Omeprazole sodium lyophilized powder composition for injection and use thereof

Abstract

The present invention relates to a freeze-dried powder composition of omeprazole sodium for injection and its use. On the one hand, the freeze-dried powder injection composition of omeprazole sodium for injection of the present invention comprises: 40 parts of omeprazole sodium, 5 parts of disodium edetate, and an appropriate amount of sodium hydroxide, so that the composition is dissolved in water to form a solution containing 4 mg / ml of omeprazole, and the pH value is 10.1-11.1. The present invention also provides a method for preparing the freeze-dried powder injection composition, and the following pharmaceutical uses of the freeze-dried powder injection composition: peptic ulcer bleeding, anastomotic ulcer bleeding; acute gastric mucosal damage complicated by stress state, acute gastric mucosal damage caused by non-steroidal anti-inflammatory drugs; prevention of upper gastrointestinal bleeding caused by stress state of severe diseases (such as cerebral hemorrhage, severe trauma, etc.) and gastric surgery; as an alternative therapy for the following diseases when oral therapy is not applicable: duodenal ulcer, gastric ulcer, reflux esophagitis and Z-E syndrome. The freeze-dried powder injection composition of the present invention has excellent performance.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and relates to a proton pump inhibitor, and in particular to a method for stabilizing a proton pump inhibitor, wherein the proton pump inhibitor is preferably a sodium salt of omeprazole. The present invention also relates to a freeze-dried composition for injection prepared using the proton pump inhibitor as an active drug, such as an omeprazole sodium freeze-dried powder composition for injection. The present invention also relates to a method for preparing the omeprazole sodium freeze-dried powder composition for injection and their pharmaceutical uses. Background Art

[0002] Digestive system diseases are common and frequently occurring diseases, and they are also chronic diseases that are prone to recurrence. So far, there is no effective means to completely cure them, which has become one of the key research topics in the field of pharmacy. Statistical analysis shows that the incidence of digestive system diseases in the world accounts for 10-12% of the human population, and the incidence of digestive system diseases in urban areas in my country is 11.43%, which is basically similar to many developed countries in Europe and the United States. Due to the characteristics of the dietary structure, the incidence of residents in southern cities and southwest regions is relatively high, and the incidence of peptic ulcers in middle-aged and elderly people is relatively high, and they have become the main consumers of digestive system drugs.

[0003] The advent of proton pump inhibitors (PPIs) opened up a new way of action for anti-peptic ulcer drugs. It rose in the 1980s. The first generation of product, omeprazole, was synthesized in 1979 and launched in Switzerland in 1988. Its acid-suppressing effect does not lie in blocking various receptors, but in entering the high-acid environment of the secretory tubules of gastric parietal cells to interact with H + Combined with H + / K + -ATPase sulfhydryl dehydration coupling, resulting in H + / K + -ATPase activity is permanently inhibited. The drug is highly selective and can inhibit the final step of gastric acid formation, so it can effectively inhibit both basic gastric acid secretion and various forms of stress gastric acid secretion. The drug has complete acid suppression, strong effect, and long duration. It has a higher efficacy for peptic ulcers, a shorter course of treatment, and the ulcer heals faster than H2 receptor antagonists.

[0004] Omeprazole sodium is the first proton pump inhibitor to be marketed. It was successfully developed by Swedish Astra Pharmaceuticals (the predecessor of AstraZeneca Pharmaceuticals) and was first marketed in Switzerland in 1988 under the trade name "Antra". It entered the US market in 1989 and is used to treat duodenal ulcers, gastric ulcers, reflux esophagitis and Zollinger-Ellison syndrome under the trade name "Losec". Since then, Losec has become popular all over the world and has become one of the most prescribed drugs in the United States. From 1998 to 2000, it ranked first in the world's best-selling drugs for three consecutive years. In 2000, the global sales of Losec were US$6.26 billion, which can be called a "blockbuster" at the end of the 20th century.

[0005] The chemical name of omeprazole sodium is: 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl]-sulfinyl}-1H-benzimidazole sodium monohydrate, English name: Omeprazole Sodium, molecular weight: 385.4, molecular formula: C 17 H 18 N3NaO3S·H2O, the structural formula is as follows:

[0006]

[0007] Omeprazole sodium can highly selectively bind to H + / K + -ATPase binds to it, making it inactive, thereby controlling and blocking the final link of gastric acid secretion, making H in the gastric wall cells + It cannot be transported to the stomach and is a strong inhibitor of gastric acid secretion. It has significant therapeutic effects on duodenal ulcer, gastric ulcer, reflux esophagitis, Zollinger-Ellison syndrome, etc.

[0008] Omeprazole for injection is usually administered in its sodium salt, such as omeprazole sodium and lyophilized powder injection included in the 2020 edition of the Chinese Pharmacopoeia. The omeprazole sodium included in the Pharmacopoeia and commercially available is a monohydrate of the sodium salt. However, it has been found that the existing omeprazole sodium still needs to be improved. For example, those skilled in the art expect to provide a method for stabilizing proton pump inhibitors.

[0009] In the prior art, a large amount of research work is devoted to the development of omeprazole lyophilized powder injection. For example, Chinese patent application No. 200610042004.1 discloses a new prescription of omeprazole sodium lyophilized preparation for injection, which is composed of omeprazole sodium 20-80g, ethylenediaminetetraacetic acid disodium 0.5-5g, and mannitol 50-500g; Chinese patent application No. 200910056113.2 relates to an omeprazole sodium preparation for injection, which is prepared from omeprazole sodium, ethylenediaminetetraacetic acid disodium and sterile water for injection, and is lyophilized to prepare omeprazole sodium for injection; Chinese patent application No. 201110119352.5 provides an omeprazole sodium composition for injection, which contains omeprazole sodium and ethylenediaminetetraacetic acid disodium, and the weight ratio is 1:0.02-0.1.

[0010] However, those skilled in the art still expect to provide omeprazole preparations with good pharmaceutical properties for clinical use, such as omeprazole sodium freeze-dried powder injection for injection. Summary of the invention

[0011] The present invention aims to provide a method for stabilizing proton pump inhibitors, for example, the method is used to improve the quality of existing omeprazole sodium. Another object of the present invention is to provide an omeprazole sodium, which is expected to present one or more advantages. Another object of the present invention is to provide a method for preparing the omeprazole sodium, and a further object of the present invention is to provide pharmaceutical uses of the prepared omeprazole sodium. It has been unexpectedly found that the use of the method of the present invention to prepare omeprazole sodium can present one or more advantages, and the present invention is completed based on this discovery.

[0012] To this end, the first aspect of the present invention provides a compound shown in the following formula I:

[0013]

[0014] The compound according to the first aspect of the present invention is omeprazole sodium, that is, 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl]-sulfinyl}-1H-benzimidazole sodium salt.

[0015] According to the compound described in the first aspect of the present invention, its melting point is 169.0-172.0°C, for example, 169.5-172.0°C, preferably 170.0-171.5°C, as determined by "0612 Melting Point Determination Method" "A. Temperature Transfer Liquid Heating Method" of Part IV of the 2020 Edition of the Chinese Pharmacopoeia.

[0016] The compound according to the first aspect of the present invention uses Cu-Kα radiation and has diffraction peaks at 9.46°±0.20°, 14.50°±0.20°, 18.90°±0.20°, 19.74°±0.20°, 20.16°±0.20°, 22.90°±0.20°, 24.00°±0.20°, 26.02°±0.20°, and 26.88°±0.20° in a powder X-ray diffraction pattern expressed in 2θ angles.

[0017] The compound according to the first aspect of the present invention uses Cu-Kα radiation and has diffraction peaks at 9.46°±0.10°, 14.50°±0.10°, 18.90°±0.10°, 19.74°±0.10°, 20.16°±0.10°, 22.90°±0.10°, 24.00°±0.10°, 26.02°±0.10°, and 26.88°±0.10° in a powder X-ray diffraction pattern expressed in 2θ angles.

[0018] The compound according to the first aspect of the present invention uses Cu-Kα radiation and has diffraction peaks at 9.46°, 14.50°, 18.90°, 19.74°, 20.16°, 22.90°, 24.00°, 26.02° and 26.88° in a powder X-ray diffraction pattern expressed in 2θ angles.

[0019] The compound according to the first aspect of the present invention uses Cu-Kα radiation and has diffraction peaks at 9.46°±0.20°, 14.50°±0.20°, 18.90°±0.20°, 19.74°±0.20°, 20.16°±0.20°, 22.90°±0.20°, 24.00°±0.20°, 24.68°±0.20°, 26.02°±0.20°, 26.88°±0.20°, 27.44°±0.20°, and 31.72°±0.20° in a powder X-ray diffraction pattern expressed in 2θ angles.

[0020] The compound according to the first aspect of the present invention uses Cu-Kα radiation and has diffraction peaks at 9.46°±0.10°, 14.50°±0.10°, 18.90°±0.10°, 19.74°±0.10°, 20.16°±0.10°, 22.90°±0.10°, 24.00°±0.10°, 24.68°±0.10°, 26.02°±0.10°, 26.88°±0.10°, 27.44°±0.10°, and 31.72°±0.10° in a powder X-ray diffraction pattern expressed in 2θ angles.

[0021] The compound according to the first aspect of the present invention uses Cu-Kα radiation and has diffraction peaks at 9.46°, 14.50°, 18.90°, 19.74°, 20.16°, 22.90°, 24.00°, 24.68°, 26.02°, 26.88°, 27.44°, and 31.72° in the powder X-ray diffraction pattern expressed in 2θ angles.

[0022] According to the first aspect of the present invention, the compound, using Cu-Kα radiation, has Figure 1 Powder X-ray diffraction pattern shown.

