CN108553413A - Injection esomeprazole sodium - Google Patents
Injection esomeprazole sodium Download PDFInfo
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- CN108553413A CN108553413A CN201810517912.4A CN201810517912A CN108553413A CN 108553413 A CN108553413 A CN 108553413A CN 201810517912 A CN201810517912 A CN 201810517912A CN 108553413 A CN108553413 A CN 108553413A
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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 a kind of injection esomeprazole sodium.It is 40mg gauge hypodermic esomeprazole sodium, and recipe ingredient is：Esomeprazole sodium 42.5mg, mosatil 2.5mg, Sodium hydroxide q.s. adjust pH11.5 ± 0.3, medical charcoal 1mg, water for injection to be weighed surely to 1000mg.The present invention has the advantages that be avoided that adverse reaction, stabilization, list are miscellaneous and total miscellaneous less.
Description
Technical field
The present invention relates to pharmaceutical preparations technology fields, more specifically say it is injection esomeprazole sodium.
Background technology
Esomeprazole is the S- optical isomers of Omeprazole, is the first isomers proton pump preparation in the whole world, by A Si
Li Kang pharmaceutical Co. Ltds develop, and in March, 2005 is ratified to list by FDA.Esomeprazole is made by the targeting of specificity
Gastric acid secretion is reduced with mechanism, parietal cell proton pump is inhibited to reduce gastric acid secretion.Site of action and mechanism are esomeprazole
It is dense and be converted into active form in the high acid environment that parietal cell secretes sour micro-pipe, to inhibit the H+/K+-ATP (matter at the position
Son pump), inhibition is generated to basal gastric acid secretion and gastric acid secretion.
Esomeprazole sodium chemical name is：S-5- methoxyl groups -2- [(4- methoxyl group -3,5- dimethyl -2- pyridyl groups) first
Base] sulfinyl-1 H-benzimidazole sodium, skeleton symbol is as follows：
Injection esomeprazole sodium is aseptic freeze-dried product, and main component is Esomeprazole sodium.Esomeprazole
As anti-peptic ulcer drug, stomach wall inner proton pump can be directly acted on, specifically inhibits H++K++ATP enzymes, to have
Effect ground gastric acid secretion inhibiting, works rapid, effect is strong, and adverse reaction is few.Currently, clinically injection esomeprazole sodium has been
It is widely used in acute upper gastrointestinal caused by treatment duodenal ulcer, gastric ulcer, acute interior non-cancer lesion, combined Peptic Ulcer etc.
Gastrointestinal hemorrhage.
Oral esomeprazole can obtain good clinical effectiveness at present, but in certain patients, as dysphagia, vomiting,
Acute hemorrhage of upper gastrointestinal tract and surgery patient cannot be administered orally approach, and Intravenous administration route is with regard to headed by
The mode of choosing.Esomeprazole sodium is as sodium salt, favorable solubility in water.But Esomeprazole sodium is alkaline matter, it is right
Alkali is stablized；Esomeprazole sodium stability is poor, all very sensitive to light, heat, oxygen, water etc., especially in acid condition, chemistry knot
Destructive variation can occur for structure, occur changing colour and polymerism.In addition, Esomeprazole freeze-dried preparation is in process of production, it is long
It can change colour after time contacting metal container, generate tan-yellow material, which may be with metal ion complex and oxidation
Impurity is related.Lyophilized preparation obtained may generate after long-term storage under the effect of the integrated conditions such as storage temperature, interior packaging material
Particulate matter, cause redissolve after preparation visible foreign matters and particulate matter it is unqualified, generate adverse reaction in Clinical practice,
Increase clinical application risk.
CN103006585A includes Esomeprazole sodium, natrium adetate；Disodium ethylene diamine tetraacetate (natrium adetate)
It is a kind of outstanding complexing of metal ion agent, can be complexed under alkaline condition with most metal ions, to keep preparation
Stabilization.But due to can be complexed simultaneously with calcium, it may cause calcium loss, internal blood calcium decline that may lead after inputting human body
Cause a series of clinical problem；Therefore, esomeprazole preparation of sodium for a long time storage stability problem, there is an urgent need to safety,
Effective method solves.
