application, the disintegrant may be selected from one of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose or Many kinds, 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 this 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 hypromellose, starch slurry, mucilage, povidone, methylcellulose, One or more of ethyl cellulose and sodium carboxymethyl cellulose. The content of the binder can 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, the content of the lubricant can be 0.1%-5% of the total weight of the pharmaceutical composition , 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 the present application, the glidant can be selected from one or more of silica, corn starch, micronized silica gel, and talc, preferably silica, and the content of the glidant 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 the application, the pharmaceutical composition contains the active substance ( R )-5-cyano-N-(1-(2-hydroxy-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 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, most preferably 0.1%-1.5 %; The glidant is silica, 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 by the application, ( R )-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzene) The content of bifuran-5-yl)ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide or its pharmaceutically acceptable salt can be 0.5mg-100mg, preferably 0.5mg, 1mg, 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 , 23mg, 24mg, 25mg, most preferably 0.5mg, 1mg, 2mg, 3mg, 4mg.

The pharmaceutical composition provided in this application may be a tablet, granule, powder (including fine granules) or 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, ethyl cellulose, methyl cellulose, hydroxy Propyl cellulose, povidone, polyvinyl acetate resin polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer dispersion One or more of Opadry.

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

The ( R )-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzene) described in the preferred pharmaceutical composition of this application Parafuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide pharmaceutically acceptable salt selected from hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate Salt, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate Acid salt, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate , Succinate, gluconate, citrate, besylate, hydrobromide, fumarate, hydrobromide, lactobionate or lauryl sulfonate, etc., preferably L-tartrate or Malate, L-tartrate is most preferred.

Another aspect of the application provides a method for preparing the above-mentioned pharmaceutical composition, 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 and selected from fillers and optionally self-disintegrating The step of mixing at least one pharmaceutical excipient among the antiseptic, glidant and lubricant, 2) the step of wet granulation, dry granulation, direct compression or capsule filling of the mixture obtained from step 1), so 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 the group consisting of 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 Pieces), 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.

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 desired granular shapes 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 medicine 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, cardiac insufficiency, lung 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 in 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 exceed It exceeds 1.0%, preferably not more than 0.5%.

Hereinafter, the present application will be explained in more detail with reference to the embodiments. The embodiments of the present application are only used to illustrate the technical solutions of the present application, and do not limit the essence and scope of the present 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-methoxypyridinecarboxamide 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 ( R )-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) Ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide L(+)-tartrate is mixed with lactose, microcrystalline cellulose, croscarmellose sodium, and the binder is poly The aqueous solution of vinylpyrrolidone K30 is prepared by high-speed shearing 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 uniformly and compressed into tablets to obtain composition 1.

The active pharmaceutical ingredient ( R )-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, Magnesium stearate was mixed uniformly and compressed into tablets to obtain composition 2.

The active pharmaceutical ingredient ( R )-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) Ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide L(+)-tartrate and cellulose-lactose, croscarmellose sodium, silicon dioxide, magnesium stearate Mix evenly and compress into tablets to obtain composition 3. ingredient Composition 1 Composition 2 Composition 3 Dose (mg/tablet) proportion(%) Dose (mg/tablet) proportion(%) Dose (mg/tablet) proportion(%) Active drug 0.5 0.625 0.5 0.625 0.5 0.625 lactose 54.52 51.15 54.52 51.15 N/A N/A Microcrystalline cellulose 18.18 22.725 18.18 22.725 N/A N/A Cellulose-lactose N/A N/A N/A N/A 74.7 93.375 Croscarmellose Sodium 3.2 4.0 3.2 4.0 3.2 4.0 Povidone K30 2.8 3.5 2.8 3.5 N/A N/A Silicon dioxide N/A N/A N/A N/A 0.8 1.0 Magnesium stearate 0.8 1.0 0.8 1.0 0.8 1.0 total 80.0 100 80.0 100 80.0 100

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, to investigate the stability of the tablet Sex. The results are shown in Table 3. table 3. Time (days) Composition 1 Composition 2 Composition 3 Impurity A content (%) Impurity B content (%) Impurity A content (%) Impurity B content (%) Impurity A content (%) Impurity B content (%) 0 0.07 0.08 0.04 0.00 0.04 0.08 5 0.28 0.24 0.04 0.04 0.04 0.12 10 0.44 0.39 0.05 0.05 0.04 0.13 30 0.81 1.38 0.06 0.13 0.07 0.48