[0023] The compound according to the first aspect of the present invention is prepared using a method comprising the following steps:

[0024] (a) adding sodium hydroxide to glycerol to dissolve it;

[0025] (b) adding omeprazole and acetone-glycerol mixed solvent into a reaction vessel under heating conditions, stirring, adding sodium hydroxide solution and continuing stirring, filtering, washing the filter with acetone, and combining the filtrate and the washings to obtain a mixed solution;

[0026] (c) Cooling the mixed solution to 25-30°C, for example, and then standing for 3-5 hours, for example, 4 hours, followed by stirring for 2-10 minutes, for example, 5 minutes, and then standing at -8-5°C for 20-30 hours, filtering, washing with cold acetone, and drying to obtain the target compound.

[0027] According to the compound of the first aspect of the present invention, in step (a), the ratio of sodium hydroxide to glycerol is 0.37 mol: 50-70 ml.

[0028] According to the compound of the first aspect of the present invention, in step (a), sodium hydroxide and glycerol are dissolved at a temperature of 32-38°C, for example, 35°C.

[0029] According to the compound described in the first aspect of the present invention, in step (b), the acetone-glycerol mixed solvent is a mixed solvent with a volume ratio of 3.5 to 4.5:1, such as 3.8 to 4.2:1.

[0030] According to the compound of the first aspect of the present invention, in step (b), the ratio of omeprazole to the mixed solvent is 0.35 mol:400-500 ml, for example, 0.35 mol:450 ml.

[0031] According to the compound of the first aspect of the present invention, in step (a) and step (b), the ratio of omeprazole to sodium hydroxide is 0.35 mol:0.37 mol.

[0032] According to the compound of the first aspect of the present invention, in step (b), omeprazole and the mixed solvent are first stirred at 42-45° C. for 25-40 min, for example, for 30 min.

[0033] According to the compound of the first aspect of the present invention, in step (b), sodium hydroxide solution is added under heat preservation and stirring conditions and then stirred for 2 hours. Optionally, 5-7 g (for example, 3A) molecular sieve is added and stirred for 1 hour, and then filtered.

[0034] According to the compound described in the first aspect of the present invention, the operation of step (b) is: add 0.35 mol of omeprazole and 450 ml of acetone-glycerol (3.8-4.2:1, v / v) mixed solvent into a three-necked reaction bottle, stir at 42-45°C for 25-40 min, then add sodium hydroxide solution under insulation and stirring conditions and stir for 2 hours, add 5-7 g of 3A molecular sieve and stir for 1 hour, filter, wash the filter with 20 ml of acetone, combine the filtrate and the washing liquid to obtain a mixed solution.

[0035] According to the compound described in the first aspect of the present invention, the operation of step (c) is: the reaction mixture of the previous step is cooled to 26-28°C and then allowed to stand for 3-5 hours, then stirred for 5 minutes, and then allowed to stand at -8--5°C for 22-28 hours, filtered, washed twice with 50 ml of cold acetone (-5°C), and dried at 50°C for 3-6 hours to obtain the target compound.

[0036] Furthermore, the second aspect of the present invention provides a method for preparing the compound shown in the following formula I:

[0037]

[0038] The method comprises the following steps:

[0039] (a) adding sodium hydroxide to glycerol to dissolve it;

[0040] (b) adding omeprazole and acetone-glycerol mixed solvent into a reaction vessel under heating conditions, stirring, adding sodium hydroxide solution and continuing stirring, filtering, washing the filter with acetone, and combining the filtrate and the washings to obtain a mixed solution;

[0041] (c) Cooling the mixed solution to 25-30°C, for example, and then standing for 3-5 hours, for example, 4 hours, followed by stirring for 2-10 minutes, for example, 5 minutes, and then standing at -8-5°C for 20-30 hours, filtering, washing with cold acetone, and drying to obtain the target compound.

[0042] According to the method of the second aspect of the present invention, in step (a), the ratio of sodium hydroxide to glycerol is 0.37 mol: 50-70 ml.

[0043] According to the method of the second aspect of the present invention, in step (a), sodium hydroxide and glycerol are dissolved at a temperature of 32-38°C, for example, 35°C.

[0044] According to the method of the second aspect of the present invention, in step (b), the acetone-glycerol mixed solvent is a mixed solvent with a volume ratio of 3.5 to 4.5:1, such as 3.8 to 4.2:1.

[0045] According to the method of the second aspect of the present invention, in step (b), the ratio of omeprazole to mixed solvent is 0.35 mol:400-500 ml, for example, 0.35 mol:450 ml.

[0046] According to the method described in the second aspect of the present invention, in step (a) and step (b), the ratio of omeprazole to sodium hydroxide is 0.35 mol:0.37 mol.

[0047] According to the method of the second aspect of the present invention, in step (b), omeprazole and the mixed solvent are first stirred at 42-45° C. for 25-40 min, for example, for 30 min.

[0048] According to the method of the second aspect of the present invention, in step (b), sodium hydroxide solution is added under heat preservation and stirring conditions and then stirred for 2 hours. Optionally, 5-7 g of molecular sieve (such as 3A) is added and stirred for 1 hour, and then filtered.

[0049] According to the method described in the second aspect of the present invention, the operation of step (b) is as follows: 0.35 mol of omeprazole and 450 ml of a mixed solvent of acetone-glycerol (3.8-4.2:1, v / v) are added to a three-necked reaction flask, and stirred at 42-45° C. for 25-40 min, followed by adding a sodium hydroxide solution and stirring for 2 hours under heat preservation and stirring conditions, adding 5-7 g of 3A molecular sieve and stirring for 1 hour, filtering, washing the filter with 20 ml of acetone, and combining the filtrate and the washing liquid to obtain a mixed solution.

[0050] According to the method described in the second aspect of the present invention, the operation of step (c) is as follows: the reaction mixture of the previous step is cooled to 26-28°C and then allowed to stand for 3-5 hours, then stirred for 5 minutes, and then allowed to stand at -8--5°C for 22-28 hours, filtered, washed twice with 50 ml of cold acetone (-5°C), and dried at 50°C for 3-6 hours to obtain the target compound.

[0051] According to the method of the second aspect of the present invention, the compound is omeprazole sodium, that is, 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl]-sulfinyl}-1H-benzimidazole sodium salt.

[0052] According to the method described in the second aspect of the present invention, the compound obtained has a melting point of 169.0-172.0°C, for example, 169.5-172.0°C, preferably 170.0-171.5°C, as determined by "0612 Melting Point Determination Method" "A. Temperature Transfer Liquid Heating Method" in Part IV of the 2020 Edition of the Chinese Pharmacopoeia.

[0053] According to the method described in the second aspect of the present invention, the compound prepared uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°±0.20°, 14.50°±0.20°, 18.90°±0.20°, 19.74°±0.20°, 20.16°±0.20°, 22.90°±0.20°, 24.00°±0.20°, 26.02°±0.20°, and 26.88°±0.20°.

[0054] According to the method described in the second aspect of the present invention, the compound prepared uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°±0.10°, 14.50°±0.10°, 18.90°±0.10°, 19.74°±0.10°, 20.16°±0.10°, 22.90°±0.10°, 24.00°±0.10°, 26.02°±0.10°, and 26.88°±0.10°.

[0055] According to the method described in the second aspect of the present invention, the compound prepared uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°, 14.50°, 18.90°, 19.74°, 20.16°, 22.90°, 24.00°, 26.02°, and 26.88°.

[0056] According to the method described in the second aspect of the present invention, the compound prepared uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°±0.20°, 14.50°±0.20°, 18.90°±0.20°, 19.74°±0.20°, 20.16°±0.20°, 22.90°±0.20°, 24.00°±0.20°, 24.68°±0.20°, 26.02°±0.20°, 26.88°±0.20°, 27.44°±0.20°, and 31.72°±0.20°.

[0057] According to the method described in the second aspect of the present invention, the compound prepared therefrom uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°±0.10°, 14.50°±0.10°, 18.90°±0.10°, 19.74°±0.10°, 20.16°±0.10°, 22.90°±0.10°, 24.00°±0.10°, 24.68°±0.10°, 26.02°±0.10°, 26.88°±0.10°, 27.44°±0.10°, and 31.72°±0.10°.

[0058] According to the method described in the second aspect of the present invention, the compound prepared uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°, 14.50°, 18.90°, 19.74°, 20.16°, 22.90°, 24.00°, 24.68°, 26.02°, 26.88°, 27.44°, and 31.72°.

[0059] According to the method of the second aspect of the present invention, the compound prepared by the method uses Cu-Kα radiation, and has Figure 1 Powder X-ray diffraction pattern shown.

[0060] Furthermore, the third aspect of the present invention provides the use of any one of the compounds of the first aspect of the present invention in the preparation of a medicament for the following diseases or conditions:

[0061] Bleeding from peptic ulcer and anastomotic ulcer;

[0062] Acute gastric mucosal damage during stress and acute gastric mucosal damage caused by nonsteroidal anti-inflammatory drugs;

[0063] Preventing stress caused by severe diseases (such as cerebral hemorrhage, severe trauma, etc.) and upper gastrointestinal bleeding caused by gastric surgery, etc.;

[0064] As an alternative treatment for the following conditions when oral therapy is not appropriate: duodenal ulcer, gastric ulcer, reflux esophagitis and Zollinger-Ellison syndrome.

[0065] Furthermore, the fourth aspect of the present invention provides a freeze-dried powder injection composition of omeprazole sodium for injection, which comprises: 40 parts by weight of omeprazole sodium, 4 to 6 parts by weight of edetate disodium, and an appropriate amount of sodium hydroxide.

