CN108553413B - Esomeprazole sodium for injection - Google Patents

Esomeprazole sodium for injection Download PDF

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CN108553413B
CN108553413B CN201810517912.4A CN201810517912A CN108553413B CN 108553413 B CN108553413 B CN 108553413B CN 201810517912 A CN201810517912 A CN 201810517912A CN 108553413 B CN108553413 B CN 108553413B
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injection
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drying
sodium
esomeprazole sodium
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CN108553413A (en
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李爱菊
伍雄辉
朱胜节
赵砥
余记川
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Fuan Pharmaceutical Group Hubei People's Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

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Abstract

The invention discloses esomeprazole sodium for injection. The injection is 40mg standard esomeprazole sodium for injection, and the formula components are as follows: 42.5mg of esomeprazole sodium, 2.5mg of calcium disodium edetate and a proper amount of sodium hydroxide, the pH is adjusted to 11.5 +/-0.3, 1mg of medicinal charcoal and 1000mg of water for injection are weighed. The invention has the advantages of capability of avoiding adverse reaction, stability and less single impurity and total impurity.

Description

Esomeprazole sodium for injection
Technical Field
The invention relates to the technical field of medicinal preparations, in particular to esomeprazole sodium for injection.
Background
Esomeprazole is the S-optical isomer of omeprazole, the first isomer of proton pump preparation worldwide, developed by Asricon pharmaceutical Co., Ltd, approved by the FDA to market in 3 months 2005. The esomeprazole reduces gastric acid secretion through a specific targeting action mechanism, and inhibits proton pumps of gastric parietal cells to reduce gastric acid secretion. The action site and mechanism are that esomeprazole is concentrated and converted into an active form in the high acid environment of parietal cell acid secretion microtubules, so that H +/K + -ATP (proton pump) of the site is inhibited, and inhibition is generated on basic gastric acid secretion and stimulation of gastric acid secretion.
The chemical name of the esomeprazole sodium is as follows: s-5-methoxy-2- [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfinyl-1H-benzimidazole sodium, which has the following structural formula:
Figure BDA0001674178130000011
the esomeprazole sodium for injection is an aseptic freeze-dried product, and the main component of the esomeprazole sodium is esomeprazole sodium. The esomeprazole serving as an anti-peptic ulcer drug can directly act on a proton pump in a stomach wall and specifically inhibit H + + K + + ATP enzyme, so that gastric acid secretion is effectively inhibited, and the esomeprazole has the advantages of rapid effect, strong effect and few adverse reactions. At present, the esomeprazole sodium for clinical injection is widely applied to treating acute upper gastrointestinal hemorrhage caused by duodenal ulcer, gastric ulcer, acute internal mucous membrane lesion, compound ulcer and the like.
Currently, oral esomeprazole can achieve good clinical effects, but in certain patients, such as dysphagia, vomiting, acute upper gastrointestinal hemorrhage and patients in recovery period of surgical operation, the oral administration route cannot be adopted, and the intravenous injection route is the preferred mode. Esomeprazole sodium as a sodium salt is well soluble in water. However, esomeprazole sodium is an alkaline substance and is stable to alkali; the esomeprazole sodium has poor stability, is sensitive to light, heat, oxygen, water and the like, and particularly under an acidic condition, the chemical structure of the esomeprazole sodium can be destructively changed, and the phenomena of discoloration and polymerization occur. In addition, the esomeprazole lyophilized preparation undergoes discoloration after contacting a metal container for a long time during the production process, resulting in a yellowish brown substance which may be associated with metal ion complexes and oxidation impurities. After the prepared freeze-dried preparation is stored for a long time, insoluble particles can be generated under the comprehensive conditions of storage temperature, inner packing materials and the like, so that visible foreign matters and the insoluble particles of the preparation after redissolution are unqualified, adverse reactions are generated during clinical use, and the clinical medication risk is increased.
CN103006585A contains esomeprazole sodium and edetate disodium; disodium ethylenediaminetetraacetate (disodium edetate) is an excellent metal ion complexing agent, and can be complexed with most metal ions under alkaline conditions, so that the stability of the preparation is maintained. However, since the calcium complex can be complexed with calcium, calcium loss can be caused after the calcium complex is input into a human body, and a series of clinical problems can be caused due to the decrease of blood calcium in the body; therefore, the problem of the stability of the esomeprazole sodium preparation during long-term storage is urgently needed to be solved by a safe and effective method.