It is found by retrieving the prior art, for Esomeprazole sodium to metal ion, light, heat, oxygen and water unstable
Problem, common solution are that the additives such as Esomeprazole sodium and metal ion chelation agent, antioxidant are prepared into freeze-dried powder
Injection, however metal ion chelation agent can lead to human body calcium loss, antioxidant sodium hydrogensulfite is to skin, eye, respiratory tract spinosity
Swash property, can cause allergic reaction, corneal injury, blindness, asthma, carry out hidden danger to patient medication safety belt.
In addition, the prior art is by adding the additives such as various freeze-drying proppants, metal ion chelation agent and antioxidant, with
Solve the problems, such as that esomeprazole stable sodium is poor；However,《Chemicals injection main technique requirements》In point out, injection
Auxiliary material select basic principle be：(1) auxiliary material for meeting injection requirement should be used；(2) under the premise of meeting needs, injection
The type and dosage of auxiliary material used in agent should be lacked as far as possible；(3) should auxiliary material often be used using injection as far as possible；Therefore, system is being improved
Under the premise of agent stability, if it is possible to using common auxiliary material in injection, and dosage is few as possible, this be those skilled in the art and
Patient is easier to receiving.
Invention content
The purpose of the invention is to provide a kind of injection esomeprazole sodium, it is avoided that adverse reaction, stability
Preferably, safety, it is single miscellaneous, total miscellaneous less.
To achieve the goals above, the technical scheme is that：Injection esomeprazole sodium, it is characterised in that：
For 40mg gauge hypodermic esomeprazole sodium, recipe ingredient is：
Sodium hydroxide is PH conditioning agents；Medical charcoal and water for injection are the substance for using and finally removing in preparing；
The method for preparing the injection esomeprazole sodium, which is characterized in that include the following steps：
Step 1：Bottle, plug and aluminium lid pre-treatment
1. bottle is lyophilized：Middle borosilicate cillin bottle cleaning, drying and sterilizing, confirmatory detection particulate matter and visible foreign matters, it is standby
With；
2. rubber plug：Coated rubber plug cleaning, sterilizing, dry, confirmatory detection particulate matter and coated rubber plug loss on drying,
Coated rubber plug loss on drying≤0.5% is controlled, it is spare；
3. aluminium-plastic combined cover：It is spare after sterilizing；
Step 2：It is molten to match
1. 2%NaOH solution is prepared：A certain amount of sodium hydroxide is weighed, adds appropriate water for injection with obtained a concentration of 2%
NaOH solution, be cooled to room temperature spare；
2. matrix solution is prepared：Weigh formula ratio mosatil (EDTA-Ca2Na) it is dissolved in the cooling of 94% prescription total amount
To the water for injection of room temperature, water for injection temperature is less than 30 DEG C, with above-mentioned 2%NaOH solution tune pH value to 11.8 ± 0.05；
Match 3. liquid is molten：Formula ratio main ingredient is added into matrix solution, pH value is detected after dissolving completely, when pH value does not exist
When 11.5 ± 0.3 range, continue finally to be weighed surely to place with water for injection to 11.5 ± 0.3 with above-mentioned 2%NaOH solution tune pH value
Square total amount；When pH value is in 11.5 ± 0.3 range, weighed surely with water for injection to prescription total amount；
Step 3：Depyrogenation and decarbonization filtering
Formula ratio medical charcoal is added, stirs evenly rear standing adsorption not less than 30min with depyrogenation, is then filtered with 0.22 μm of micropore