[0066] According to the freeze-dried powder injection composition of the fourth aspect of the present invention, the amount of sodium hydroxide used is such that when the composition is dissolved in water for injection to form a solution containing 4 mg / ml of omeprazole, the pH value of the solution is 10.1-11.1, especially the pH value is 10.3-10.7, and especially the pH value is 10.4-10.6.

[0067] According to the freeze-dried powder injection composition of the fourth aspect of the present invention, the concentration of omeprazole sodium in terms of omeprazole in the drug solution before freeze-drying is 17.5-22.5 mg / ml, for example, 20 mg / ml.

[0068] According to the fourth aspect of the freeze-dried powder injection composition of the present invention, the moisture content thereof is less than 6% as measured by the moisture determination method of Method 1, Part 0832, General Rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0069] The freeze-dried powder injection composition according to the fourth aspect of the present invention is sealed in a glass bottle, and the omeprazole sodium in each bottle is 10-100 mg, especially 20-80 mg, especially 20-60 mg, especially 20-40 mg, especially 20 mg or 40 mg, calculated as omeprazole.

[0070] The freeze-dried powder injection composition according to the fourth aspect of the present invention is sealed in a glass bottle, and the bottle is filled with nitrogen at a pressure of 400-500mba.

[0071] According to the freeze-dried powder injection composition of the fourth aspect of the present invention, the omeprazole sodium used as the raw material is the omeprazole sodium described in any one of the first aspect of the present invention, or the omeprazole sodium prepared by the method described in any one of the second aspect of the present invention.

[0072] According to the fourth aspect of the freeze-dried powder injection composition of the present invention, the liquid composition before freeze-drying is:

[0073] Omeprazole sodium (calculated as omeprazole) 35-45 mg, for example 40 mg,

[0074] Edetate disodium 0.4-0.6 mg, for example 0.5 mg,

[0075] Sodium hydroxide (used to adjust the pH value so that the pH value of the powder injection is 10.1 to 11.1, for example, 10.3 to 10.7, when the pH value of the drug solution is diluted with water for injection to a concentration of 4 mg / ml),

[0076] 2ml of water for injection.

[0077] The freeze-dried powder injection composition according to the fourth aspect of the present invention is prepared according to a method comprising the following steps:

[0078] (i) dissolving edetate disodium in about 80-90% of the prescribed amount of water for injection, and adding (2M) sodium hydroxide solution to adjust the pH of the solution to 9.0-9.5;

[0079] (ii) adding a prescribed amount of omeprazole sodium, such as any one of the first aspects of the present invention, to dissolve, adding 0.1% (w / v) activated carbon by volume of the solution, stirring for 30 minutes, filtering to remove carbon, adding water for injection to a volume close to the full amount of the prescription, adding (2M) sodium hydroxide solution to adjust the pH value of the solution (so that the pH value of the solution is 10.4 to 10.6 when diluted with water for injection to a concentration of 4 mg / ml of the active ingredient), and then adding water for injection to the full amount of the prescription;

[0080] (iii) filtering the obtained drug solution first with a 0.45 μm microporous membrane and then twice with a 0.22 μm microporous membrane, and then filling 1 to 2 ml of the drug solution into vials and half-stoppering them;

[0081] (iv) The drug solution is sent into a freeze dryer, and the air atmosphere in the freeze drying chamber is replaced with nitrogen. The freeze drying is performed according to the freeze drying curve B described in CN104666255A until the moisture content is less than 5.5%. Dry nitrogen is then filled into the freeze drying chamber to a pressure of 400-500 mba, and then the rubber stopper is sealed by hydraulic stoppering and an aluminum cap is pierced to obtain an omeprazole freeze-dried powder injection composition for injection.

[0082] According to the freeze-dried powder injection composition of the fourth aspect of the present invention, in the preparation step (ii), omeprazole sodium is first prepared according to any method described in the second aspect of the present invention, and then raw materials are added to prepare the powder injection composition.

[0083] Furthermore, the fifth aspect of the present invention provides a method for preparing a freeze-dried powder injection composition of omeprazole sodium for injection, wherein the liquid composition of the freeze-dried powder injection composition before freeze-drying is:

[0084] Omeprazole sodium (calculated as omeprazole) 35-45 mg, for example 40 mg,

[0085] Edetate disodium 0.4-0.6 mg, for example 0.5 mg,

[0086] Sodium hydroxide (used to adjust the pH value so that the pH value of the powder injection is 10.1 to 11.1, for example, 10.3 to 10.7, when the pH value of the drug solution is diluted with water for injection to a concentration of 4 mg / ml),

[0087] Water for injection 2ml;

[0088] The method comprises the following steps:

[0089] (i) dissolving edetate disodium in about 80-90% of the prescribed amount of water for injection, and adding (2M) sodium hydroxide solution to adjust the pH of the solution to 9.0-9.5;

[0090] (ii) adding a prescribed amount of omeprazole sodium, such as any one of the first aspects of the present invention, to dissolve, adding 0.1% (w / v) activated carbon by volume of the solution, stirring for 30 minutes, filtering to remove carbon, adding water for injection to a volume close to the full amount of the prescription, adding (2M) sodium hydroxide solution to adjust the pH value of the solution (so that the pH value of the solution is 10.4 to 10.6 when diluted with water for injection to a concentration of 4 mg / ml of the active ingredient), and then adding water for injection to the full amount of the prescription;

[0091] (iii) filtering the obtained drug solution first with a 0.45 μm microporous membrane and then twice with a 0.22 μm microporous membrane, and then filling 1 to 2 ml of the drug solution into vials and half-stoppering them;

[0092] (iv) The drug solution is sent into a freeze dryer, and the air atmosphere in the freeze drying chamber is replaced with nitrogen. The freeze drying is performed according to the freeze drying curve B described in CN104666255A until the moisture content is less than 5.5%. Dry nitrogen is then filled into the freeze drying chamber to a pressure of 400-500 mba, and then the rubber stopper is sealed by hydraulic stoppering and an aluminum cap is pierced to obtain an omeprazole freeze-dried powder injection composition for injection.

[0093] According to the method of the fifth aspect of the present invention, in step (ii), omeprazole sodium is first prepared according to any method described in the second aspect of the present invention, and then the raw materials are added to prepare the powder injection composition.

[0094] According to the method of the fifth aspect of the present invention, the freeze-dried powder injection composition of omeprazole sodium for injection prepared therefrom comprises: 40 parts by weight of omeprazole sodium, 4-6 parts by weight of edetate disodium, and an appropriate amount of sodium hydroxide.

[0095] According to the method of the fifth aspect of the present invention, the amount of sodium hydroxide used in the freeze-dried powder injection composition of omeprazole sodium for injection prepared therefrom is such that when the composition is dissolved in water for injection to form a solution containing 4 mg / ml of omeprazole, the pH value of the solution is 10.1-11.1, especially the pH value is 10.3-10.7, especially the pH value is 10.4-10.6.

[0096] According to the method of the fifth aspect of the present invention, the freeze-dried powder injection composition of omeprazole sodium for injection prepared therefrom has a concentration of omeprazole sodium calculated as omeprazole in the liquid before freeze-drying of 17.5-22.5 mg / ml, for example 20 mg / ml.

[0097] According to the method of the fifth aspect of the present invention, the freeze-dried powder injection composition of omeprazole sodium for injection prepared thereby has a moisture content of less than 6% as determined by the moisture determination method of Method 1, Part 0832, General Rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0098] According to the method of the fifth aspect of the present invention, the freeze-dried powder injection composition of omeprazole sodium for injection prepared therefrom is sealed in a glass bottle, and the omeprazole sodium in each bottle is 10-100 mg, especially 20-80 mg, especially 20-60 mg, especially 20-40 mg, especially 20 mg or 40 mg, calculated as omeprazole.

[0099] According to the method of the fifth aspect of the present invention, the freeze-dried powder injection composition of omeprazole sodium for injection prepared therefrom is sealed with a glass bottle, and the bottle is filled with nitrogen at a pressure of 400-500mba.

[0100] According to the method of the fifth aspect of the present invention, the omeprazole sodium used as the raw material is the omeprazole sodium described in any one of the first aspect of the present invention, or the omeprazole sodium prepared by the method described in any one of the second aspect of the present invention.

[0101] Furthermore, the sixth aspect of the present invention provides the use of the freeze-dried powder injection composition of omeprazole sodium for injection according to any one of the fourth aspects of the present invention in the preparation of medicines for the following diseases or conditions:

[0102] Bleeding from peptic ulcer and anastomotic ulcer;

[0103] Acute gastric mucosal damage during stress and acute gastric mucosal damage caused by nonsteroidal anti-inflammatory drugs;

[0104] Preventing stress caused by severe diseases (such as cerebral hemorrhage, severe trauma, etc.) and upper gastrointestinal bleeding caused by gastric surgery, etc.;

[0105] As an alternative treatment for the following conditions when oral therapy is not appropriate: duodenal ulcer, gastric ulcer, reflux esophagitis and Zollinger-Ellison syndrome.

[0106] According to any aspect of the present invention, especially the first aspect, the omeprazole sodium which can be used as a pharmaceutical raw material is measured according to the moisture determination method of 0832, Method 1, General Rules of Part Four of the 2020 Edition of the Chinese Pharmacopoeia, and its moisture content is less than 2%, preferably less than 1.5%, preferably less than 1%, and preferably less than 0.5%.

[0107] In the steps of the above-mentioned preparation method of the present invention, although the specific steps described therein are different from the steps described in the preparation examples in the specific implementation mode part below in some details or language descriptions, those skilled in the art can fully summarize the above-mentioned method steps based on the detailed disclosure of the full text of the present invention.

[0108] Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical features in other embodiments, as long as they do not conflict.

[0109] The present invention is further described below.