The above results indicate that composition 2 has better stability during the stability test. It shows that 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 ( R )-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) Ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide L(+)-tartrate and cellulose-lactose, croscarmellose sodium or low-substituted hydroxypropyl cellulose, Silicon dioxide and magnesium stearate are mixed and uniformly compressed into tablets to obtain compositions 4 and 5. Table 4. ingredient Composition 4 Composition 5 Dose (mg/tablet) proportion(%) Dose (mg/tablet) proportion(%) Active drug 0.5 0.625 0.5 0.625 Cellulose-lactose 74.7 93.375 74.7 93.375 Croscarmellose Sodium 3.2 4.0 N/A N/A Low-substituted hydroxypropyl cellulose N/A N/A 3.2 4.0 Silicon dioxide 0.8 1.0 0.8 1.0 Magnesium stearate 0.8 1.0 0.8 1.0 total 80.0 100 80.0 100

Put the tablets prepared from compositions 4 and 5 into aluminum foil bags 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 stability of the tablet Sex. The results are shown in Table 5. table 5. Time (days) Composition 4 Composition 5 Impurity A content (%) Impurity B content (%) Impurity A content (%) Impurity B content (%) 0 0.04 0.08 0.04 0.11 5 0.04 0.14 0.04 0.13 10 0.04 0.14 0.04 0.13 30 0.07 0.42 0.06 0.42

The above results indicate 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 used to prepare compositions 6 to 8. The composition is shown in Table 6. Table 6. ingredient Composition 6 Composition 7 Composition 8 Core composition Composition 5 Composition 5 Composition 5 Composition of film coating premix Hydroxypropyl Methyl Cellulose Titanium Dioxide Talc Hydroxypropyl methyl cellulose titanium dioxide polyethylene glycol 400 Polyvinyl Alcohol Titanium Dioxide Talc Polyethylene Glycol 3350 Lecithin

Put the tablets prepared from compositions 6 to 8 into aluminum foil bags 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 to investigate the stability of the tablet Sex. The results are shown in Table 7. Table 7. Time (days) Composition 6 Composition 7 Composition 8 Impurity A content (%) Impurity B content (%) Impurity A content (%) Impurity B content (%) Impurity A content (%) Impurity B content (%) 0 0.04 0.11 0.04 0.13 0.04 0.16 5 0.05 0.14 0.05 0.13 0.04 0.54 10 0.05 0.15 0.05 0.22 0.05 1.42 30 0.07 0.19 0.06 0.56 0.07 2.37

The above results show that during the stability test, the pharmaceutical composition 6 without polyethylene glycol and polyvinyl alcohol has better stability.

Example 4

Put the composition 6 into a thermostat at 40℃, 60℃, 25℃±2℃/RH75%±5% and 25℃±2℃/RH90%±5%, light (total illumination greater than 1.2*10 ⁶ Placed under Lux hr) without packaging, samples were taken at 5 days, 10 days, and 30 days to detect the impurity content and dissolution rate. The measurement results are shown in Table 8. Table 8: Stability test results Assessment conditions Index time (days) 30 minutes dissolution rate (%) Impurity A content (%) Impurity B content (%) 0 90.0 0.04 0.03 40℃ 5 98.3 0.04 0.04 10 94.1 0.04 0.06 30 94.0 0.06 0.04 60℃ 5 99.3 0.04 0.04 10 93.6 0.04 0.06 30 93.3 0.06 0.04 RH75% 5 94.1 0.04 0.03 10 96.2 0.03 0.03 30 93.2 0.03 0.03 RH90% 5 90.6 0.03 0.04 10 92.9 0.04 0.03 30 82.9 0.03 0.09 illumination 5 93.6 0.09 0.06 10 93.1 0.06 0.08 30 94.8 0.08 0.08