Film carries out decarbonization filtering, obtains intermediate；Intermediate is sampled, is detected by intermediate quality standard；Intermediate can be
Room temperature is protected from light lower storage 24 hours；
Step 4：Aseptic filtration
Intermediate liquid is subjected to aseptic filtration to the storage between B grades of filtrates receptions with 0.22 μm of miillpore filter of concatenated two-stage
In flow container, filter pressure control is controlled in 0.1~0.2MPa, filtration time in 6 hours；
Step 5：Sterile filling
According to intermediates content measurement result, filling center loading amount is calculated：
Control loading amount precision is that ± 3% progress liquid is sub-packed in middle borosilicate cillin bottle and partly jumps a queue；In pouring process
Answer the filling loading amount of timely casual inspection；In the case where A grades of laminar flows are protected, the liquid dispensed is sent into freeze dryer immediately；
Step 6：Freeze-drying
1. pre-freeze：Arranging plate layer temperature is -45 DEG C, and when plate layer temperature reaches -45 DEG C, plate layer temperature is raised to -15 rapidly
DEG C, 1h is kept the temperature, then plate layer temperature is dropped to -45 DEG C, keeps the temperature 2h；
2. primary drying：Then -15 DEG C, heating-up time 240min of arranging plate layer temperature is kept the temperature to observing product ice crystal
1~3h is kept the temperature after disappearance again, you can carry out parsing-desiccation；
3. parsing-desiccation：Heating-up time 60min is set, and keep the temperature to observe products temperature to keep the temperature again after 30 DEG C 4h with
On；
4. shutting down, vacuum tamponade, outlet；
Step 7：Roll lid, visual inspection outsourcing, warehousing finished products
By outlet product pressure rolling aluminium lid；Lid product will be rolled and carry out lamp inspection, pick out labeling and outer packing after defective work；It send into
Product full inspection is put in storage.
In the above-mentioned technical solutions, in step 3, miillpore filter is polyether sulfone material miillpore filter；In step 4, micropore filter
Film is polyether sulfone material miillpore filter.
In the above-mentioned technical solutions, in step 4, integrity of filtration membranes is carried out after carrying out the filter membrane of aseptic filtration before filtration
Detection.
In the above-mentioned technical solutions, in step 5, completed in 8 hours it is filling, partly jump a queue, be transferred in freeze dryer, fill in cover
Film rubber plug.
In the above-mentioned technical solutions, in the primary drying of step 6, total 8~10h of soaking time.
The invention has the advantages that：
(1) it can be effectively prevented from the abnormal phenomenon of sterile product, improve product quality；The present invention is made using mosatil
Adverse reaction can be effectively avoided for auxiliary material；Borosilicate glass bottle can ensure that product quality as injection bottle in, ensure storage
When do not generate impurity, do not generate glass flake；Using coated rubber plug as injection bottle stopper, liquid and rubber plug contact can be reduced,
Avoid rubber plug particulate matter and drug contact；
(2) use multigelation technique, product stability preferable；Single miscellaneous, total miscellaneous less, safety；
(3) simple for process, it is suitble to big production requirement.
Specific implementation mode
With reference to the embodiment performance that the present invention will be described in detail, but they do not constitute limitation of the invention,
It is only for example.Keep advantages of the present invention more clear by explanation simultaneously and is readily appreciated that.
