PHARMACEUTICAL COMPOSITION CONTAINING ILAPRAZOLE OR SALT THEREOF AND PREPARATION METHOD THEREFOR

Abstract

The present invention relates to a pharmaceutical composition containing ilaprazole or a salt thereof, and a preparation method therefor. The pharmaceutical composition contains or consists of ilaprazole or a salt thereof, and a ilaprazole derivative, wherein the amount of the ilaprazole derivative in the pharmaceutical composition is not higher than 1.3 wt % (less than or equal to 1.3 wt %). The composition can be used for treating peptic ulcer bleeding and stress ulcer and preventing upper gastrointestinal hemorrhage caused by severe diseases.

Claims

1. A pharmaceutical composition, comprising or consisting of ilaprazole or a salt thereof and an ilaprazole derivative, wherein the amount of the ilaprazole derivative in the composition is no more than 1.3 wt % 1.3 wt %).

2. The pharmaceutical composition according to claim 1, wherein the amount of the ilaprazole derivative in the composition is no more than 1.2 wt %, preferably no more than 1.1 wt %, more preferably no more than 1.0 wt %, further preferably no more than 0.9 wt %, most preferably no more than 0.8 wt %, such as no more than 0.7 wt %, no more than 0.6 wt %, no more than 0.5 wt %, no more than 0.4 wt %, no more than 0.3 wt %, or no more than 0.2 wt %.

3. The pharmaceutical composition according to claim 1, wherein the salt of ilaprazole is ilaprazole sodium; preferably, the purity of the ilaprazole or a salt thereof is no less than 99.9%; preferably, the ilaprazole derivative is selected from one or more of ilaprazole sulfone, ilaprazole thioether, and ilaprazole ylide; preferably, the ilaprazole ylide is selected from one or more of ilaprazole carboxyl ylide, ilaprazole hydroxyl ylide, and ilaprazole mercaptomethyl ylide.

4. The pharmaceutical composition according to claim 1, wherein the amount of the ilaprazole ylide in the composition is no more than 0.9 wt %, preferably no more than 0.8 wt %, more preferably no more than 0.7 wt %, further preferably no more than 0.6 wt %, most preferably no more than 0.5 wt %, such as no more than 0.4 wt %, no more than 0.3 wt %, or no more than 0.2 wt %.

5. The pharmaceutical composition according to claim 1, wherein the ilaprazole derivative is ilaprazole sulfone, ilaprazole thioether, ilaprazole carboxyl ylide, ilaprazole hydroxyl ylide, and ilaprazole mercaptomethyl ylide; preferably, the amount of the ilaprazole carboxyl ylide in the composition is no more than 0.3 wt %.

6. The pharmaceutical composition according to claim 1, wherein the mass ratio of the ilaprazole sulfone to the ilaprazole thioether is 1:0.5-2, preferably 1:0.5-1 or 1:1-2, more preferably 1:1.

7. The pharmaceutical composition according to claim 1, wherein the composition comprises or consists of the following parts by weight of substances: TABLE-US-00013 ilaprazole sodium 98.7-99.5 parts; ilaprazole sulfone  0.1-0.2 parts; ilaprazole thioether  0.1-0.2 parts; ilaprazole carboxyl ylide  0.1-0.3 parts; ilaprazole hydroxyl ylide  0.1-0.3 parts; ilaprazole mercaptomethyl ylide  0.1-0.3 parts; preferably, the composition comprises or consists of the following parts by weight of substances: TABLE-US-00014 ilaprazole sodium 98.7 parts; ilaprazole sulfone  0.2 parts; ilaprazole thioether  0.2 parts; ilaprazole carboxyl ylide  0.3 parts; ilaprazole hydroxyl ylide  0.3 parts; ilaprazole mercaptomethyl ylide  0.3 parts.

8. A powder for injection, comprising the pharmaceutical composition according to claim 1 and a pharmaceutically acceptable carrier; preferably, the pharmaceutically acceptable carrier is mannitol and EDTA-2Na; preferably, the weight ratio of mannitol to EDTA-2Na is 10-50:1, preferably 30:1; preferably, the weight ratio between the weight of the ilaprazole or a salt thereof and the ilaprazole derivative (ie, the pharmaceutical composition according to any one of claims 1 to 6) in total, mannitol, and EDTA-2Na in the powder for injection is 1:3-5:0.1-0.3, preferably 1:3:0.1.

9. The powder for injection according to claim 8, wherein the pH of the powder for injection is 10.5-11.5, preferably 11.