[0110] All documents cited in the present invention are incorporated herein by reference in their entirety, and if the meanings expressed in these documents are inconsistent with the present invention, the description of the present invention shall prevail. In addition, the various terms and phrases used in the present invention have the general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases. If the terms and phrases mentioned are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail.

[0111] The omeprazole sodium freeze-dried powder injection prepared by the present invention can be administered by injection, for example, it can be dissolved in 100 ml of 0.9% sodium chloride injection or 100 ml of 5% glucose injection and intravenously dripped. 40 mg at a time can be intravenously dripped in 20 to 30 minutes or longer, 1 to 2 times a day. Zollinger-Ellison syndrome patients may require a higher daily dose, and the dose should be individualized. It is recommended to drip 60 mg intravenously as a starting dose, once a day, and when the daily dose exceeds 60 mg, it is given twice. Dissolution and dilution with other solvents or drugs are prohibited. The omeprazole sodium freeze-dried powder injection prepared by the present invention is usually prepared by completely dissolving 40 mg of the active drug in 100 ml of 0.9% sodium chloride injection or 100 ml of 5% glucose injection. After being dissolved in 5% glucose injection, it should be used within 6 hours, and after being dissolved in 0.9% sodium chloride injection, it can be used within 12 hours. Intravenous drip can be started immediately after preparation.

[0112] Omeprazole is a racemic mixture of a pair of active optical enantiomers. It reduces gastric acid secretion through a highly targeted mechanism of action and is a special inhibitor of the acid pump in gastric parietal cells. This product acts rapidly, and a once-daily dose can reversibly inhibit gastric acid secretion. Omeprazole is a weakly alkaline substance that is concentrated and converted into active substances in the highly acidic environment of the tubules in gastric parietal cells, inhibiting H+, K+-ATPase (proton pump). This inhibitory effect on the final step of gastric acid formation is dose-related, and highly inhibits basal gastric acid secretion and irritant gastric acid secretion, but has nothing to do with irritants. Intravenous administration of omeprazole in humans inhibits gastric acid secretion in a dose-related manner. In order to quickly achieve the same effect of reducing gastric acidity as multiple oral administrations of 20 mg, it is recommended to give 40 mg of omeprazole intravenously for the first time. Intravenous injection of 40 mg of omeprazole rapidly reduces gastric acidity, with an average decrease of 90% within 24 hours. The inhibitory effect of omeprazole on gastric acid secretion is related to the area under the drug-time curve (AUC), but has nothing to do with the blood drug concentration at the time of administration. Helicobacter pylori is associated with acid peptic diseases, including duodenal ulcers and gastric ulcers, with 95% and 70% of duodenal ulcers and gastric ulcers, respectively, being associated with Helicobacter pylori infection. Helicobacter pylori is the main cause of gastritis. Helicobacter pylori and gastric acid together are the main causes of peptic ulcers. Omeprazole combined with antibiotics can eradicate Helicobacter pylori, which is associated with rapid relief of symptoms, high rates of gastric mucosal repair, and long-term remission of peptic ulcer disease, thereby reducing complications such as gastrointestinal bleeding and the need for long-term treatment with anti-acid drugs. Any method, including the reduction of gastric acid caused by proton pump inhibitors, increases the number of normal flora in the gastrointestinal tract. Treatment with acid-suppressing drugs may slightly increase the risk of gastrointestinal infection with Salmonella and Campylobacter. In studies of rats given long-term omeprazole, enlargement of gastric ECL cells and benign tumors were observed, which is the result of persistent hypergastrinemia due to gastric acid suppression. Similar findings were also seen after treatment with H2 receptor antagonists, proton pump inhibitors, and partial fundus resection. Apparently, these changes were not a direct effect of the above drugs.

[0113] In terms of the pharmacokinetics of omeprazole sodium, the volume of distribution in healthy people is about 0.3L / kg, and patients with renal insufficiency also have a similar volume of distribution. The volume of distribution in the elderly or patients with hepatic insufficiency is slightly lower, and the plasma protein binding rate is about 95%. Regarding metabolism and excretion, the average terminal phase half-life of the drug-time curve of intravenous administration of omeprazole is about 40 minutes, and the total plasma clearance rate is 0.3-0.6L / min. The half-life does not change during treatment. Omeprazole is mainly completely metabolized by the cytochrome P450 (CYP) enzyme system in the liver. Among them, it mainly relies on the specific isoform CYP2C19 (S-mephenytoin hydroxylase), the genetic expression of which is polymorphic. Omeprazole is catalyzed by CYP2C19 to produce hydroxyomeprazole, which is the main metabolite in plasma. In view of this, omeprazole and other substrates of CYP2C19 may produce metabolic drug-drug interactions due to competitive inhibition. Omeprazole metabolites have no effect on gastric acid secretion. About 80% of the intravenous dose is excreted in the urine as metabolites, and the rest is mainly secreted by bile and excreted in the feces. The clearance of omeprazole in patients with renal failure is unchanged, and the elimination half-life is increased in patients with liver impairment, but no accumulation of omeprazole is observed with a once-daily oral dose.

[0114] As described in the context of the present invention, the omeprazole sodium and the omeprazole sodium freeze-dried powder for injection prepared by the present invention have excellent properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0115] Figure 1 :X-ray powder diffraction (XRPD) pattern of omeprazole sodium DETAILED DESCRIPTION

[0116] The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be appreciated by those skilled in the art that various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. The present invention provides general and / or specific descriptions of the materials and test methods used in the test. Although many materials and operating methods used to achieve the purpose of the present invention are well known in the art, the present invention is still described in as much detail as possible at this point.

[0117] Example 1: Preparation of Omeprazole Sodium

[0118] (a) 14.8 g (0.37 mol) of sodium hydroxide was added to 60 ml of glycerol (35° C.) and dissolved;

[0119] (b) 120.9 g (0.35 mol) of omeprazole and 450 ml of a mixed solvent of acetone-glycerol (4:1, v / v) were added to a three-necked reaction flask, and the mixture was stirred at 42-45° C. for 30 min. Then, sodium hydroxide solution was added under heat preservation and stirring conditions, and the mixture was stirred for 2 hours. 6 g of 3A molecular sieve was added, and the mixture was stirred for 1 hour. The mixture was filtered, and the filter was washed with 20 ml of acetone. The filtrate and the washing solution were combined to obtain a mixed solution.

[0120] (c) The mixed solution was cooled to 26-28°C and allowed to stand for 4 hours. The mixture was then stirred for 5 minutes and allowed to stand at -8-5°C for 24 hours. The mixture was filtered and washed twice with 50 ml of cold acetone (-5°C). The mixture was dried at 50°C for 4 hours to obtain 103.6 g of a white crystalline powder with a yield of 80.6% and a melting point of 170.2-170.9°C.

[0121] Example 2: Preparation of Omeprazole Sodium

[0122] (a) 14.8 g (0.37 mol) of sodium hydroxide was added to 70 ml of glycerol (32° C.) and dissolved;

[0123] (b) 120.9 g (0.35 mol) of omeprazole and 450 ml of a mixed solvent of acetone-glycerol (3.8:1, v / v) were added to a three-necked reaction flask, and the mixture was stirred at 42-45° C. for 40 min. Then, a sodium hydroxide solution was added under heat preservation and stirring conditions, and the mixture was stirred for 2 hours. After adding 7 g of 3A molecular sieves, the mixture was stirred for 1 hour, and the mixture was filtered. The filter was washed with 20 ml of acetone, and the filtrate and the washing solution were combined to obtain a mixed solution.

[0124] (c) The mixed solution was cooled to 26-28°C and allowed to stand for 3 hours. The mixture was then stirred for 5 minutes and allowed to stand at -8-5°C for 28 hours. The mixture was filtered and washed twice with 50 ml of cold acetone (-5°C). The mixture was dried at 50°C for 3 hours to obtain 102.9 g of a white crystalline powder with a yield of 80.0% and a melting point of 170.4-171.2°C.

[0125] Example 3: Preparation of Omeprazole Sodium

[0126] (a) 14.8 g (0.37 mol) of sodium hydroxide was added to 50 ml of glycerol (38° C.) and dissolved;

[0127] (b) 120.9 g (0.35 mol) of omeprazole and 450 ml of a mixed solvent of acetone-glycerol (4.2:1, v / v) were added to a three-necked reaction flask, and the mixture was stirred at 42-45° C. for 25 min. Then, sodium hydroxide solution was added under heat preservation and stirring conditions, and the mixture was stirred for 2 hours. 5 g of 3A molecular sieve was added, and the mixture was stirred for 1 hour. The mixture was filtered, and the filter was washed with 20 ml of acetone. The filtrate and the washing solution were combined to obtain a mixed solution.

[0128] (c) The mixed solution was cooled to 26-28°C and allowed to stand for 5 hours. The mixture was then stirred for 5 minutes and allowed to stand at -8-5°C for 22 hours. The mixture was filtered and washed twice with 50 ml of cold acetone (-5°C). The mixture was dried at 50°C for 6 hours to obtain 104.4 g of a white crystalline powder with a yield of 81.2% and a melting point of 170.1-170.7°C.

[0129] Example 4: Preparation of Omeprazole Sodium

[0130] (a) 148 g (3.7 mol) of sodium hydroxide was added to 600 ml of glycerol (35° C.) and dissolved;

[0131] (b) Add 1209 g (3.5 mol) of omeprazole and 4500 ml of a mixed solvent of acetone-glycerol (4:1, v / v) to a three-necked reaction flask, stir at 42-45° C. for 45 min, then add sodium hydroxide solution and stir for 2 hours under heat preservation and stirring conditions, add 6 g of 3A molecular sieve and stir for 1 hour, filter, wash the filter with 250 ml of acetone, combine the filtrate and the washing solution to obtain a mixed solution;

[0132] (c) The mixed solution was cooled to 26-28°C and allowed to stand for 5 hours. The mixture was then stirred for 10 minutes and allowed to stand at -8-5°C for 28 hours. The mixture was filtered and washed twice with 500 ml of cold acetone (-5°C). The mixture was dried at 50°C for 6 hours to obtain 1017.2 g of a white crystalline powder with a yield of 79.1% and a melting point of 170.3-171.4°C.