The search of the prior art shows that aiming at the problem that esomeprazole sodium is unstable to metal ions, light, heat, oxygen and water, the common solution is to prepare the esomeprazole sodium, a metal ion chelating agent, an antioxidant and other additives into a freeze-dried powder injection, however, the metal ion chelating agent can cause calcium loss of a human body, and the antioxidant sodium bisulfite has irritation to skin, eyes and respiratory tracts, can cause anaphylactic reaction, corneal damage, blindness and asthma, and brings hidden troubles to the medication safety of patients.
In addition, in the prior art, various additives such as freeze-dried propping agents, metal ion chelating agents, antioxidants and the like are added to solve the problem of poor stability of esomeprazole sodium; however, the basic principle of the choice of the auxiliary materials for injections is as follows, as indicated in the "basic technical requirements for chemical injections": (1) auxiliary materials meeting the requirement of injection are adopted; (2) on the premise of meeting the requirements, the types and the dosage of the auxiliary materials used by the injection are as small as possible; (3) common auxiliary materials for injection are adopted as far as possible; therefore, on the premise of improving the stability of the preparation, if auxiliary materials commonly used in injections can be adopted, and the dosage is as small as possible, the preparation is more acceptable to the technicians in the field and patients.
Disclosure of Invention
The invention aims to provide esomeprazole sodium for injection, which can avoid adverse reaction, has better stability and safety, and has less single impurity and total impurity.
In order to achieve the purpose, the technical scheme of the invention is as follows: espressole sodium for injection, which is characterized in that: the injection esomeprazole sodium with the specification of 40mg comprises the following components in percentage by weight:
Figure BDA0001674178130000031
sodium hydroxide is used as a pH regulator; the medicinal charcoal and the water for injection are substances used in the preparation and finally removed;
the preparation method of the esomeprazole sodium for injection is characterized by comprising the following steps:
step 1: bottle, stopper and aluminum cap pretreatment
① lyophilizing bottle, cleaning borosilicate bottle, oven drying, sterilizing, and checking insoluble particles and visible foreign matter;
② cleaning, sterilizing and drying the rubber plug, checking the drying weight loss of the insoluble particles and the coated rubber plug, and controlling the drying weight loss of the coated rubber plug to be less than or equal to 0.5 percent for standby;
③ aluminum-plastic combined cover, sterilizing;
step 2: dissolving and preparing
① 2% NaOH solution is prepared by weighing a certain amount of sodium hydroxide, adding an appropriate amount of water for injection to obtain 2% NaOH solution, and cooling to room temperature;
② the matrix solution is prepared by weighing calcium disodium edetate (EDTA-Ca)2Na) is dissolved in 94 percent of the total amount of the prescription, the water for injection is cooled to room temperature, the temperature of the water for injection is lower than 30 ℃, and the pH value is adjusted to 11.8 +/-0.05 by using the 2 percent NaOH solution;
③ dissolving in water, adding the basic medicinal materials, dissolving, detecting pH, adjusting pH to 11.5 + -0.3 with 2% NaOH solution when the pH is not 11.5 + -0.3, and weighing with water for injection to the total amount of the prescription when the pH is 11.5 + -0.3;
and step 3: pyrogen removal and decarburizing filtration
Adding medicinal carbon, stirring, standing for adsorbing for at least 30min to remove pyrogen, and filtering with 0.22 μm microporous membrane to obtain intermediate; sampling the intermediate, and detecting according to the quality standard of the intermediate; the intermediate can be stored for 24 hours at room temperature in a dark place;
and 4, step 4: sterilizing filtration
Sterilizing and filtering the intermediate liquid medicine by using two-stage 0.22 mu m microporous filter membranes connected in series into a liquid storage tank between B-stage filtrate receiving rooms, controlling the filtering pressure to be 0.1-0.2 MPa, and controlling the filtering time to be within 6 hours;
and 5: aseptic filling
And (3) calculating the filling amount of the filling center according to the determination result of the content of the intermediate:
Figure BDA0001674178130000041
controlling the filling precision to be +/-3%, subpackaging the liquid medicine into borosilicate bottles and half plugging; the filling amount should be checked randomly in time during the filling process; under the protection of A-level laminar flow, the subpackaged liquid medicine is immediately sent into a freeze dryer;
step 6: freeze-drying
① prefreezing, namely setting the temperature of the plate layer to be-45 ℃, rapidly increasing the temperature of the plate layer to-15 ℃ when the temperature of the plate layer reaches-45 ℃, preserving heat for 1h, then reducing the temperature of the plate layer to-45 ℃ and preserving heat for 2 h;
② primary drying, namely setting the temperature of a plate layer to be 15 ℃ below zero, raising the temperature for 240min, then preserving the heat until ice crystals of the product disappear, and then preserving the heat for 1-3 h, namely performing resolution drying;
③ drying, setting temperature rise time for 60min, keeping the temperature until the temperature of the product is 30 deg.C, and keeping the temperature for more than 4 h;
④ stopping the machine, pressing the stopper in full vacuum, and discharging;
and 7: rolling cover, visual inspection, external packing and finished product warehousing
Rolling an aluminum cover on the product discharged from the box; performing lamp inspection on the rolled products, and sticking labels and outer packages after unqualified products are removed; and (5) sending the finished product to a warehouse for full inspection.