10. A method for preparing the powder for injection according to claim 8, comprising the following steps: (1) weighing the ilaprazole or a salt thereof, the ilaprazole derivative, and the pharmaceutically acceptable carrier according to their prescribed amounts; (2) dissolving the pharmaceutically acceptable carrier in water for injection, and adjusting the pH of the solution obtained to 10.5-11.5, preferably 10.5 with 2 mol/L sodium hydroxide solution, then adding the prescribed amounts of the ilaprazole or a salt thereof and the ilaprazole derivative to the solution, and after the ilaprazole or a salt thereof and the ilaprazole derivative fully dissolve, adjusting the pH of the solution obtained to 10.5-11.5, preferably 11 with 2 mol/L sodium hydroxide solution, and finally adding water for injection of 4° C. to the solution up to 15000 mg; (3) sterilizing the solution obtained in step (2) through filtering two times with a filter membrane having a pore size of 0.2 μm and freeze-drying the filtrate obtained to obtain freeze-dried powders for injection, which are then sealed with a stopper in a vacuum pump, removed from the vacuum pump and capped with an aluminum cap.

11. A pharmaceutical composition, consisting of ilaprazole sodium and an ilaprazole derivative, wherein the ilaprazole derivative is ilaprazole polysulfide dimer, and/or is selected from one or more of ilaprazole sulfone, ilaprazole thioether and ilaprazole ylide; preferably, the amount of the ilaprazole derivative is no more than 1.7 wt % (1.7 wt %).

12. The pharmaceutical composition according to claim 11, wherein the amount of the ilaprazole derivative is no more than 1.6 wt %, preferably no more than 1.5 wt %, more preferably no more than 1.4 wt %, further preferably no more than 1.3 wt %, such as no more than 1.2 wt %, no more than 1.1 wt %, no more than 1.0 wt %, no more than 0.9 wt %, no more than 0.8 wt %, no more than 0.7 wt %, no more than 0.6 wt %, no more than 0.5 wt %, no more than 0.4 wt %, or no more than 0.3 wt %.

13. The pharmaceutical composition according to claim 11, wherein the purity of the ilaprazole sodium is no less than 99.9%; preferably, the ilaprazole polysulfide dimer is ilaprazole disulfide dimer and/or ilaprazole trisulfide dimer; preferably, the ilaprazole ylide is selected from one or more of ilaprazole carboxyl ylide, ilaprazole hydroxyl ylide and ilaprazole mercaptomethyl ylide; preferably, the ilaprazole derivative is ilaprazole polysulfide dimer, ilaprazole sulfone, ilaprazole thioether, ilaprazole carboxyl ylide, ilaprazole hydroxyl ylide, and ilaprazole mercaptomethyl ylide.

14. The pharmaceutical composition according to claim 11, wherein the amount of the ilaprazole ylide is no more than 0.9 wt %, preferably no more than 0.8 wt %, more preferably no more than 0.7 wt %, preferably no more than 0.6 wt %, preferably no more than 0.5 wt %, preferably no more than 0.4 wt %, preferably no more than 0.3 wt %, preferably no more than 0.2 wt %; preferably, the amount of the ilaprazole carboxyl ylide in the composition is no more than 0.3 wt %; preferably, the mass ratio of the ilaprazole sulfone to the ilaprazole thioether is 1:0.5-2, preferably 1:0.5-1 or 1:1-2, more preferably 1:1; preferably, the amount of the ilaprazole polysulfide dimer is no more than 0.4 wt %, preferably no more than 0.3 wt %.

15. The pharmaceutical composition according to claim 11, wherein the ilaprazole polysulfide dimer is ilaprazole disulfide dimer and ilaprazole trisulfide dimer; preferably, the weight ratio of the ilaprazole disulfide dimer to the ilaprazole trisulfide dimer is 1:0.5-2, preferably 1:0.5-1 or 1:1-2, more preferably 1:1.