Injection esomeprazole sodium, it is characterised in that：For 40mg gauge hypodermic esomeprazole sodium, formula group
It is divided into：
Sodium hydroxide is PH conditioning agents；Medical charcoal and water for injection are the substance for using and finally removing in preparing；
The method for preparing the injection esomeprazole sodium, which is characterized in that include the following steps：
Step 1：Bottle, plug and aluminium lid pre-treatment
1. bottle is lyophilized：Middle borosilicate cillin bottle cleaning, drying and sterilizing, confirmatory detection particulate matter and visible foreign matters, it is standby
With；Middle borosilicate cillin bottle can ensure that quality, avoids generating impurity when storage, avoids generating glass flake；
2. rubber plug：Coated rubber plug cleaning, sterilizing, dry, confirmatory detection particulate matter and coated rubber plug loss on drying,
Coated rubber plug loss on drying≤0.5% is controlled, it is spare；
3. aluminium-plastic combined cover：It is spare after sterilizing；
Step 2：It is molten to match
1. 2%NaOH solution is prepared：A certain amount of sodium hydroxide is weighed, adds appropriate water for injection with obtained a concentration of 2%
NaOH solution, be cooled to room temperature spare；
2. matrix solution is prepared：Weigh formula ratio EDTA-Ca2Na is dissolved in the injection of 94% prescription total amount being cooled to room temperature
With water, water for injection temperature is less than 30 DEG C, with above-mentioned 2%NaOH solution tune pH value to 11.8 ± 0.05；Mosatil can be kept away
Exempt from the generation of adverse reaction；
Match 3. liquid is molten：Formula ratio main ingredient is added into matrix solution, pH value is detected after dissolving completely, when pH value does not exist
When 11.5 ± 0.3 range, continue finally to be weighed surely to place with water for injection to 11.5 ± 0.3 with above-mentioned 2%NaOH solution tune pH value
Square total amount；When pH value is in 11.5 ± 0.3 range, weighed surely with water for injection to prescription total amount；
Step 3：Depyrogenation and decarbonization filtering
Formula ratio medical charcoal is added, stirs evenly rear standing adsorption not less than 30min with depyrogenation, is then filtered with 0.22 μm of micropore
Film carries out decarbonization filtering, obtains intermediate；Intermediate is sampled, is detected by intermediate quality standard；Intermediate can be
Room temperature is protected from light lower storage 24 hours；
Step 4：Aseptic filtration
Intermediate liquid is subjected to aseptic filtration to the storage between B grades of filtrates receptions with 0.22 μm of miillpore filter of concatenated two-stage
In flow container, filter pressure control is controlled in 0.1~0.2MPa, filtration time in 6 hours；
Step 5：Sterile filling
According to intermediates content measurement result, filling center loading amount is calculated：
Control loading amount precision is that ± 3% progress liquid is sub-packed in middle borosilicate cillin bottle and partly jumps a queue；In pouring process
Answer the filling loading amount of timely casual inspection；In the case where A grades of laminar flows are protected, the liquid dispensed is sent into freeze dryer immediately；
Step 6：Freeze-drying
1. pre-freeze：Arranging plate layer temperature is -45 DEG C, and multigelation is (when plate layer temperature reaches -45 DEG C, rapidly by plate layer temperature
Degree is raised to -15 DEG C, keeps the temperature 1h, then plate layer temperature is dropped to -45 DEG C, keeps the temperature 2h)；
2. primary drying：Then -15 DEG C, heating-up time 240min of arranging plate layer temperature is kept the temperature to observing product ice crystal
1~3h is kept the temperature after disappearance again, you can carry out parsing-desiccation；
3. parsing-desiccation：Heating-up time 60min is set, and keep the temperature to observe products temperature to keep the temperature again after 30 DEG C 4h with
On；
4. shutting down, vacuum tamponade, outlet；
Step 7：Roll lid, visual inspection outsourcing, warehousing finished products
By outlet product pressure rolling aluminium lid；Lid product will be rolled and carry out lamp inspection, pick out labeling and outer packing after defective work；It send into
Product full inspection is put in storage.
Further, in step 3, miillpore filter is polyether sulfone material miillpore filter；In step 4, miillpore filter is polyethers
Sulfone material miillpore filter.
Further, in step 4, integrity of filtration membranes detection is carried out after carrying out the filter membrane of aseptic filtration before filtration.
Further, in step 5, completed in 8 hours it is filling, partly jump a queue, be transferred in freeze dryer, fill in for coated rubber plug,
Avoid rubber plug particulate matter and drug contact.
Further, in the primary drying of step 6, total 8~10h of soaking time.