In the above technical scheme, in the step 3, the microfiltration membrane is a polyethersulfone microfiltration membrane; in the step 4, the microporous filter membrane is made of polyether sulfone.
In the above technical scheme, in step 4, the filter membrane for performing aseptic filtration is subjected to filter membrane integrity detection before and after filtration.
In the technical scheme, in the step 5, the filling, the half plugging and the transferring into a freeze dryer are completed within 8 hours, and the plug is a film-coated rubber plug.
In the technical scheme, in the primary drying in the step 6, the total heat preservation time is 8-10 hours.
The invention has the following advantages:
(1) the abnormal phenomenon of the sterile product can be effectively avoided, and the product quality is improved; according to the invention, calcium disodium edetate is used as an auxiliary material, so that adverse reactions can be effectively avoided; the medium borosilicate glass bottle is used as an injection bottle, so that the product quality can be ensured, and impurities and glass flaking are avoided during storage; the coated rubber plug is used as the injection bottle plug, so that the contact between the liquid medicine and the rubber plug can be reduced, and the contact between particles of the rubber plug and the medicine can be avoided;
(2) the product stability is better by adopting a repeated freeze thawing process; single impurity, less total impurity and safety;
(3) the process is simple and is suitable for large-scale production requirements.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited to these examples. While the advantages of the invention will be clear and readily understood by the description.
Espressole sodium for injection, which is characterized in that: the injection esomeprazole sodium with the specification of 40mg comprises the following components in percentage by weight:
Figure BDA0001674178130000051
sodium hydroxide is used as a pH regulator; the medicinal charcoal and the water for injection are substances used in the preparation and finally removed;
the preparation method of the esomeprazole sodium for injection is characterized by comprising the following steps:
step 1: bottle, stopper and aluminum cap pretreatment
① freeze-drying bottle, wherein the borosilicate bottle is cleaned, dried and sterilized, and the insoluble particles and visible foreign matters are detected with verification for standby;
② cleaning, sterilizing and drying the rubber plug, checking the drying weight loss of the insoluble particles and the coated rubber plug, and controlling the drying weight loss of the coated rubber plug to be less than or equal to 0.5 percent for standby;
③ aluminum-plastic combined cover, sterilizing;
step 2: dissolving and preparing
① 2% NaOH solution is prepared by weighing a certain amount of sodium hydroxide, adding an appropriate amount of water for injection to obtain 2% NaOH solution, and cooling to room temperature;
② preparing the matrix solution by weighing the EDTA-Ca2Dissolving Na in 94% of the total amount of the prescription, cooling to room temperature water for injection, wherein the temperature of the water for injection is lower than 30 ℃, and adjusting the pH value to 11.8 +/-0.05 by using the 2% NaOH solution; the edetate calcium sodium can avoid the generation of adverse reactions;
③ dissolving in water, adding the basic medicinal materials, dissolving, detecting pH, adjusting pH to 11.5 + -0.3 with 2% NaOH solution when the pH is not 11.5 + -0.3, and weighing with water for injection to the total amount of the prescription when the pH is 11.5 + -0.3;
and step 3: pyrogen removal and decarburizing filtration
Adding medicinal carbon, stirring, standing for adsorbing for at least 30min to remove pyrogen, and filtering with 0.22 μm microporous membrane to obtain intermediate; sampling the intermediate, and detecting according to the quality standard of the intermediate; the intermediate can be stored for 24 hours at room temperature in a dark place;
and 4, step 4: sterilizing filtration
Sterilizing and filtering the intermediate liquid medicine by using two-stage 0.22 mu m microporous filter membranes connected in series into a liquid storage tank between B-stage filtrate receiving rooms, controlling the filtering pressure to be 0.1-0.2 MPa, and controlling the filtering time to be within 6 hours;
and 5: aseptic filling
And (3) calculating the filling amount of the filling center according to the determination result of the content of the intermediate:
Figure BDA0001674178130000061
controlling the filling precision to be +/-3%, subpackaging the liquid medicine into borosilicate bottles and half plugging; the filling amount should be checked randomly in time during the filling process; under the protection of A-level laminar flow, the subpackaged liquid medicine is immediately sent into a freeze dryer;