16. The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition comprises or consists of the following parts by weight of substances: TABLE-US-00015 ilaprazole sodium 98.3-99.3 parts; ilaprazole sulfone  0.1-0.2 parts; ilaprazole thioether  0.1-0.2 parts; ilaprazole carboxyl ylide  0.1-0.3 parts; ilaprazole hydroxyl ylide  0.1-0.3 parts; ilaprazole mercaptomethyl ylide  0.1-0.3 parts; ilaprazole disulfide dimer  0.1-0.2 parts; ilaprazole trisulfide dimer  0.1-0.2 parts; preferably, the pharmaceutical composition comprises or consists of the following parts by weight of substances: TABLE-US-00016 ilaprazole sodium 98.3 parts; ilaprazole sulfone  0.2 parts; ilaprazole thioether  0.2 parts; ilaprazole carboxyl ylide  0.3 parts; ilaprazole hydroxyl ylide  0.3 parts; ilaprazole mercaptomethyl ylide  0.3 parts; ilaprazole disulfide dimer  0.2 parts; ilaprazole trisulfide dimer  0.2 parts.

17. A powder for injection, comprising the pharmaceutical composition according to claim 11 and a pharmaceutically acceptable carrier; preferably, the pharmaceutically acceptable carrier is mannitol and EDTA-2Na; preferably, the weight ratio of mannitol to EDTA-2Na is 10-50:1, preferably 30:1; preferably, the weight ratio between the weight of the ilaprazole or a salt thereof and the ilaprazole derivative (ie, the pharmaceutical composition according to any one of claims 1 to 6) in total, mannitol, and EDTA-2Na in the powder for injection is 1:3-5:0.1-0.3, preferably 1:3:0.1.

18. The powder for injection according to claim 17, wherein the pH of the powder for injection is 10.5-11.5, preferably 11.

19. A method for preparing the powder for injection according to claim 17, comprising the following steps: (1) weighing the ilaprazole or a salt thereof, the ilaprazole derivative, and the pharmaceutically acceptable carrier according to their prescribed amounts; (2) dissolving the pharmaceutically acceptable carrier in water for injection, and adjusting the pH of the solution obtained to 10.5-11.5, preferably 10.5 with 2 mol/L sodium hydroxide solution, then adding the prescribed amounts of the ilaprazole or a salt thereof and the ilaprazole derivative to the solution, and after the ilaprazole or a salt thereof and the ilaprazole derivative fully dissolve, adjusting the pH of the solution obtained to 10.5-11.5, preferably 11 with 2 mol/L sodium hydroxide solution, and finally adding water for injection of 4° C. to the solution up to 15000 mg; (3) sterilizing the solution obtained in step (2) through filtering two times with a filter membrane having a pore size of 0.2 μm and freeze-drying the filtrate obtained to obtain freeze-dried powders for injection which are then sealed with a stopper in a vacuum pump, removed from the vacuum pump and capped with an aluminum cap.

20. A method for treating digestive tract disease, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 1 to a patient in need, wherein, preferably, the digestive tract disease is selected from the group consisting of duodenal ulcers, gastric ulcers and reflux esophagitis.

Description

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0075] The present invention will be further described below in conjunction with specific examples. It should be understood that the examples of the present invention are only used to illustrate the present invention, and are not intended to limit the scope of the present invention.

[0076] Experimental methods without specific conditions in the following examples are usually carried out under conventional conditions or according to conditions recommended by manufacturers. Unless otherwise defined, all professional and scientific terms used in the context have the same meaning as those familiar to those skilled in the art.

[0077] In addition, any method and material similar or equivalent to the content described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0078] Sources of Materials:

[0079] ilaprazole sodium: Livzon (Group) Pharmaceutical Factory

[0080] ilaprazole sulfone: prepared by the progress as described in the specification of the present application

[0081] ilaprazole thioether: prepared by the progress as described in the specification of the present application

[0082] ilaprazole carboxyl ylide: prepared by the progress as described in the specification of the present application

[0083] ilaprazole hydroxyl ylide: prepared by the progress as described in the specification of the present application

[0084] ilaprazole mercaptomethyl ylide: prepared by the progress as described in the specification of the present application

[0085] ilaprazole disulfide dimer: prepared by the progress as described in the specification of the present application

[0086] ilaprazole trisulfide dimer: prepared by the progress as described in the specification of the present application

[0087] The purity of the above drugs is 99.9%.