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

Example 5

Pack the composition 7 in a polyester/aluminum/polyethylene medicinal composite bag, and place it at 40℃±2℃/RH75%±5% for 6 months and 25℃±2℃/RH60%±5%. After standing for 12 months, the stability of the impurity content and dissolution rate of Composition 7 was investigated. The measurement results are shown in Table 9 and Table 10. Table 9: Stability test results under 40℃±2℃/RH75%±5% conditions sample Project conditions 30 minutes dissolution rate (%) Impurity content (%) Impurity A Impurity B Batch 1 Start 95~97 0.04 0.03 January 96~100 0.04 0.04 February 100-103 0.05 0.06 March 95~103 0.06 0.04 June 95~100 0.08 0.04 Batch 2 Start 85~93 0.04 0.03 January 87~96 0.04 0.04 February 93-101 0.05 0.07 March 89~101 0.06 0.04 June 90~103 0.08 0.04 Batch 3 Start 90~99 0.04 0.04 January 89~96 0.04 0.04 February 91-102 0.04 0.05 March 81~98 0.06 0.06 June 95~98 0.08 0.05 Table 10: Stability test results under 25℃±2℃/RH60%±5% conditions sample Project conditions 30 minutes dissolution rate (%) Impurity content (%) Impurity A Impurity B Batch 1 Start 85~93 0.04 0.03 March 93~101 0.04 0.04 June 93~101 0.04 0.04 September 85-99 0.04 0.03 December 84-102 0.05 0.04 Batch 2 Start 90~99 0.04 0.04 March 94~102 0.04 0.05 June 84~99 0.04 0.04 September 88-96 0.04 0.04 December 88-101 0.05 0.05 Batch 3 Start 95~97 0.04 0.03 March 94~105 0.04 0.04 June 91~99 0.04 0.03 September 94-101 0.04 0.03 December 90-104 0.04 0.03

The above results indicate that during the stability test, the composition 7 has good stability of impurity A, impurity B and dissolution rate under various conditions; it is only placed at 40℃±2℃/RH75%±5% for 6 months The content of impurity A increased slightly.

Example 6

The active pharmaceutical ingredient ( R )-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) Ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide L(+)-tartrate and cellulose-lactose, croscarmellose sodium or low-substituted hydroxypropyl cellulose, Silicon dioxide and magnesium stearate are uniformly mixed and compressed into tablets, and coated with a film coating premix to obtain composition 9. Table 11. ingredient Composition 9 Dose (mg/tablet) proportion(%) Core composition Active drug 5.0 6.25 Cellulose-lactose 70.2 87.75 Low-substituted hydroxypropyl cellulose 3.2 4.0 Silicon dioxide 0.8 1.0 Magnesium stearate 0.8 1.0 total 80.0 100 Composition of film coating premix Hydroxypropyl methyl cellulose titanium dioxide polyethylene glycol 400

Pack the composition 9 in a polyester/aluminum/polyethylene medicinal compound bag, and place it at 40℃±2℃/RH75%±5% for 6 months and 25℃±2℃/RH60%±5%. After standing for 12 months, the stability of the impurity content and dissolution rate of Composition 9 was investigated. The measurement results are shown in Table 12 and Table 13. Table 12: Stability test results under 40℃±2℃/RH75%±5% conditions sample Project conditions 30 minutes dissolution rate (%) Impurity content (%) Impurity A Impurity B Batch 1 Start 95~96 0.04 0.02 January 98~101 0.04 0.01 February 97-101 0.05 0.03 March 96~100 0.04 0.01 June 96~100 0.07 0.02 Batch 2 Start 88~97 0.04 0.01 January 95~98 0.04 0.01 February 92-99 0.04 0.02 March 94-97 0.05 0.01 June 98~100 0.06 0.01 Batch 3 Start 88~99 0.04 0.01 January 91~99 0.04 0.01 February 97-101 0.05 0.02 March 96-99 0.05 0.01 June 96~100 0.06 0.01 Table 13: Stability test results under 25℃±2℃/RH60%±5% conditions sample Project conditions 30 minutes dissolution rate (%) Impurity content (%) Impurity A Impurity B Batch 1 Start 88~97 0.04 0.01 March 91~100 0.04 0.01 June 93~99 0.04 0.01 September 95-97 0.05 not detected December 96-101 0.04 0.01 Batch 2 Start 88~99 0.04 0.01 March 98~100.5 0.04 0.02 June 97~99 0.04 0.01 September 93-97 0.04 not detected December 95-98 0.05 0.01 Batch 3 Start 95~96 0.04 0.02 March 95~103 0.06 0.01 June 96~98 0.04 0.01 September 95-98 0.04 not detected December 98-101 0.05 0.01

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. . Therefore, the scope of protection of the present invention is limited by the scope of the attached patent application.