step 6: freeze-drying
① prefreezing, namely setting the temperature of the plate layer at-45 ℃, and repeatedly freezing and thawing (when the temperature of the plate layer reaches-45 ℃, quickly raising the temperature of the plate layer to-15 ℃, preserving heat for 1h, then lowering the temperature of the plate layer to-45 ℃ and preserving heat for 2 h);
② primary drying, namely setting the temperature of a plate layer to be 15 ℃ below zero, raising the temperature for 240min, then preserving the heat until ice crystals of the product disappear, and then preserving the heat for 1-3 h, namely performing resolution drying;
③ drying, setting temperature rise time for 60min, keeping the temperature until the temperature of the product is 30 deg.C, and keeping the temperature for more than 4 h;
④ stopping the machine, pressing the stopper in full vacuum, and discharging;
and 7: rolling cover, visual inspection, external packing and finished product warehousing
Rolling an aluminum cover on the product discharged from the box; performing lamp inspection on the rolled products, and sticking labels and outer packages after unqualified products are removed; and (5) sending the finished product to a warehouse for full inspection.
Further, in the step 3, the microporous filter membrane is made of polyether sulfone; in the step 4, the microporous filter membrane is made of polyether sulfone.
Further, in step 4, the filter membrane subjected to sterile filtration is subjected to filter membrane integrity detection before and after filtration.
Further, in the step 5, the filling, the half plugging and the transferring into a freeze dryer are completed within 8 hours, and the plug is a film-coated rubber plug, so that the contact between rubber plug particles and medicines is avoided.
Furthermore, in the primary drying in the step 6, the total heat preservation time is 8-10 h.
The stability of the esomeprazole sodium for injection is researched, and the stability comprises the following contents:
1. influential/thermal cycling test
The influence factor test/thermal cycle test sample information of the esomeprazole sodium for injection and the commercial product is shown in table 1; the test results are shown in tables 2 and 3; the invention selects the sample with the batch number of 20150304; the sample with the lot number MF2209 is selected as a commercial product.
TABLE 1 influence factor test/thermal cycle test sample information Table
Figure BDA0001674178130000071
Figure BDA0001674178130000081
TABLE 2 Eimeprazole sodium for injection of the invention and commercially available product influencing factor/thermal cycle test result I (specification: 40mg)
Figure BDA0001674178130000082
Figure BDA0001674178130000091
Figure BDA0001674178130000101
TABLE 3 Eimeprazole sodium for injection of the invention and commercially available product influencing factor/thermal cycle test result II (specification: 40mg)
Figure BDA0001674178130000102
Figure BDA0001674178130000111
As can be seen from tables 2 and 3, the esomeprazole sodium for injection of the present invention has less single impurity and total impurity and better stability compared with the commercially available products.
The contents of impurities of esomeprazole sodium are as follows:
impurity A
Chemical name: 2-mercapto-5-methoxy-1H-benzimidazoles
Structural formula (xvi):
Figure BDA0001674178130000121
the molecular formula is as follows: c8H8N2OS
Molecular weight: 180.23
Impurity D
Chemical name: 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl ] sulfonyl ] -1H-benzimidazole
Structural formula (xvi):
Figure BDA0001674178130000122
the molecular formula is as follows: c17H19N3O4S
Molecular weight: 361.42
Impurity I
Chemical name: 1, 4-dihydro-1- (5-methoxy-1H-benzimidazol-2-yl) -3, 5-dimethyl-4-oxo-2-pyridinecarboxylic acid
Structural formula (xvi):
Figure BDA0001674178130000123
the molecular formula is as follows: c16H15N3O4
Molecular weight: 313.31
Impurity J
Chemical name: 2- [ [ (5-methoxy-1H-benzimidazol-2-yl) sulfinyl ] methyl ] -3, 5-dimethyl-4 (1H) -1-pyridone
Structural formula (xvi):
Figure BDA0001674178130000131
the molecular formula is as follows: c16H17N3O3S
Molecular weight: 331.39
Impurity G
Chemical name: 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl ] sulfinyl ] -1-methylbenzimidazole and 6-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl ] sulfinyl ] -1-methylbenzimidazole
Structural formula (xvi):
Figure BDA0001674178130000132
the molecular formula is as follows: c18H21N3O3S
Molecular weight: 359.44
2. General stability study
The content of the conventional stability test investigation of the esomeprazole sodium for injection is shown in table 4, and the content of the conventional stability test investigation of the commercially available product is shown in table 5; the conventional stability investigation results of the esomeprazole sodium for injection and the commercial products are shown in table 6.