Example 1: Preparation of Ilaprazole Sodium Powder for Injection

[0088] (1) materials were weighed according to prescribed amounts: ilaprazole sodium 98.7 mg, ilaprazole sulfone 0.2 mg, ilaprazole thioether 0.2 mg, ilaprazole carboxyl ylide 0.3 mg, ilaprazole hydroxyl ylide 0.3 mg, ilaprazole mercaptomethyl ylide 0.3 mg, mannitol 300 mg, EDTA-2Na 10 mg;

[0089] (2) mannitol and disodium edetate were dissolved in water for injection, and the pH of the solution obtained was adjusted to 10.5 with 2 mol/L sodium hydroxide solution; the ilaprazole sodium (purity: 99.9%), ilaprazole sulfone, ilaprazole thioether, ilaprazole carboxyl ylide, ilaprazole hydroxyl ylide, and ilaprazole mercaptomethyl ylide weighed in step (1) were added to the solution, and after they had fully dissolved, the pH of the solution obtained was adjusted to 11 with 2 mol/L sodium hydroxide solution, and finally water for injection of 4° C. was added to the solution up to 15000 mg;

[0090] (3) the solution obtained in step (2) was sterilized through filtering two times with a filter membrane having a pore size of 0.2 μm and the filtrate obtained was freeze-dried to obtain freeze-dried powders for injection, which are then sealed with a stopper in a vacuum pump, removed from the vacuum pump and capped with an aluminumcap.

Examples 2-8

[0091] Formulations of Examples 2-8 are shown in Table 1, and preparation methods are the same as that described in Example 1.

TABLE-US-00005 TABLE 1 Formulations of Examples 1-8 ilaprazole ilaprazole ilaprazole mercapto- Component ilaprazole ilaprazole ilaprazole carboxyl hydroxyl methyl (mg) sodium sulfone thioether ylide ylide ylide Mannitol EDTA-2Na Example 1 98.7 0.2 0.2 0.3 0.3 0.3 300 10 Example 2 98.7 0.2 0.2 0.3 0.3 0.3 500 10 Example 3 98.7 0.2 0.2 0.3 0.3 0.3 300 30 Example 4 98.7 0.2 0.2 0.3 0.3 0.3 500 30 Example 5 98.7 0.2 0.1 0.4 0.3 0.3 300 10 Example 6 98.4 0.3 0.3 0.2 0.4 0.4 300 10 Example 7 98.7 0.2 0.1 0.3 0.4 0.3 300 10 Example 8 98.7 0.2 0.1 0.3 0.3 0.4 300 10

Experimental Example 9

[0092] 1. Clarity Test

[0093] 30 mg of ilaprazole sodium powder for injection prepared in Example 1 and ilaprazole sodium powders for injection prepared in the following three groups A, B, and C were taken, to which water for injection was added up to 1 g to obtain solutions. The solutions were placed at 4° C., 16° C., 25° C., 40° C., respectively with bottles containing the solutions opened. Changes in color and clarity of the solutions were observed. As a blank group for detection, 30 mg of mannitol and 1 mg of EDTA-2Na were dissolved in a suitable amount of water for injection, to which water for injection was added up to 1 g, and tested simultaneously. Results are shown in Table 2.

[0094] ilaprazole composition of Group A: ilaprazole sodium powder for injection (abbreviated as A) was obtained according to the preparation method as described in Example 2 in CN102038648A;

[0095] ilaprazole composition of Group B: ilaprazole sodium powder for injection (abbreviated as B) was obtained according to the preparation method as described in Example 1 in CN105769778A;

[0096] ilaprazole composition of Group C: ilaprazole sodium powder for injection (abbreviated as C) was obtained according to the preparation method as described in Example 2 in CN105055342A.