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Claims (19)

A pharmaceutical composition containing the active substance ( R )-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 and at least one pharmaceutical excipient, the content of impurity A in the pharmaceutical composition is less than the active 0.5% of the total weight of the 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 the relative retention time is 0.62 (impurity B) impurity, the detection method is as follows: Chromatographic column: Phenomenex Luna, 4.6mm×200mm, 5μm; column temperature: 35℃; flow rate: 1.0mL/min; detection wavelength: 240nm; mobile phase: phosphoric acid Dihydrogen ammonium buffer solution: acetonitrile=95:5 is mobile phase A, acetonitrile is mobile phase B, gradient elution is performed according to the following table; Table 1 Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 90 10 25 50 50 35 15 85 35.1 90 10 45 90 10 . A pharmaceutical composition containing the active substance ( R )-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 and at least one pharmaceutical excipient, the pharmaceutical composition does not contain polyethylene glycol and / Or polyvinyl alcohol. 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. The pharmaceutical composition according to claim 3, wherein the filler is selected from the group consisting of glucose, sucrose, mannitol, sorbitol, lactose, pregelatinized starch, dextrin, silicified microcrystalline cellulose, microcrystalline cellulose, and fiber One or more of vegetarian-lactose, preferably one or more of lactose, microcrystalline cellulose, and cellulose-lactose. In the pharmaceutical composition according to claim 4, the content of the filler is 20%-99% of the total weight of the pharmaceutical composition, preferably 50%-95%. The pharmaceutical composition according to claim 3, wherein the disintegrant is selected from one of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose Or more, preferably low-substituted hydroxypropyl cellulose and/or croscarmellose sodium, most preferably low-substituted hydroxypropyl cellulose. In the pharmaceutical composition according to claim 6, the content of the disintegrant is 0.5%-20% of the total weight of the pharmaceutical composition, preferably 1%-10%. 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, hard One or more of calcium fatty 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%. The pharmaceutical composition according to claim 3, wherein the glidant is selected from one or more of silica, corn starch, micronized silica gel, and talc, preferably silica, and the content of the glidant can be It is 0.1%-8% of the total weight of the pharmaceutical composition, preferably 0.5%-5%, most preferably 1.0%-3.0%. According to the pharmaceutical composition according to any one of claims 1-9, 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%. A pharmaceutical composition containing the active substance ( 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 at least one pharmaceutical excipient, the content of impurity A in the composition is less than the active 0.5% of the total weight of the material, 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, cellulose-lactose, and the content is 20% of the total weight of the composition -99%, 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 the total amount of the pharmaceutical composition 0.5%-20% by weight, preferably 1%-10%; the lubricant is magnesium stearate, the content is 0.1%-3% of the total weight of the pharmaceutical composition, preferably 0.1%-1.5%; the glidant is dioxide The content of silicon is 0.5%-5% of the total weight of the pharmaceutical composition, preferably 1.0%-3.0%. The pharmaceutical composition according to any one of claims 1-11, wherein ( R )-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl- The content of 1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide or its pharmaceutically acceptable salt is 0.5mg-100mg, 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 according to claim 12, which is a tablet, powder, granule or capsule, preferably a tablet. The pharmaceutical composition according to claim 13, wherein the tablet or granule further contains at least one coating material, and the coating material may be selected from hypromellose, ethylcellulose, and methylcellulose , Hydroxypropyl cellulose, povidone, polyvinyl acetate resin, polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer One or more of dispersion, Opadry. The pharmaceutical composition according to claim 12, wherein the ( R )-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-di Hydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide or its pharmaceutically acceptable salt. The particle size d0.9 is less than 80μm, preferably d0.9 is less than 60 μm, most preferably d0.9 is less than 40 μm. The pharmaceutical composition according to any one of claims 1-15, wherein the ( R )-5-cyano-N-(1-(2-hydroxy-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, benzenesulfonate, p-toluenesulfonate or hydrobromide, preferably L-tartrate or Malate, L-tartrate is most preferred. A method for preparing the pharmaceutical composition according to 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 its pharmaceutically acceptable salt and selected from filler The step of mixing a disintegrant and at least one pharmaceutical excipient optionally selected from a disintegrant, a glidant and a lubricant; 2) Wet granulation, dry granulation, direct compression or filling of the mixture obtained in step 1) In the step of capsule, the step 2) is preferably dry granulation or direct compression. The preparation method of the pharmaceutical composition according to claim 17, which further comprises a coating step, and the coating agent used may be selected from one or more of Opadry, hypromellose, and ethylcellulose, preferably Opadry Instead, the Opadry does not contain polyvinyl alcohol and/or polyethylene glycol. The 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 insufficiency, One or more of nephrotic syndrome, pulmonary hypertension, cardiovascular disease, myocardial infarction, stroke, heart failure, pulmonary hypertonia, atherosclerosis, and kidney stones.