Table 4 summary table of conventional stability study content of esomeprazole sodium for injection of the present invention
Figure BDA0001674178130000133
Figure BDA0001674178130000141
TABLE 5 summary of conventional stability studies for commercial products
Figure BDA0001674178130000142
Figure BDA0001674178130000151
TABLE 6 conclusions of conventional stability test investigations
Figure BDA0001674178130000152
Figure BDA0001674178130000161
As can be seen from the above table, the conventional stability of esomeprazole sodium for injection is better.
3. Product stability survey in use
The results of the compatibility stability test of the esomeprazole sodium for injection are shown in table 7.
TABLE 7 conclusion of the compatibility stability test
Figure BDA0001674178130000171
As can be seen from the above table, the esomeprazole sodium for injection has good compatibility stability.
Animal experiments
The esomeprazole sodium for injection is provided by Hubei people pharmaceutical Co., Ltd, and the special safety test research of the esomeprazole sodium is completed by Chengdu Qihuang medicine non-clinical research Co., Ltd.
According to the requirements of the national food and drug administration 'drug registration management method', the test scheme is designed and the test work is completed, and the results are as follows:
(1) in the injection esomeprazole sodium vascular irritation test, the rabbit ear vein control group, the market-sold group and the tested group have no hyperemia, hemorrhage and degenerative necrosis, and have no pathological damage, which indicates that the injection esomeprazole sodium (the sample with the batch number of 20150304 is selected by the invention) does not generate irritation reaction on the rabbit ear blood vessels after intravenous administration;
(2) in the intramuscular single-administration irritation test of the esomeprazole sodium for injection, the rabbit leg biceps femoris muscle control group, the market group and the tested group have no red swelling, congestion and degenerative necrosis, and have no pathological damage, which indicates that the intramuscular single injection of the esomeprazole sodium for injection (the batch number is 20150304) does not generate irritation reaction on the rabbit biceps femoris muscle;
(3) in the intramuscular administration stimulation test of the esomeprazole sodium for injection for multiple times, the rabbit leg biceps femoris muscle control group has no red swelling, congestion and degenerative necrosis phenomena, and has no pathological damage; one rabbit's biceps femoris muscle is subject to degeneration, necrosis and inflammatory cell infiltration after the commercially available group and the tested group stop taking the medicine for 48 hours; after the commercial group recovers for 7 days, degeneration, necrosis and inflammatory cell infiltration of the biceps femoris of one rabbit can be seen; shows that the injection esomeprazole sodium (batch number is 20150304) has certain stimulation to the biceps femoris of the rabbit after intramuscular multiple injection, but has recoverability;
(4) in the hemolysis test of the esomeprazole sodium for injection, the esomeprazole sodium for injection (batch number is 20150304) has no hemolysis phenomenon in a test tube, and erythrocytes can be dispersed and have no coagulation phenomenon after shaking;
(5) in the general active anaphylaxis test of the esomeprazole sodium for injection, no general allergic reaction occurs when the guinea pigs of a tested group are excited (dorsal foot intravenous injection), which indicates that the esomeprazole sodium for injection (with the batch number of 20150304) does not generate the general active anaphylaxis to the guinea pigs;
(6) in the passive skin allergy test of the esomeprazole sodium for injection, after the guinea pig is excited, the diameter of the blue spot of a tested group and the absorbance of a leaching solution have no difference compared with those of a negative group, and have obvious difference compared with that of a positive group, which indicates that the esomeprazole sodium for injection (the batch number is 20150304) does not generate passive skin allergy to the guinea pig.
And (4) conclusion: in the special safety test of the esomeprazole sodium for injection with the batch number of 20150304, no relevant stimulation, hemolysis and anaphylactic reaction are seen in a blood vessel stimulation test and a muscle single administration stimulation test; the intramuscular multiple administration irritation test shows that intramuscular multiple injections have certain irritation to the biceps femoris of the rabbits, but have recoverability; taking notes in the drug instruction: intramuscular injection is limited to use when administration is required by this route and repeated injections at the same site should be avoided; it is suggested that multiple intramuscular injections at the same site should be avoided in clinical use.