[0133] Example 11: Referring to Example 1, the only difference is that the glycerol used in step (a) is replaced by an equal volume of acetone (38°C), and 450 ml of acetone is used as the solvent in step (b) instead of a mixed solvent. The remaining operations and conditions are the same, and 82.4 g of white crystalline powder is obtained with a yield of about 64% and a melting point of 170.6-171.3°C. The results show that when acetone is used instead of glycerol in the two steps, although the melting point of the product is the same as in Example 1, its yield is significantly reduced.

[0134] Example 12: Referring to Example 1, the only difference is that the glycerol used in step (a) is replaced by an equal volume of isopropanol, and 450 ml of isopropanol-glycerol (4:1, v / v) mixed solvent is used in step (b), and the remaining operations and conditions are the same, to obtain 105.8 g of white crystalline powder with a yield of about 82% and a melting point of 162.4-164.1°C; the melting point is significantly lower than that of the product in Example 1, indicating that its crystal form is different from the product in Example 1.

[0135] Example 13: Referring to Example 1, the only difference is that in step (c), the mixed solution is directly cooled to -8 to -5°C and allowed to stand for 28 hours, instead of being allowed to stand at 26°C for 4 hours. 95.6 g of white crystalline powder is obtained with a yield of about 74% and a melting point of 171.2 to 175.9°C. Compared with Example 1, the yield of Example 13 is significantly lower, and the product has a wide melting range, indicating that there may be multiple forms of crystals.

[0136] Example 14: This example uses a reference method to prepare omeprazole sodium. A solution containing 13.2 g of sodium hydroxide (0.33 mol) (dissolved in 26.7 g of water), 120 g of omeprazole (0.347 mol), and 480 ml of isopropyl ketone are added to a three-necked reaction flask. The resulting slurry is stirred for 40 minutes at room temperature and then filtered. The filter is washed with 20 ml of isopropyl alcohol, and the isopropyl alcohol washings and the filtrate are combined to obtain a mixed solution; 6 g of type B omeprazole sodium (dissolved in 25 ml of isopropyl alcohol) is used to seed the above-mentioned mixture; the slurry is stirred for 25 hours, the product is filtered, and dried at 40°C for 6 hours to obtain 105.2 g of a white crystalline powder with a yield of about 82.5% and a melting point of 166.3 to 167.1°C.

[0137] Test Example 1: Testing the quality of omeprazole sodium

[0138] Unless otherwise specified, this test example refers to the items under Omeprazole Sodium on page 1679 of Part II of the 2020 edition of the Chinese Pharmacopoeia, and detects Examples 1 to 4 and Examples 11 to 14 as well as a commercially available product (Omeprazole Sodium API produced and sold by a certain enterprise in Nanjing). The detection method and some results are as follows:

[0139] Properties: All samples were white crystalline powder and odorless when observed with the naked eye.

[0140] Solubility: Water, ethanol and dichloromethane were used as solvents for the test. All samples were found to be easily soluble in water, slightly soluble in methanol and slightly soluble in dichloromethane.

[0141] Identification 1: Absorbance ratio. All samples have maximum absorption at wavelengths of 305 nm and 276 nm, and their absorbance ratios are all in the range of 1.66 to 1.75. For example, the absorbance ratio of the sample in Example 1 = 1.71.

[0142] Identification 2: Infrared absorption spectrum, tested using KBr tablet method, all samples are about (±3cm -1 ) at 1615cm -1 、1570cm -1 、1480cm -1 、1385cm -1 、1270cm -1 、1205cm -1、1155cm -1 、1080cm -1 、1035cm -1 、845cm -1 、810cm -1 There are characteristic peaks.

[0143] Identification 3: The results of the determination according to the method in General Rules 0301 of Part IV of the 2020 edition of the Chinese Pharmacopoeia showed that all tested samples showed the reaction of sodium salt identification (1).

[0144] Alkalinity: Take 0.20 g of the test sample and add 10 ml of water to dissolve it. According to the method described in 0631 of the General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia, the pH value of each sample is in the range of 10.3 to 11.3. For example, the pH values ​​of the samples in Example 1 and Example 14 are 10.81 and 10.63, respectively.

[0145] Solution clarity and color: Take 0.20g of the test sample and add 10ml of water to dissolve it. The results show that the solutions of all samples are clear and colorless.

[0146] Heavy metals: Take 1.0g of the test sample and measure it according to the method described in Method 0821, Part IV, General Rules, Method 3, Chinese Pharmacopoeia 2020 Edition. The heavy metal content of all samples is less than 10 parts per million.

[0147] Residual solvents: According to the residual solvent determination method of the second method of 0861 of the fourth general rules of the 2020 edition of the Chinese Pharmacopoeia, the reference mixed solution contains methanol, ethanol, ethyl acetate, acetone, dichloromethane, glycerol, and isopropanol at appropriate concentrations (determined by preliminary tests); as a result, the residual amounts of the above seven solvents in all samples met the limits specified in the Pharmacopoeia, for example, the acetone and glycerol in the sample of Example 1 were both <0.01%, indicating that the residual solvent amount of omeprazole sodium prepared by the present invention is extremely low.

[0148] Moisture content: Take a sample of this product for testing and determine the moisture content according to the method for determining moisture in Method 1, Part 0832, General Rules of Part 4 of the 2020 edition of the Chinese Pharmacopoeia.

[0149] Content determination: Take about 0.3g of the test sample, weigh it accurately, add 50ml of water to dissolve it, and determine it according to the potentiometric titration method in 0701 of the General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia. Titrate with hydrochloric acid titrant (0.1mol / L), and calculate the content based on 1ml of hydrochloric acid titrant (0.1mol / L) being equivalent to 36.74mg of C17H18N3NaO3S.

[0150] Related substances: refer to the method under the related substances inspection of omeprazole sodium in the European Pharmacopoeia 10.0;

[0151] Test solution: Dissolve 3 mg of the test sample in mobile phase and dilute to 25.0 mL.

[0152] Reference solution (a): Dissolve 1 mg of omeprazole reference substance and 1 mg of omeprazole impurity D reference substance in mobile phase and dilute to 10.0 mL.

[0153] Control solution (b): dilute 1.0 mL of the test solution to 100.0 mL with mobile phase, and then dilute 1.0 mL of the solution to 10.0 mL with mobile phase.

[0154] Control solution (c): 3 mg of omeprazole peak identification reference (containing impurity E, Sigma Aldrich) was dissolved in the mobile phase and diluted to 25.0 mL;

[0155] Chromatographic column: octylsilane bonded silica gel as filler column (125mm×4.6mm, 5μm);

[0156] Mobile phase: a mixture of phosphate solution and acetonitrile in a volume ratio of 73:27, wherein the phosphate solution is a 1.4 g / L disodium hydrogen phosphate dodecahydrate solution and the pH value is adjusted to 7.6 with phosphoric acid;

[0157] Flow rate 1 mL / min, detection wavelength 280 nm, injection volume 40 μL;

[0158] Recording time: 5 times the retention time of omeprazole;

[0159] Impurity identification: Use the chromatogram attached to the omeprazole peak identification reference and the chromatogram obtained from the reference solution (c) to determine the impurity E peak, and use the chromatogram obtained from the reference solution (a) to determine the impurity D peak;

[0160] Relative retention time compared with omeprazole (retention time about 9 min): impurity E = about 0.6, impurity D = about 0.8;

[0161] System suitability test: Using control solution (a) for testing, the separation degree between impurity D and omeprazole is greater than 3.0. If necessary, the pH value of the aqueous phase or the concentration of acetonitrile can be adjusted;

[0162] Limits: European Pharmacopoeia stipulates that impurities D and E should be less than 0.15% (not more than 1.5 times the main peak area in the control solution (b)), other individual impurities should be less than 0.1%, and the sum of all impurities should be less than 0.5%. Impurities less than 0.025% are not counted;

[0163] in,

[0164] Impurity D is: 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfonyl]-1H-benzimidazole (omeprazole sulfone), and its structural formula is:

[0165]

[0166] Impurity E is: 4-methoxy-2-[[(RS)-(5-methoxy-1H-benzimidazol-2-yl)sulfinyl]methyl]-3,5-dimethylpyridine 1-oxide, and its structural formula is:

[0167] and its enantiomers.

[0168] The method of Test Example 1 was used to detect the moisture, content, and related substances of the omeprazole sodiums of Examples 1 to 4, the omeprazole sodiums of Examples 11 to 14, and the commercially available omeprazole sodium. The results are shown in Table 1.

[0169] Table 1:

[0170]

[0171] In the above table, * is the content result directly measured / calculated by potentiometric titration, # is the content result calculated according to the anhydrous substance, the theoretical crystal water content of omeprazole sodium monohydrate is 4.67%, and Example 14 and the commercially available product in the above table contain 1 crystal water and adsorbed water. The higher moisture content of the commercially available product may be related to the slightly longer storage time and water absorption. These data are confirmed in the provided drying loss percentage, where the drying loss is measured by drying to constant weight at 105°C according to the 0831 method of the general rules of the fourth part of the 2020 edition of the Chinese Pharmacopoeia.