Injection esomeprazole stable sodium of the present invention is studied, including following content：
1, influence factor experiment/thermal cycling test
Injection esomeprazole sodium of the present invention and influence factor experiment/thermal cycling test sample message of commercially available product are shown in
Table 1；Test result is shown in Table 2, table 3；It is 20150304 sample that the present invention, which selects lot number,；It is MF2209's that commercially available product, which selects lot number,
Sample.
1 influence factor experiment of table/thermal cycling test sample message table
2 injection esomeprazole sodium of the present invention of table and commercially available product influence factor/one (specification of thermal cycling test result：
40mg)
3 injection esomeprazole sodium of the present invention of table and commercially available product influence factor/two (specification of thermal cycling test result：
40mg)
It is single miscellaneous and total miscellaneous less by table 2 and table 3 it is found that injection esomeprazole sodium of the present invention is compared with commercially available product,
Stability is preferable.
The impurity content of esomeprazole sodium is as follows：
Impurity A
Chemical name：2- sulfydryl -5- methoxyl group -1H- benzimidazoles
Structural formula：
Molecular formula：C8H8N2OS
Molecular weight：180.23
Impurity D
Chemical name：5- methoxyl groups -2- [[(4- methoxyl group -3,5- dimethyl -2- pyridyl groups) methyl] sulfonyl] -1H-
Benzimidazole
Structural formula：
Molecular formula：C17H19N3O4S
Molecular weight：361.42
Impurity I
Chemical name：1,4- dihydros -1- (5- methoxyl groups -1H- benzimidazolyl-2 radicals-yl) -3,5- dimethyl -4- oxos -2-
Picolinic acid
Structural formula：
Molecular formula：C16H15N3O4
Molecular weight：313.31
Impurity J
Chemical name：2- [[(5- methoxyl groups -1H- benzimidazolyl-2 radicals-yl) sulfinyl] methyl] -3,5- dimethyl -4
(1H) -1- pyridones
Structural formula：
Molecular formula：C16H17N3O3S
Molecular weight：331.39
Impurity G
Chemical name：5- methoxyl groups -2- [[(4- methoxyl group -3,5- dimethyl -2- pyridyl groups) methyl] sulfinyl] -1-
Tolimidazole and 6- methoxyl groups -2- [[(4- methoxyl group -3,5- dimethyl -2- pyridyl groups) methyl] sulfinyl] -1- first
Base benzimidazole
Structural formula：
Molecular formula：C18H21N3O3S
Molecular weight：359.44
2, standard stability is investigated
The content that the standard stability trials that injection esomeprazole sodium of the present invention carries out are investigated is shown in Table 4, commercially available product
The standard stability of progress investigates content and is shown in Table 5；Injection esomeprazole sodium of the present invention is examined with commercially available product standard stability
It examines and the results are shown in Table 6.
4 injection esomeprazole sodium standard stability research contents summary sheet of the present invention of table
5 commercially available product standard stability research contents summary sheet of table
The conclusion that 6 standard stability trials of table are investigated
As seen from the above table, injection esomeprazole sodium standard stability of the present invention is preferable.
3, product stability is investigated in use
The compatibility stability investigation that injection esomeprazole sodium of the present invention carries out the results are shown in Table 7.
The conclusion of 7 compatibility stability experiment investigation of table
As seen from the above table, the compatibility stability of injection esomeprazole sodium of the present invention is preferable.
Zoopery
Injection esomeprazole sodium is provided by Hubei people pharmaceutical Co. Ltd, is ground by Chengdu qi xanthate object is non-clinical
Study carefully the specific safety experimental study that Co., Ltd completes the medicine.