TABLE-US-00006 TABLE 2 Group 4° C. 16° C. 25° C. 40° C. Blank group Having a turbidity Having a turbidity Having a turbidity Having a turbidity lower than that of lower than that of No. lower than that of lower than that of No. 1 turbidity 1 turbidity standard No. 1 turbidity No. 1 turbidity standard solution at solution at 24 hours standard solution at standard solution at 24 hours 24 hours 24 hours Example 1 Having a turbidity Having a turbidity Having a turbidity Having a turbidity equivalent to that of equivalent to that of equivalent to that of equivalent to that of No. 1 turbidity No. 1 turbidity No. 1 turbidity No. 1 turbidity standard solution at standard solution at standard solution at standard solution at 14 hours, and 12 hours, and 11 hours, and 6 hours, and equivalent to that of equivalent to that of equivalent to that of equivalent to that of No. 2 turbidity No. 2 turbidity No. 2 turbidity No. 2 turbidity standard solution standard solution standard solution standard solution after 20 hours after 18 hours after 17 hours after 11 hours A Having a turbidity Having a turbidity Having a turbidity Having a turbidity equivalent to that of equivalent to to that of equivalent to that of equivalent to that of No. 1 turbidity No. 1 turbidity No. 1 turbidity No. 1 turbidity standard solution at standard solution at 4 standard solution at 4 standard solution at 3.5 hours, and hours, and equivalent hours, and equivalent 1 hour, and equivalent to that of to that of No. 2 to that of No. 2 equivalent to that of No. 2 turbidity turbidity standard turbidity standard No. 2 turbidity standard solution solution after 7 hours solution after 6 hours standard solution after 5 hours after 3 hours B Having a turbidity Having a turbidity Having a turbidity Having a turbidity equivalent to that of equivalent to that of equivalent to that of equivalent to that of No. 1 turbidity No. 1 turbidity No. 1 turbidity No. 1 turbidity standard solution at standard solution at 8 standard solution at 8 standard solution at 5.5 hours, and hours, and equivalent hours, and equivalent 3 hours, and equivalent to that of to that of No. 2 to that of No. 2 equivalent to that of No. 2 turbidity turbidity standard turbidity standard No. 2 turbidity standard solution solution after 12 solution after 10 standard solution after 8 hours hours hours after 6 hours C Having a turbidity Having a turbidity Having a turbidity Having a turbidity equivalent to that of equivalent to that of equivalent to that of equivalent to that of No. 1 turbidity No. 1 turbidity No. 1 turbidity No. 1 turbidity standard solution at 3 standard solution at 2 standard solution at standard solution at hours, and equivalent hours, and equivalent 1.5 hours, and 0.5 hours, and to that of No. 2 to that of No. 2 equivalent to that of equivalent to that of turbidity standard turbidity standard No. 2 turbidity No. 2 turbidity solution after 7 hours solution after 4 hours standard solution standard solution after 3 hours after 2 hours

[0097] From the above results, it can be seen that the powder for injection prepared in Example 1 has better clarity under the conditions of 4° C., 16° C., 25° C. and 40° C. than the powders for injection of Group A, Group B and Group C.

[0098] 2. Stability Test

[0099] Powders for injection prepared in Examples 1-S were placed at a temperature of 60° C. and a relative humidity of 95% for 30 days, and samples were taken. Specific test results are shown in Table 3 below.

TABLE-US-00007 TABLE 3 Ilaprazole sodium Reduction of ilaprazole sodium content (%) content compared to 0 day (%) Condition 0 day 10 days 30 days Example 1 98.7 0.28 0.63 Example 2 98.7 0.37 0.79 Example 3 98.7 0.35 0.81 Example 4 98.7 0.39 0.78 Example 5 98.7 1.35 1.93 Exarnple 6 98.4 0.53 0.98 Example 7 98.7 0.47 0.91 Example 8 98.7 0.45 0.92

[0100] As shown in the table above, the content of ilaprazole sodium in the powders for injection prepared in Examples 1-4 and 6-8 decreased at a slower rate under the conditions of high temperature and high humidity, i.e. a temperature of 60° C. and a relative humidity of 95%. The content of ilaprazole sodium in the powder for injection prepared in Example 1 decreased at the slowest rate, having the best effect. The content of ilaprazole sodium in the powder for injection prepared in Example 5 decreased fast.

[0101] 3. Pharmacodynamic Test

[0102] (I) Test Model:

[0103] Rat model of acute gastric ulcer bleeding was selected (to simulate the hemostatic effect of the ilaprazole sodium composition for injection under the condition of direct gastric ulcer bleeding).

[0104] (2) Dosage Selection:

[0105] It can be known by conversion from clinically effective doses of ilaprazole sodium for injection and non-clinical research data that, the dosage of ilaprazole sodium for injection effective for a rat model of gastric ulcer induced in laboratory should be in the range of 1-10 mg/kg.

[0106] (3) Administration Dosage:

[0107] Administration dosage range was 0.5-10 mg/kg (0.5, 2, 5, 10 in the rodent study, and blank control group was injected intravenously with 1 mi/kg vehicle.

[0108] (4) Establishment of the Rat Model of Acute Gastric Ulcer Bleeding

[0109] SD rats weighing 180-250 g were randomly divided into 5 groups, with 5 rats in each group. After intraperitoneally anesthetized with 25 g/L pentobarbital sodium (1 ml/kg), they were fixed on plates, and injected with drugs to be tested or vehicle via femoral vein.