[0172] Test Example 2: Hygroscopicity measurement

[0173] Take 5 grams of each sample in Table 1 and place them in a flat dish with a radius of 10 cm that has been dried to constant weight in advance, spread them evenly, weigh them accurately, and then place them in a sealed container with a relative humidity of 70% for 5 days, weigh them accurately, and take the percentage of the quotient obtained by dividing the moisture absorption weight by the initial sample weight as the moisture absorption rate.

[0174] As a result, the moisture absorption rates of the five samples of Examples 1 to 4 and Example 11 were all within the range of 1.17 to 1.34%. For example, the moisture absorption rate of the sample of Example 1 was 1.21%, the moisture absorption rates of the two samples of Examples 12 and 13 were 5.53% and 4.16%, respectively, and the moisture absorption rates of Example 14 and the commercial product were 7.53% and 8.31%, respectively. It can be seen that the monohydrate has obvious hygroscopicity, while the moisture absorption rates of the anhydrous substances obtained in Examples 1 to 4 and Example 11 are quite small. The two samples of Examples 12 to 13 are anhydrous substances in terms of water content and drying loss determination results, but their hygroscopicity is significantly higher than that of the samples of Example 1, etc., which may be related to their different crystal forms.

[0175] Test Example 3: Stability Study

[0176] The samples in Table 1 were placed in a sealed, light-proof environment at a temperature of 40°C and a relative humidity of 50% for 6 months. The moisture, content and related substances of the samples at 0 and 6 months were determined using the method of Test Example 1. In addition, the drying loss was determined to compare the moisture. The content calculated as anhydrous was the percentage obtained by dividing the content in 6 months by the content in 0 months and then multiplying it by 100% as the residual rate of active ingredients in 6 months. Results:

[0177] Regarding the moisture content in June, the moisture content of the five samples of Examples 1 to 4 and Example 11 is 1.35-1.53% (the drying loss is within the range of 1.26-1.45%). For example, the moisture content in June of the sample of Example 1 is 1.44% (the drying loss is 1.39%), the moisture content of the two samples of Examples 12 to 13 is 5.74% and 6.32% respectively (the drying loss is 3.42% and 3.87% respectively), and the moisture content of the two samples of Example 14 and the commercial product is 9.64% and 9.13% (the drying loss is 4.91% and 3.38% respectively), indicating that the samples of Examples 1 to 4 will not become hydrates even if they are placed for a long time, while the two samples of Examples 12 to 13 will partially generate hydrates according to the moisture content and drying loss results;

[0178] Regarding the residual rate of active ingredients, the five samples of Examples 1 to 4 and Example 11 were 98.73 to 99.84%. For example, the residual rate of the sample of Example 1 in 6 months was 99.63%, the residual rates of the two samples of Examples 12 to 13 in 6 months were 97.65% and 97.35%, and the residual rates of the two samples of Example 14 and the commercial product in 6 months were 97.28% and 97.52%;

[0179] The main changes of the relevant substances involve impurities D and E, so the results are characterized by the sum of the two (recorded as impurity DE). For each batch of samples, the difference obtained by subtracting the impurity DE in June from the impurity DE in October is divided by the impurity DE in June and then multiplied by 100% to obtain the percentage obtained as the impurity DE growth rate. The results are as follows: the impurity DE growth rate of the five samples of Examples 1 to 4 and Example 11 is within the range of 66 to 83%. For example, the impurity DE growth rate of the sample of Example 1 is 69.3%, and the sum of the two impurities of these samples does not exceed 0.3%. The impurity DE growth rates of the two samples of Examples 12 to 13 are 185.3% and 167.6%, respectively. The impurity DE growth rates of the two samples of Example 14 and the commercial product are 217.5% and 194.3%, respectively, and both exceed 0.3%. The above results show that some omeprazole sodium prepared by the present invention has excellent stability. The sample of Example 14 shows a certain degree of oxidation, which puts higher requirements on the storage conditions of the raw material.

[0180] Test Example 4: Testing of Omeprazole Sodium

[0181] This test example is to test the final product omeprazole sodium of Example 1 of the present invention.

[0182] Elemental analysis was performed using a Perkin Elmer 240B automatic elemental analyzer, and the results were consistent with the molecular formula of C17H18N3NaO3S. The theoretical values ​​of elemental analysis were: C 55.57%, H 4.94%, S 8.73%, N 11.44%, O13.06%, Na 6.26%; the measured values ​​were: C 55.53%, H4.96%, S 8.75%, N 11.40%, O 13.07%, Na6.29%.

[0183] Using the "A. Temperature Transfer Liquid Heating Method" of "0612 Melting Point Determination Method" in Part IV of the 2020 Edition of the Chinese Pharmacopoeia, the melting points of the final product omeprazole sodium of Examples 1 to 4 are all in the range of 170.1 to 171.4°C. It can be expected that the melting point range of the product obtained in the present invention is 169.0 to 172.0°C, for example, 169.5 to 172.0°C, preferably 170.0 to 171.5°C.

[0184] Determination of the X-ray powder diffraction (XRPD) characteristic pattern of the final product omeprazole sodium in Example 1: The XRPD pattern of omeprazole sodium was determined on an Ultima III X-ray powder diffractometer using Cu-Kα rays. The instrument was equipped with a fine focus X-ray tube, and the tube voltage and current were set to 40 kV and 40 mA, respectively. The emission slit and scattering slit were 1°, and the receiving slit was 0.3 mm. The diffraction lines were detected by a scintillation detector. The 2θ angle was continuously scanned from θ to 2θ at 5° / min from 3° to 50°. It is well known that fluctuations of + / -0.2° or + / -0.1° at the 2θ position are completely acceptable and recognized. The XRPD pattern of omeprazole sodium obtained in Example 1 is shown in FIG. Figure 1 , where the 2θ angles and relative intensities of typical diffraction peaks are shown in Table 2.

[0185] Table 2:

[0186] No. 2θ d-value I / Io I / Io (40℃-6 months) 1 9.460 9.3412 14 15 2 14.500 6.1037 100 100 3 18.900 4.6915 67 64 4 19.740 4.4937 7 8 5 20.160 4.4010 6 7 6 22.900 3.8803 8 7 7 24.000 3.7048 21 22 8 24.680 3.6043 8 7 9 26.020 3.4216 15 18 10 26.880 3.3141 33 30 11 27.440 3.2477 10 11 12 31.720 2.8186 13 12

[0187] More typical diffraction peaks are No. 1-7 and No. 9-10.

[0188] In addition, as shown in the stability study of Experimental Example 3, after the sample of Example 1 was placed at 40°C for 6 months, the XRPD was measured by the same method as above, and the 2θ and d-value were basically the same as those in Table 2 (the 2θ value fluctuated by + / -0.2° compared with Table 2), and their I / Io was shown in the fifth column of Table 2, indicating that the crystal form of Example 2 still maintained its original crystal form after long-term storage.

[0189] In the following specific examples of preparing powder injections, unless otherwise specified, the omeprazole sodium raw material used is prepared by the method of Example 1 of the present invention, having a melting point of about 170.5°C and an XRPD pattern similar to Figure 1 The same omeprazole sodium raw material. In the following specific examples of preparing powder injections, the units used to express the formula are schematic, and the omeprazole sodium added in each test is 200 g in terms of omeprazole.

[0190] Example 21: Preparation of Omeprazole Sodium Freeze-Dried Powder Injection

[0191] formula:

[0192] Omeprazole sodium (as omeprazole) 40 mg,

[0193] Edetate disodium 0.5mg,

[0194] Sodium hydroxide (used to adjust the pH value so that the pH value of the powder injection is 10.1-11.1, for example, 10.3-10.7, when the pH value of the drug solution is diluted with water for injection to a concentration of 4 mg / ml)

[0195] 2 ml of water for injection (used when preparing the solution, removed after freeze-drying).

[0196] Preparation method:

[0197] (i) dissolving edetate disodium in about 85% of the prescribed amount of water for injection, and adding (2M) sodium hydroxide solution to adjust the pH of the solution to 9.0-9.5;

[0198] (ii) Add the prescribed amount of omeprazole sodium to dissolve, add 0.1% (w / v) activated carbon according to the volume of the solution, stir for 30 minutes, filter to remove the carbon, add water for injection to nearly the full amount of the prescription, add (2M) sodium hydroxide solution to adjust the pH value of the solution (so that the pH value of the solution is 10.4-10.6 when diluted with water for injection to contain 4 mg / ml of active ingredient, the same below), and then add water for injection to the full amount of the prescription;

[0199] (iii) filtering the obtained drug solution through a 0.45 μm microporous membrane and then filtering it twice through a 0.22 μm microporous membrane, and then filling each bottle with 2 ml of the drug solution into 5 ml vials (or filling each bottle with 1 ml of the drug solution into each bottle with 3 ml vials so that each bottle contains 20 mg of omeprazole), and half-stoppering;

[0200] (iv) The drug solution is sent to a freeze dryer, and the air atmosphere in the freeze drying chamber is replaced with nitrogen. The freeze drying is performed according to the freeze drying curve B described in CN104666255A until the moisture content is less than 5.5%. Dry nitrogen is then filled into the freeze drying chamber to a pressure of 400-500 mba, and then the rubber stopper is sealed by hydraulic stoppering and an aluminum cap is pierced to obtain an omeprazole freeze-dried powder injection composition for injection containing 40 mg of omeprazole per bottle.