By State Food and Drug Administration《Drug registration management method》Prescribed requirement, devise this testing program
And experiment work is completed, it is as a result as follows：
(1) in injection esomeprazole sodium vascular stimulation tests, rabbit auricular vein control group, commercially available group and by
Examination group occurs without congested, bleeding and degeneration necrosis phenomenon, also without pathologic lesion, shows injection Chinese mugwort Si Aomeila of the present invention
Azoles sodium (it is 20150304 sample that the present invention, which selects lot number) intravenously administrable does not generate stimulate the reaction to rabbit ear blood vessel；
(2) in injection esomeprazole sodium muscle single-dose irritation test, rabbit leg biceps muscle of thigh control group,
Commercially available group and tested group occurs without red and swollen, congested and degeneration necrosis phenomenon, also without pathologic lesion, shows injection Chinese mugwort of the present invention
Department's Omeprazole Sodium (lot number 20150304) intramuscular single injection does not generate stimulate the reaction to rabbit biceps muscle of thigh；
(3) in injection esomeprazole sodium muscle multiple dosing irritation test, rabbit leg biceps muscle of thigh control group
Occur without red and swollen, congested and degeneration necrosis phenomenon, also without pathologic lesion；Commercially available group and tested group of drug withdrawal respectively have one in 48 hours
The visible denaturation of rabbit biceps muscle of thigh, necrosis and cell infiltration；Commercially available group of recovery visible rabbit biceps muscle of thigh denaturation in 7 days,
Necrosis and cell infiltration；Show the intramuscular multiple injection pair of injection esomeprazole sodium (lot number 20150304) of the present invention
Rabbit biceps muscle of thigh has certain irritation, but has restorability；
(4) in the experiment of injection esomeprazole sodium hemolytic, (lot number is for injection esomeprazole sodium of the present invention
20150304) test tube to occur without haemolysis, red blood cell is dispersible after shaking, no coacervation；
(5) in injection esomeprazole sodium whole body active sensitivity test, (instep vein when tested group of cavy excites
Injection) do not occur systemic anaphylaxis, show injection esomeprazole sodium (lot number 20150304) of the present invention to cavy
Predisposing medical conditions are not generated；
(6) in injection esomeprazole sodium passive cutaneous anaphylaxis test, after cavy excitation, tested group of locus coeruleus diameter,
Leachate absorbance indifference compared with negative group, there were significant differences compared with positive group, shows injection Ai Siao of the present invention
U.S. draws azoles sodium (lot number 20150304) not generate passive cutaneous anaphylaxis to cavy.
Conclusion：In the injection esomeprazole sodium specific safety experiment that lot number of the present invention is 20150304, blood vessel
Irritation test, muscle single-dose irritation test have no related stimulus, have no haemolysis and allergic reaction；Muscle multiple dosing
Irritation test shows that intramuscular multiple injection has certain irritation to rabbit biceps muscle of thigh, but has restorability；In conjunction with drug
The points for attention of specification：Intramuscular injection is only limitted to use when this approach being needed to be administered, and same position should be avoided to inject repeatedly；
It prompts that when Clinical practice the multiple intramuscular administration in same position should be avoided.
Other unaccounted parts belong to the prior art.