[0110] At a certain time after administration (a reference value is 30 min, adjusted according to pre-experiments), the abdomen of each of the rats was exposed and cut along midline, then the stomach was opened, and one piece of each of gastric antrum and gastric mucosa was taken simultaneously using small biopsy forceps to form an acute bleeding lesion, thereby building an ulcer bleeding model. Gastric mucosal bleeding time (GMBT) of each rat was recorded, and the average, median, and standard deviation were calculated and statistically tested.

[0111] (5) Test Grouping:

[0112] Each test was set up with blank control group, group of Example 1, group A, group B, and group C, and the preparation methods of drugs administrated in group A, group B, and group C were the same as those in the clarity test. Test results are shown in Table 4.

TABLE-US-00008 TABLE 4 Group/GMBT Dosage (mg/kg) (second) 0.5 1 2 5 10 Example 1  73.0 ± 3.0 68.0 ± 2.0 62.0 ± 3.0 58.0 ± 2.0 53.0 ± 2.0 A  94.0 ± 2.0 88.0 ± 2.0 82.0 ± 2.0 74.0 ± 2.0 72.0 ± 2.0 B 105.0 ± 2.0 98.0 ± 2.0 86.0 ± 2.0 80.0 ± 2.0 78.0 ± 2.0 C  96.0 ± 2.0 89.0 ± 3.0 82.0 ± 3.0 75.0 ± 2.0 72.0 ± 3.0 Blank control 158 ± 2.0 group

[0113] As shown in the table above, the powder for injection prepared in Example 1 can stop bleeding more effectively against acute gastric ulcer bleeding in rats, having a better effect.

Example 10: Preparation of Ilaprazole Sodium Powder for Injection

[0114] (1) materials were weighed according to prescribed amounts: ilaprazole sodium (purity: 99.9%) 98.7 mg, ilaprazole sulfone 0.2 mg, ilaprazole thioether 0.2 mg, ilaprazole carboxyl ylide 0.3 mg, ilaprazole hydroxyl ylide 0.3 mg, ilaprazole mercaptomethyl ylide 0.3 mg, ilaprazole disulfide dimer 0.2 mg, ilaprazole trisulfide dimer 0.2 mg, mannitol 300 mg, EDTA-2Na 10 mg.

[0115] (2) mannitol and disodium edetate were dissolved in water for injection, and the pH of the solution obtained was adjusted to 10.5 with 2 mol/L sodium hydroxide solution; the ilaprazole sodium (purity: 99.9%), ilaprazole sulfone, ilaprazole thioether, ilaprazole carboxyl ylide, ilaprazole hydroxyl ylide, ilaprazole mercaptomethyl ylide, ilaprazole disulfide dimer, and ilaprazole trisulfide dimer weighed in step (1) were added to the solution, and after they had fully dissolved, the pH of the solution obtained was adjusted to 11 with 2 mol/L sodium hydroxide solution, and finally water for injection of/1° C. was added to the solution up to 15000 mg;

[0116] (3) the solution obtained in step (2) was sterilized through filtering two times with a filter membrane having a pore size of 0.2 μm and the filtrate obtained was freeze-dried to obtain freeze-dried powders for injection, which are then sealed with a stopper in a vacuum pump, removed from the vacuum pump and capped with an aluminum cap.

Examples 11-19: Preparation of Ilaprazole Sodium Powder for Injection

[0117] Formulations of Examples 11-19 are shown in Table 5, and preparation methods are the same as that described in Example 10.

TABLE-US-00009 TABLE 5 Formulations of Examples 10-19 Ilaprazole Ilaprazole Ilaprazole Ilaprazole Ilaprazole Component Ilaprazole Ilaprazole Ilaprazole carboxyl hydroxyl mercaptom disulfide trisulfide EDTA- (mg) sodium sulfone thioether ylide ylide ethyl ylide dimer dimer Mannitol 2Na Example 10 98.3 0.2 0.2 0.3 0.3 0.3 0.2 0.2 300 10 Example 11 98.3 0.2 0.2 0.3 0.3 0.3 0.2 0.2 500 10 Example 12 98.3 0.2 0.2 0.3 0.3 0.3 0.2 0.2 300 30 Example 13 98.3 0.2 0.2 0.3 0.3 0.3 0.2 0.2 500 30 Example 14 98.3 0.2 0.2 0.3 0.2 0.2 0.3 0.3 300 10 Example 15 98.0 0.4 0.3 0.3 0.3 0.4 0.2 0.1 300 10 Example 16 98.3 0.2 0.3 0.3 0.3 0.4 0.1 0.1 300 10 Example 17 98.3 0.2 0.3 0.3 0.4 0.35 0.1 0.05 300 10 Example 18 98.3 0.2 0.2 0.4 0.2 0.3 0.2 0.2 300 10 Example 19 98.2 0.3 0.3 0.2 0.3 0.3 0.2 0.2 300 10