[0201] In the experimental liquid preparation process conducted in advance, the inventors have found that when the above embodiment 21 does not prepare the pH 9.0-9.5 disodium edetate solution in step (i), but directly adds about 85% water to dissolve disodium edetate and omeprazole sodium, it is necessary to adjust the pH value of the liquid to above 9.0 as soon as possible, otherwise the liquid is easy to change color, but it is easy to cause excessive addition of sodium hydroxide when the pH is adjusted as quickly as possible, and then it is necessary to use acid to adjust the pH of the liquid downward, which is not suitable for omeprazole sodium, which is highly sensitive to stability and pH. Therefore, it is beneficial to prepare the weak alkaline disodium edetate solution in step (i) in advance in this embodiment, and it is not easy to add too much alkali and need to adjust the pH in step (ii) and the subsequent operations.

[0202] In addition, in some preliminary tests, it has been found that freeze drying in step (iv) to reduce the moisture content to less than 5.5% is easy to achieve, but it is quite difficult to further reduce the moisture content, which may be related to the formation of monohydrate after omeprazole sodium is dehydrated in aqueous solution.

[0203] Since the solid content of the drug solution before freeze-drying in Examples 1 to 3 is only about 1.7 to 2.3% (generally, a regular and maintainable cake is more easily formed when the solid content is greater than 3%) and no excipient is added, the cake formed by freeze-drying may be easily broken, especially during the period from when the freeze-dried powder exits the freeze-drying chamber to when it is packed in boxes, hard collisions may occur between bottles, during processes such as aluminum capping and labeling machines, which may easily cause the freeze-dried cake in the bottle to break. The uneven appearance of the product caused by the breakage of freeze-dried cake in individual medicine bottles may cause unnecessary doubts or illusions about product defects to the medical staff who ultimately use the medicine, thereby adversely affecting the image of the product.

[0204] As shown in step (iv) of Example 21, after freeze drying, dry nitrogen is filled into the freeze drying chamber until the air pressure is 400-500mba, and then the rubber plug is sealed by hydraulic plugging, whereby the glass bottle is filled with nitrogen at about half an atmospheric pressure. It has been found that after this atmosphere treatment, the freeze-dried powder cake blocks can be prevented from being broken due to hard collisions during the period from when the powder injection exits the freeze drying chamber to before being boxed, so that the freeze-dried powder cake blocks maintain excellent integrity. More unexpectedly, the phenomenon that the above-mentioned sealed half-atmospheric pressure nitrogen treatment is conducive to maintaining excellent integrity of the freeze-dried powder cake blocks only occurs in the powder injection prepared by using the omeprazole sodium obtained by the method of Example 1 of the present invention as the raw material, while the omeprazole sodium raw material prepared by the prior art or the commercially available raw material shows obvious freeze-dried powder cake block breakage. These findings were obtained through the following observation method: in the process of preparing powder injections in Examples 21 to 27 of the present invention, after the vials were sealed with rubber stoppers in step (iv), they were removed from the freeze-drying chamber, and the integrity of the freeze-dried powder cakes of the whole batch of powder injections (the whole tray of neatly stacked medicines) was observed with the naked eye (since the transparent glass bottles were only stoppered at the bottle mouths, observation was very convenient), the number of broken bottles and the total number of bottles in the batch were recorded, and the breakage rate a (%, n = 4500 to 4800) was calculated; then the whole batch of powder injections was subjected to aluminum capping, labeling by a labeling machine (the label paper covered half of the bottles, which made it easy to observe the state of the freeze-dried powder cakes inside), etc. until boxing, each bottle was put into a small paper box, and the integrity of the freeze-dried powder cakes of each bottle was observed during the boxing process, the number of broken bottles and the total number of bottles counted were recorded, and the breakage rate b (% , n=2000-2200); As a result, the fragmentation rates a of the powder injections of Examples 21-27 were all within the range of 0-0.09%. For example, the fragmentation rate a of the powder injection of Example 21 was 0.042% (2 / 4730) and was between 0 and 4 bottles. The fragmentation rates b of the powder injections of Examples 21-23 were 0.51% (11 / 2150), 0.75% (16 / 2120) and 0.41% (9 / 2200), respectively. The fragmentation rates b of the powder injections of Examples 24-25 were 3.26% (71 / 2180) and 8.13% (174 / 2140), respectively. The fragmentation rates b of the powder injections of Examples 26-27 were 5.81% (125 / 2153) and 6.67% (138 / 2070), respectively. The data in brackets are the number of fragmentations / number of observed bottles.

[0205] Example 22: Preparation of Omeprazole Sodium Freeze-Dried Powder Injection

[0206] formula:

[0207] Omeprazole sodium (calculated as omeprazole) 35mg,

[0208] Edetate disodium 0.4mg,

[0209] Sodium hydroxide (used to adjust the pH value so that the pH value of the powder injection is 10.1-11.1, for example, 10.3-10.7, when the pH value of the drug solution is diluted with water for injection to a concentration of 4 mg / ml)

[0210] 2 ml of water for injection (used when preparing the solution, removed after freeze-drying).

[0211] Preparation method:

[0212] (i) dissolving edetate disodium in about 80% of the prescribed amount of water for injection, and adding (2M) sodium hydroxide solution to adjust the pH of the solution to 9.0-9.5;

[0213] (ii) Add the prescribed amount of omeprazole sodium to dissolve, add 0.1% (w / v) activated carbon according to the volume of the solution, stir for 30 minutes, filter to remove the carbon, add water for injection to nearly the full amount of the prescription, add (2M) sodium hydroxide solution to adjust the pH value of the solution (so that the pH value of the solution is 10.4-10.6 when diluted with water for injection to contain 4 mg / ml of active ingredient, the same below), and then add water for injection to the full amount of the prescription;

[0214] (iii) filtering the obtained drug solution through a 0.45 μm microporous membrane and then filtering it twice through a 0.22 μm microporous membrane, and then filling each bottle with 2 ml of the drug solution into 5 ml vials (or filling each bottle with 1 ml of the drug solution into each bottle with 3 ml vials so that each bottle contains 20 mg of omeprazole), and half-stoppering;

[0215] (iv) The drug solution is sent to a freeze dryer, and the air atmosphere in the freeze drying chamber is replaced with nitrogen. The freeze drying is performed according to the freeze drying curve B described in CN104666255A until the moisture content is less than 5.5%. Dry nitrogen is then filled into the freeze drying chamber to a pressure of 400-500 mba, and then the rubber stopper is sealed by hydraulic stoppering and an aluminum cap is pierced to obtain an omeprazole freeze-dried powder injection composition for injection containing 40 mg of omeprazole per bottle.

[0216] Example 23: Preparation of Omeprazole Sodium Freeze-Dried Powder Injection

[0217] formula:

[0218] Omeprazole sodium (calculated as omeprazole) 45mg,

[0219] Edetate disodium 0.6mg,

[0220] Sodium hydroxide (used to adjust the pH value so that the pH value of the powder injection is 10.1-11.1, for example, 10.3-10.7, when the pH value of the drug solution is diluted with water for injection to a concentration of 4 mg / ml)

[0221] 2 ml of water for injection (used when preparing the solution, removed after freeze-drying).

[0222] Preparation method:

[0223] (i) dissolving edetate disodium in about 90% of the prescribed amount of water for injection, and adding (2M) sodium hydroxide solution to adjust the pH of the solution to 9.0-9.5;

[0224] (ii) Add the prescribed amount of omeprazole sodium to dissolve, add 0.1% (w / v) activated carbon according to the volume of the solution, stir for 30 minutes, filter to remove the carbon, add water for injection to nearly the full amount of the prescription, add (2M) sodium hydroxide solution to adjust the pH value of the solution (so that the pH value of the solution is 10.4-10.6 when diluted with water for injection to contain 4 mg / ml of active ingredient, the same below), and then add water for injection to the full amount of the prescription;

[0225] (iii) filtering the obtained drug solution through a 0.45 μm microporous membrane and then filtering it twice through a 0.22 μm microporous membrane, and then filling each bottle with 2 ml of the drug solution into 5 ml vials (or filling each bottle with 1 ml of the drug solution into each bottle with 3 ml vials so that each bottle contains 20 mg of omeprazole), and half-stoppering;

[0226] (iv) The drug solution is sent to a freeze dryer, and the air atmosphere in the freeze drying chamber is replaced with nitrogen. The freeze drying is performed according to the freeze drying curve B described in CN104666255A until the moisture content is less than 5.5%. Dry nitrogen is then filled into the freeze drying chamber to a pressure of 400-500 mba, and then the rubber stopper is sealed by hydraulic stoppering and an aluminum cap is pierced to obtain an omeprazole freeze-dried powder injection composition for injection containing 40 mg of omeprazole per bottle.

[0227] Example 24: Refer to the formulation and preparation method of Example 21, except that after freeze-drying in step (iv) to a moisture content of less than 5.5%, nitrogen is not injected but the bottle is directly stoppered and covered with an aluminum cap (the air pressure in the bottle is less than 10 mba) to obtain an omeprazole freeze-dried powder injection composition for injection containing 40 mg of omeprazole in each bottle.

[0228] Example 25: Refer to the formulation and preparation method of Example 21, except that in step (iv), after freeze-drying to a moisture content of less than 5.5%, nitrogen is introduced until the pressure in the freeze-drying chamber reaches 1 atmosphere (1013 mba), followed by plugging and sealing with an aluminum cap to obtain an omeprazole freeze-dried powder injection composition for injection containing 40 mg of omeprazole in each bottle.

[0229] Example 26: Referring to the formula and preparation method of Example 21, the only difference is that the omeprazole sodium obtained in Example 14 of the present invention is used as the raw material to obtain an omeprazole freeze-dried powder injection composition for injection containing 40 mg of omeprazole in each bottle.

[0230] Example 27: Referring to the formulation and preparation method of Example 21, the only difference is that the commercially available omeprazole sodium described herein is used as the raw material to obtain an omeprazole freeze-dried powder injection composition for injection containing 40 mg of omeprazole per bottle.