Claims (5)
1. injection esomeprazole sodium, it is characterised in that：For 40mg gauge hypodermic esomeprazole sodium, recipe ingredient
For：
The method for preparing the injection esomeprazole sodium, which is characterized in that include the following steps：
Step 1：Bottle, plug and aluminium lid pre-treatment
1. bottle is lyophilized：Middle borosilicate cillin bottle cleaning, drying and sterilizing, confirmatory detection particulate matter and visible foreign matters, it is spare；
2. rubber plug：Coated rubber plug cleaning, sterilizing, dry, confirmatory detection particulate matter and coated rubber plug loss on drying, control
Coated rubber plug loss on drying≤0.5%, it is spare；
3. aluminium-plastic combined cover：It is spare after sterilizing；
Step 2：It is molten to match
1. 2%NaOH solution is prepared：A certain amount of sodium hydroxide is weighed, adds appropriate water for injection with obtained a concentration of 2%
NaOH solution is cooled to room temperature spare；
2. matrix solution is prepared：Weigh the injection being cooled to room temperature that formula ratio mosatil is dissolved in 94% prescription total amount
Water, water for injection temperature is less than 30 DEG C, with above-mentioned 2%NaOH solution tune pH value to 11.8 ± 0.05；
Match 3. liquid is molten：Formula ratio main ingredient is added into matrix solution, pH value is detected after dissolving completely, when pH value not 11.5 ±
When 0.3 range, continue finally to be weighed surely with water for injection total to prescription to 11.5 ± 0.3 with above-mentioned 2%NaOH solution tune pH value
Amount；When pH value is in 11.5 ± 0.3 range, weighed surely with water for injection to prescription total amount；
Step 3：Depyrogenation and decarbonization filtering
Be added formula ratio medical charcoal, stir evenly rear standing adsorption not less than 30min with depyrogenation, then with 0.22 μm of miillpore filter into
Row decarbonization filtering, obtains intermediate；Intermediate is sampled, is detected by intermediate quality standard；Intermediate can be in room temperature
It is protected from light lower storage 24 hours；
Step 4：Aseptic filtration
Intermediate liquid is subjected to aseptic filtration to the fluid reservoir between B grades of filtrates receptions with 0.22 μm of miillpore filter of concatenated two-stage
Interior, filter pressure control is controlled in 0.1~0.2MPa, filtration time in 6 hours；
Step 5：Sterile filling
According to intermediates content measurement result, filling center loading amount is calculated：
Control loading amount precision is that ± 3% progress liquid is sub-packed in middle borosilicate cillin bottle and partly jumps a queue；Answered in pouring process and
When the filling loading amount of casual inspection；In the case where A grades of laminar flows are protected, the liquid dispensed is sent into freeze dryer immediately；
Step 6：Freeze-drying
1. pre-freeze：Arranging plate layer temperature is -45 DEG C, and when plate layer temperature reaches -45 DEG C, plate layer temperature is raised to -15 DEG C rapidly, is protected
Warm 1h, then plate layer temperature is dropped to -45 DEG C, keep the temperature 2h；
2. primary drying：- 15 DEG C, heating-up time 240min of arranging plate layer temperature, then keep the temperature to observe product ice crystal disappear
Keep the temperature 1~3h again afterwards, you can carry out parsing-desiccation；
3. parsing-desiccation：Heating-up time 60min is set, and is kept the temperature to observing products temperature to keeping the temperature 4h or more again after 30 DEG C；
4. shutting down, vacuum tamponade, outlet；
Step 7：Roll lid, visual inspection outsourcing, warehousing finished products
By outlet product pressure rolling aluminium lid；Lid product will be rolled and carry out lamp inspection, pick out labeling and outer packing after defective work；Send finished product complete
Check in library.
2. injection esomeprazole sodium according to claim 1, it is characterised in that：In step 3, miillpore filter is poly-
Ether sulfone material miillpore filter；In step 4, miillpore filter is polyether sulfone material miillpore filter.
3. injection esomeprazole sodium according to claim 2, it is characterised in that：In step 4, aseptic filtration is carried out
Filter membrane before filtration after carry out integrity of filtration membranes detection.
4. injection esomeprazole sodium according to claim 3, it is characterised in that：It is complete in 8 hours in step 5
At it is filling, partly jump a queue, be transferred in freeze dryer, fill in for coated rubber plug.
5. injection esomeprazole sodium according to claim 4, it is characterised in that：In the primary drying of step 6, always
8~10h of soaking time.
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| CN111973562A (en) * | 2020-09-04 | 2020-11-24 | 四川制药制剂有限公司 | Esomeprazole sodium for injection and preparation method thereof |
| CN114159396A (en) * | 2021-10-21 | 2022-03-11 | 济南同路医药科技发展有限公司 | Espressol omeprazole sodium freeze-dried preparation for injection and preparation method thereof |
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| CN108553413B (en) | 2020-07-07 |
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