Other parts not described belong to the prior art.

Claims (3)

1. Espressole sodium for injection, which is characterized in that: the injection esomeprazole sodium with the specification of 40mg comprises the following components in percentage by weight:
Figure FDA0002278192560000011
the preparation method of the esomeprazole sodium for injection is characterized by comprising the following steps of:
step 1: bottle, stopper and aluminum cap pretreatment
① lyophilizing bottle, cleaning borosilicate bottle, oven drying, sterilizing, and checking insoluble particles and visible foreign matter;
② cleaning, sterilizing and drying the rubber plug, checking the drying weight loss of the insoluble particles and the coated rubber plug, and controlling the drying weight loss of the coated rubber plug to be less than or equal to 0.5 percent for standby;
③ aluminum-plastic combined cover, sterilizing;
step 2: dissolving and preparing
① 2% NaOH solution is prepared by weighing a certain amount of sodium hydroxide, adding an appropriate amount of water for injection to obtain 2% NaOH solution, and cooling to room temperature;
② preparing matrix solution by dissolving edetate calcium sodium in 94% of the total amount of the formula, cooling to room temperature, and adjusting pH to 11.8 + -0.05 with the above 2% NaOH solution at a temperature lower than 30 deg.C;
③ dissolving in water, adding the basic medicinal materials, dissolving, detecting pH, adjusting pH to 11.5 + -0.3 with 2% NaOH solution when the pH is not 11.5 + -0.3, and weighing with water for injection to the total amount of the prescription when the pH is 11.5 + -0.3;
and step 3: pyrogen removal and decarburizing filtration
Adding medicinal carbon, stirring, standing for adsorbing for at least 30min to remove pyrogen, and filtering with 0.22 μm microporous membrane to obtain intermediate; sampling the intermediate, and detecting according to the quality standard of the intermediate; the intermediate can be stored for 24 hours at room temperature in a dark place;
and 4, step 4: sterilizing filtration
Sterilizing and filtering the intermediate liquid medicine by using two-stage 0.22 mu m microporous filter membranes connected in series into a liquid storage tank between B-stage filtrate receiving rooms, controlling the filtering pressure to be 0.1-0.2 MPa, and controlling the filtering time to be within 6 hours;
and 5: aseptic filling
And (3) calculating the filling amount of the filling center according to the determination result of the content of the intermediate:
Figure FDA0002278192560000021
controlling the filling precision to be +/-3%, subpackaging the liquid medicine into borosilicate bottles and half plugging; the filling amount should be checked randomly in time during the filling process; under the protection of A-level laminar flow, the subpackaged liquid medicine is immediately sent into a freeze dryer;
step 6: freeze-drying
① prefreezing, namely setting the temperature of the plate layer to be-45 ℃, rapidly increasing the temperature of the plate layer to-15 ℃ when the temperature of the plate layer reaches-45 ℃, preserving heat for 1h, then reducing the temperature of the plate layer to-45 ℃ and preserving heat for 2 h;
② primary drying, namely setting the temperature of a plate layer to be 15 ℃ below zero, raising the temperature for 240min, then preserving the heat until ice crystals of the product disappear, and then preserving the heat for 1-3 h, namely performing resolution drying;
③ drying, setting temperature rise time for 60min, keeping the temperature until the temperature of the product is 30 deg.C, and keeping the temperature for more than 4 h;
④ stopping the machine, pressing the stopper in full vacuum, and discharging;
and 7: rolling cover, visual inspection, external packing and finished product warehousing
Rolling an aluminum cover on the product discharged from the box; performing lamp inspection on the rolled products, and sticking labels and outer packages after unqualified products are removed; sending the finished products to a full-inspection warehouse;
in the step 5, filling, half plugging and transferring into a freeze dryer are completed within 8 hours, and the plug is a film-coated rubber plug;
and 6, in the primary drying, the total heat preservation time is 8-10 h.
2. The esomeprazole sodium for injection according to claim 1, characterized in that: in the step 3, the microfiltration membrane is made of polyether sulfone; in the step 4, the microporous filter membrane is made of polyether sulfone.
3. The esomeprazole sodium for injection according to claim 2, characterized in that: and 4, performing filter membrane integrity detection on the filter membrane subjected to sterilization filtration before and after filtration.
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