Experimental Example 20

[0118] 1. Clarity Test

[0119] 30 mg of ilaprazole sodium powder for injection prepared in Example 10 and ilaprazole sodium powders for injection prepared in the following three groups A, B, and C were taken, to which water for injection was added up to 1 g to obtain solutions. The solutions were placed at 4° C., 16° C., 25° C., 40° C., respectively with bottles containing the solutions opened. Changes in color and clarity of the solutions were observed. As a blank group for detection, 30 mg of mannitol and 1 mg of EDTA-2Na were dissolved in a suitable amount of water for injection, to which water for injection was added up to 1 g, and tested simultaneously. Results are shown in Table 6.

[0120] Ilaprazole composition of Group A: ilaprazole sodium powder for injection (abbreviated as A) was obtained according to the preparation method as described in Example 2 in CN102038648A;

[0121] Ilaprazole composition of Group B: ilaprazole sodium powder for injection (abbreviated as B) was obtained according to the preparation method as described in Example 1 in CN105769778A;

[0122] Ilaprazole composition of Group C: ilaprazole sodium powder for injection (abbreviated as C) was obtained according to the preparation method as described in Example 1 in CN105055342A.

TABLE-US-00010 TABLE 6 Group 4° C. 16° C. 25° C. 40° C. Blank group Having a turbidity Having a turbidity Having a turbidity Having a turbidity lower than that of lower than that of No. lower than that of lower than that of No. 1 turbidity 1 turbidity standard No. 1 turbidity No. 1 turbidity standard solution at solution at 24 hours standard solution at standard solution at 24 hours 24 hours 24 hours Example 10 Having a turbidity Having a turbidity Having a turbidity Having a turbidity equivalent to that of equivalent to that of equivalent to that of equivalent to that of No. 1 turbidity No. 1 turbidity No. 1 turbidity No. 1 turbidity standard solution at standard solution at standard solution at standard solution at 13 hours, and 10 hours, and 10 hours, and 6 hours, and equivalent to that of equivalent to that of equivalent to that of equivalent to that of No. 2 turbidity No. 2 turbidity No. 2 turbidity No. 2 turbidity standard liquid after standard liquid after standard liquid after standard liquid after 19 hours 17 hours 15 hours 10 hours A Having a turbidity Having a turbidity Having a turbidity Having a turbidity equivalent to that of equivalent to that of equivalent to that of equivalent to that of No. 1 turbidity No. 1 turbidity No. 1 turbidity No. 1 turbidity standard solution at standard solution at 4 standard solution at 4 standard solution at 3.5 hours, and hours, and equivalent hours, and equivalent 1 hour, and equivalent to that of to that of No. 2 to that of No. 2 equivalent to that of No. 2 turbidity turbidity standard turbidity standard No. 2 turbidity standard solution solution after 7 hours solution after 6 hours standard solution after 5 hours after 3 hours B Having a turbidity Having a turbidity Having a turbidity Having a turbidity equivalent to that of equivalent to that of equivalent to that of equivalent to that of No. 1 turbidity No. 1 turbidity No. 1 turbidity No. 1 turbidity standard solution at standard solution at 8 standard solution at 8 standard solution at 5.5 hours, and hours, and equivalent hours, and equivalent 3 hours, and equivalent to that of to that of No. 2 to that of No. 2 equivalent to that of No. 2 turbidity turbidity standard turbidity standard No. 2 turbidity standard solution solution after 12 solution after 10 standard solution after 8 hours hours hours after 6 hours C Having a turbidity Having a turbidity Having a turbidity Having a turbidity equivalent to that of equivalent to that of equivalent to that of equivalent to that of No. 1 turbidity No. 1 turbidity No. 1 turbidity No. 1 turbidity standard solution at 3 standard solution at 2 standard solution at standard solution at hours, and equivalent hours, and equivalent 1.5 hours, and 0.5 hours, and to that of No. 2 to that of No. 2 equivalent to that of equivalent to that of turbidity standard turbidity standard No. 2 turbidity No. 2 turbidity solution after 7 hours solution after 4 hours standard solution standard solution after 3 hours after 2 hours

[0123] From the above results, it can be seen that the powder for injection prepared in Example 10 has better clarity under the conditions of 4° C., 16° C., 25° C. and 40° C. than the powders for injection of Group A, Group B and Group C.