[0231] Test Example 11: Testing the Quality of Freeze-dried Powder Injection of Omeprazole Sodium for Injection

[0232] Unless otherwise specified, this test example refers to the items under Omeprazole Sodium for Injection on page 1681 of Part II of the 2020 edition of the Chinese Pharmacopoeia, and tests the powder injections obtained in Examples 21 to 23 and Examples 24 to 27. The test method and some results are as follows:

[0233] Properties: All samples were observed by naked eyes to be white loose lumps.

[0234] Identification 1: In the chromatogram recorded under the assay, the retention time of the main peak of the test solution is consistent with the retention time of the main peak of the reference solution.

[0235] Identification 2: All samples have maximum absorption at wavelengths of 305nm and 276nm, and their absorbance ratios are all in the range of 1.62 to 1.76. For example, the absorbance ratio of the sample in Example 21 = 1.69.

[0236] Identification 3: The results of the determination according to the method in General Rules 0301 of Part IV of the 2020 edition of the Chinese Pharmacopoeia showed that all tested samples showed the reaction of sodium salt identification (1).

[0237] Clarity and color of the solution: Take 5 bottles of each batch of test samples (containing 0.20g of omeprazole sodium), dissolve them in water and make a solution containing about 4.0mg of omeprazole per 1ml. The results show that the solutions of each sample are clear, and the absorbance measured at 440nm is less than 0.05.

[0238] Alkalinity: The clarity and color of the solution were determined according to the method described in General Rules 0631 of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The pH values ​​of the samples were all in the range of 10.2 to 10.8. For example, the pH value of the sample in Example 21 was 10.51.

[0239] Related substances: According to the determination method of related substances in Test Example 1 of the present invention, the concentration of the test solution is 0.12 mg / ml. The impurity D of the powder injection obtained in Examples 21 to 25 is within the range of 0.13 to 0.22%, and the impurity E is within the range of 0.14 to 0.19%. The impurity D of the powder injection obtained in Examples 26 to 27 is within the range of 0.27 to 0.31%, and the impurity E is within the range of 0.25 to 0.33%. For example, the impurity D of the powder injection in Example 21 is 0.18%, and the impurity E is 0.16%. The impurities of omeprazole sodium raw materials and powder injections are mainly reflected in impurities D and E, so they are focused on.

[0240] Moisture: Take the test samples and determine the moisture content of all samples in the range of 5.02-5.41% according to the moisture determination method of 0832 Method 1 of the General Rules of Part 4 of the 2020 Edition of the Chinese Pharmacopoeia. For example, the moisture content of the powder injection in Example 21 is 5.18%.

[0241] Content determination: According to the pharmacopoeia method, all samples contained omeprazole sodium in the range of 98-102% of the labeled amount as omeprazole. For example, the content of the powder injection in Example 21 was 99.46%.

[0242] Test Example 12: Stability Study

[0243] The powder injections obtained in Examples 21 to 23 and Examples 24 to 27 were placed in a dark environment at 40°C for 6 months, and the changes in their moisture content, content and related substances at 0 and 6 months were determined using the method of Test Example 11. Results: The moisture content of the six samples of Examples 21-23 and Examples 25-27 in June was within the range of 5.23-5.74%. For example, the moisture content of the powder injection of Example 21 in June was 5.49%, and the moisture content of the powder injection of Example 24 in June was 7.46%, which exceeded the range specified in the pharmacopoeia standard, indicating that maintaining the drug in a vacuum is prone to moisture absorption, while no obvious moisture absorption will occur in a semi-vacuum or normal pressure state; the labeled percentage content of the powder injection was calculated based on the anhydrous substance. For each sample, the percentage content in June was divided by the labeled percentage content in October and then multiplied by 100% to obtain the percentage as the residual rate of the active ingredient in June. After measurement, the four samples of Examples 21-23 and Example 25 were 97.2-99.1%. For example, the residual rate of the sample of Example 1 in June was 98.86%, and the residual rates of the three samples of Examples 24 and Examples 26-27 in June were 93.31%, 96.47% and 97.14%, respectively. The residual rate of Example 24 is significantly lower, which may be related to the increase in moisture; the sum of impurities D and E (recorded as impurity DE) is used to characterize the change of related substances. For each batch of samples, the difference between impurity DE in June and impurity DE in October is divided by impurity DE in June and then multiplied by 100% to obtain the percentage obtained as the impurity DE growth rate. As a result, the impurity DE growth rate of the four samples of Examples 21 to 23 and Example 25 is within the range of 67 to 84%. For example, the impurity DE growth rate of the sample of Example 21 is 74.3%, and the sum of the two impurities of these samples does not exceed 0.5%. The impurity DE growth rates of the three samples of Example 24 and Example 26 to 27 are 236.4%, 186.5% and 195.7% respectively. The impurity DE of Example 24 is significantly higher, which may be related to the increase in moisture, and the impurity DE of Examples 26 to 27 has increased more, which may be related to the high content of basic impurity DE in its raw material medicine, thereby inducing its formation. The above stability results show that the powder injection prepared by the raw material medicine characterized by the present invention and the preparation method of the present invention has many advantages.

[0244] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. A freeze-dried powder injection composition of omeprazole sodium for injection, comprising: 35-45 parts by weight of omeprazole sodium, 0.4-0.6 parts by weight of edetate disodium, and an appropriate amount of sodium hydroxide; the freeze-dried powder injection composition is sealed in a glass bottle, and the bottle is filled with nitrogen at a pressure of 400-500mba; wherein, The amount of sodium hydroxide used is such that when the composition is dissolved in water for injection to form a solution containing 4 mg / ml of omeprazole, the pH value of the solution is 10.1-11.1; The melting point of omeprazole sodium is 169.0-172.0°C according to "0612 Melting Point Determination Method" "A. Temperature Transfer Liquid Heating Method" of Part IV of the 2020 edition of the Chinese Pharmacopoeia; The water content of the omeprazole sodium is less than 2% as determined by the water content determination method of Method 1, Part 0832, General Rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia; The omeprazole sodium uses Cu-Kα radiation, and in the powder X-ray diffraction pattern represented by 2θ angles, there are diffraction peaks at 9.46°±0.20°, 14.50°±0.20°, 18.90°±0.20°, 19.74°±0.20°, 20.16°±0.20°, 22.90°±0.20°, 24.00°±0.20°, 26.02°±0.20°, and 26.88°±0.20°.

2. The freeze-dried powder injection composition according to claim 1, wherein the amount of sodium hydroxide is such that the pH value of the solution is 10.3-10.7 when the composition is dissolved in water for injection to a concentration of 4 mg / ml of omeprazole.

3. The freeze-dried powder injection composition according to claim 1, wherein the amount of sodium hydroxide is such that the pH value of the solution is 10.4-10.6 when the composition is dissolved in water for injection to a concentration of 4 mg / ml of omeprazole.

4. The freeze-dried powder injection composition according to claim 1, wherein the concentration of omeprazole sodium in terms of omeprazole in the liquid before freeze-drying is 17.5-22.5 mg / ml.

5. The freeze-dried powder injection composition according to claim 1, which is sealed in a glass bottle, and the omeprazole sodium in each bottle is 10-100 mg calculated as omeprazole.

6. The freeze-dried powder injection composition according to claim 1, wherein the liquid composition before freeze-drying is composed of: 35-45 mg of omeprazole sodium calculated as omeprazole, 0.4-0.6 mg of edetate disodium, an appropriate amount of sodium hydroxide for adjusting the pH value so that the pH value of the powder injection is 10.1-11.1 when the pH value of the liquid is diluted with water for injection to a concentration of 4 mg / ml, and 2 ml of water for injection.

7. The freeze-dried powder injection composition according to claim 1, wherein the liquid composition before freeze-drying is composed of: 40 mg of omeprazole sodium calculated as omeprazole, 0.4-0.6 mg of edetate disodium, an appropriate amount of sodium hydroxide for adjusting the pH value so that the pH value of the powder injection is 10.3-10.7 when the pH value of the liquid is diluted with water for injection to a concentration of 4 mg / ml, and 2 ml of water for injection.

8. The freeze-dried powder injection composition according to claim 1, wherein the liquid composition before freeze-drying is composed of: 40 mg of omeprazole sodium calculated as omeprazole, 0.5 mg of edetate disodium, an appropriate amount of sodium hydroxide for adjusting the pH value so that the pH value of the powder injection is 10.3-10.7 when the pH value of the liquid is diluted with water for injection to a concentration of 4 mg / ml, and 2 ml of water for injection.

9. The freeze-dried powder injection composition according to claim 1, wherein the omeprazole sodium has a melting point of 169.5~172.0°C as determined by "0612 Melting Point Determination Method" - "A. Temperature Transfer Liquid Heating Method" of Part IV of the 2020 Edition of the Chinese Pharmacopoeia.

10. The freeze-dried powder injection composition according to claim 1, wherein the omeprazole sodium has diffraction peaks at 9.46°±0.10°, 14.50°±0.10°, 18.90°±0.10°, 19.74°±0.10°, 20.16°±0.10°, 22.90°±0.10°, 24.00°±0.10°, 26.02°±0.10°, and 26.88°±0.10° in the powder X-ray diffraction pattern expressed in 2θ angles.

11. The freeze-dried powder injection composition according to claim 1, wherein the omeprazole sodium has diffraction peaks at 9.46°, 14.50°, 18.90°, 19.74°, 20.16°, 22.90°, 24.00°, 26.02°, and 26.88° in the powder X-ray diffraction pattern expressed in 2θ angles.

12. The freeze-dried powder injection composition according to claim 1, wherein the omeprazole sodium uses Cu-Kα radiation and has a powder X-ray diffraction pattern as shown in FIG1.

Images