[0124] 2. Stability Test

[0125] Powders for injection prepared in Examples 10-19 were placed at a temperature of 60° C. and a relative humidity of 95% for 30 days, and samples were taken. Specific test results are shown in Table 7 below.

TABLE-US-00011 TABLE 7 Ilaprazole Reduction of ilaprazole sodium content sodium content compared to 0 day (%) (%) Condition 0 day 10 days 30 days Example 10 98.3 0.29 0.59 Example 11 98.3 0.39 0.73 Example 12 98.3 0.41 0.79 Example 13 98.3 0.38 0.75 Example 14 98.3 1.13 1.71 Example 15 98.0 0.81 1.03 Example 16 98.3 0.69 0.98 Example 17 98.3 0.73 0.97 Example 18 98.3 1.21 1.95 Example 19 98.2 0.61 0.93

[0126] As shown in the table above, the content of ilaprazole sodium in the powders for injection prepared in Examples 10-13, 15-17 and 19 decreased at a slower rate under the conditions of high temperature and high humidity, i.e. a temperature of 60° C. and a relative humidity of 95%. The content of ilaprazole sodium in the powder for injection prepared in Example 10 decreased at the slowest rate, having the best effect. The content of ilaprazole sodium in the powders for injection prepared in Examples 14 and 18 decreased fast.

[0127] 3. Pharmacodynamic Test

[0128] (1) Test Model:

[0129] Rat model of acute gastric ulcer bleeding was selected (to simulate the hemostatic effect of the ilaprazole sodium composition for injection under the condition of direct gastric ulcer bleeding).

[0130] (2) Dosage Selection:

[0131] It can be known by conversion from clinically effective doses of ilaprazole sodium for injection and non-clinical research data that, the dosage of ilaprazole sodium for injection effective for a rat model of gastric ulcer induced in laboratory should be in the range of 1-10 mg/kg.

[0132] (3) Administration Dosage:

[0133] Administration dosage range was 0.5-10 mg/kg (0.5, 5, 10 mg/kg) in the rodent study, and blank control group was injected intravenously with 1 mi/kg vehicle.

[0134] (4) Establishment of the Rat Model of Acute Gastric Ulcer Bleeding

[0135] SD rats weighing 180-250 g were randomly divided into 5 groups, with 5 rats in each group. After intraperitoneally anesthetized with 25 g/L pentobarbital sodium (1 ml/kg), they were fixed on plates, and injected with drugs to be tested or vehicle via femoral vein.

[0136] At a certain time after administration (a reference value is 30 min, adjusted according to pre-experiments), the abdomen of each of the rats was exposed and cut along midline, then the stomach was opened, and one piece of each of gastric antrum and gastric mucosa was taken simultaneously using small biopsy forceps to form an acute bleeding lesion, thereby building an ulcer bleeding model. Gastric mucosal bleeding time (GMBT) of each rat was recorded, and the average, median, and standard deviation were calculated and statistically tested.

[0137] (5) Test Grouping:

[0138] Each test was set up with blank control group, group of Example 10, group A, group B, and group C, and the preparation methods of drugs administrated in group A, group B, and group C were the same as those in the clarity test. Test results are shown in Table 8.

TABLE-US-00012 TABLE 8 Group/GMBT Dosage (mg/kg) (second) 0.5 1 2 5 10 Example 10  71.0 ± 3.0 66.0 ± 2.0 60.0 ± 3.0 56.0 ± 2.0 52.0 ± 2.0 A  94.0 ± 2.0 88.0 ± 2.0 82.0 ± 2.0 74.0 ± 2.0 72.0 ± 2.0 B 105.0 ± 2.0 98.0 ± 2.0 86.0 ± 2.0 80.0 ± 2.0 78.0 ± 2.0 C  96.0 ± 2.0 89.0 ± 3.0 82.0 ± 3.0 75.0 ± 2.0 72.0 ± 3.0 Blank control 158 ± 2.0 group

[0139] As shown in the table above, the composition prepared in Example 10 can stop bleeding more effectively against acute gastric ulcer bleeding in rats, having a better effect.

[0140] It should be understood that the invention described herein is not limited to specific methodologies, experimental protocols, or reagents, as these may vary. The discussion and examples provided herein are presented to describe specific embodiments and are not intended to limit the scope of the invention, which is limited only by the claims.