CN108498468A - Methylprednisolone sodium succinate for injection - Google Patents
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Abstract
The invention discloses a kind of methylprednisolone sodium succinate for injection.It is 40mg gauge hypodermic Urbason Solubiles, and recipe ingredient is：Methylprednisolone succinate 50.75mg, sodium dihydrogen phosphate 1.6mg, Anhydrous Disodium Phosphate 17.46mg, lactose 25mg, Sodium hydroxide q.s. tune pH value, water for injection are weighed surely to 1g；When for 125mg gauge hypodermic Urbason Solubiles, recipe ingredient is：Methylprednisolone succinate 158.6mg, sodium dihydrogen phosphate 1.6mg, Anhydrous Disodium Phosphate 17.4mg, Sodium hydroxide q.s. tune pH value, water for injection add to and determine weight to 1.5g.The present invention has the advantages that stability is high, single miscellaneous and total miscellaneous less.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more specifically say it is methylprednisolone sodium succinate for injection.
Background technology
Methylprednisolone is middle effect glucocorticoid medicine, has the pharmacology such as anti-inflammatory, immunosupress, antiallergy, Hemorrhagic shock
Effect.The anti-inflammatory effect of the medicine is stronger, is equivalent to 5 times of hydrocortisone, is 1.4 times of prednisone.In numerous sugared cortex
In hormone, the affinity of methylprednisolone and glucocorticoid receptor is most strong, is 12 times of hydrocortisone, 23 times of prednisone.
And mineralocorticoid sample effect (such as water, sodium retention) is faint, about the 1/200 of deoxycortone, and significantly less than prednisone, it is right
The inhibiting effect of hypothalamus-pituitary-adrenal axis is weaker.
Methylprednisolone works rapidly, is easily absorbed by alimentary canal, itself exists in an active, without being through liver conversion
Play its pharmacological action.The drug plasma half-life period of the medicine is 2.3~4 hours, and biological half-life is 12~36 hours, with medication
Form is unrelated.It is most of in blood to be combined with plasma protein (Percentage bound is less than hydrocortisone), it is free with mating type metabolin
It is discharged from urine, is partly discharged with original shape.
The Pharmacokinetic Profile of methylprednisolone is first order kinetics, and parameter is because of experiment, sex, race and disease shape
The difference of condition and show notable difference.
Methylprednisolone is due to pharmacological actions such as powerful anti-inflammatory, immunosupress, antiallergy, Hemorrhagic shocks, clinically extensively
It is general be applied to breathing problem, endocrine disorder, rheumatic disease, collagenosis, hematologic disease, skin disease, allergic state,
The nervous system disease, enterogastric diseases, organ transplant etc..
Under high vacuum condition of the liquid that formula in the prior art is prepared described in this application (1.33Pa), eutectic point
At -5 DEG C or so, therefore when freeze temperature reaches -5 DEG C or more, has part liquid and melt generation liquid, in high vacuum condition
Under, partial liquefaction is caused, spray bottle is caused, the quality of the freeze drying powder injection influenced.
Invention content
The purpose of the invention is to provide a kind of methylprednisolone sodium succinate for injection, stability is good, list is miscellaneous and total miscellaneous
It is less.
To achieve the goals above, the technical scheme is that：Methylprednisolone sodium succinate for injection, feature exist
In：When for 40mg gauge hypodermic Urbason Solubiles, recipe ingredient is：
When for 125mg gauge hypodermic Urbason Solubiles, recipe ingredient is：
When for 500mg gauge hypodermic Urbason Solubiles, recipe ingredient is：
The method for preparing the methylprednisolone sodium succinate for injection, includes the following steps：
Step 1：Bottle, plug and aluminium lid pre-treatment
1. injection bottle：By wash bottle post SOP cleanings, drying and sterilizing, it is placed under B grades of environment under A grades of laminar flows, confirmatory inspection
Particulate matter and visible foreign matters are surveyed, it is spare；Injection bottle is middle borosilicate cillin bottle；
2. rubber plug：It cleaned, sterilized, dried by rubber plug cleaning post SOP, confirmatory detection particulate matter and rubber plug
Loss on drying controls rubber plug loss on drying≤0.5%, spare；
3. aluminium-plastic combined cover：It is spare after being sterilized by aluminium-plastic combined cover sterilizing post SOP；
Step 2：It is molten to match
1. 10%NaOH solution is prepared：A certain amount of sodium hydroxide is weighed, adds appropriate water for injection with obtained a concentration of
10% NaOH solution is cooled to room temperature spare；
2. drug solution preparing：Water for injection is cooled to 15 DEG C~25 DEG C, weighs 70% formula ratio cooling water for injection and is placed in and matches
In flow container, formula ratio sodium dihydrogen phosphate, Anhydrous Disodium Phosphate, the lactose for being only applicable to 40mg specifications is added, stirring and dissolving is extremely
Clarification, adds formula ratio Methylprednisolone succinate and is uniformly dispersed；10%NaOH solution tune pH is slowly added under stirring
Value to solution is clarified, and makes solution final ph in 7.6~7.8 ranges；It is finally weighed surely with water for injection to formula total amount；
Step 3：Depyrogenation and decarbonization filtering
0.1% medical charcoal is added, stirs evenly rear standing adsorption and is not less than 30min, then taken off with 0.22 μm of miillpore filter
Charcoal filters, and obtains intermediate；Intermediate is sampled, is detected by intermediate quality standard；Intermediate can store up at room temperature
It deposits 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；The filter membrane of aseptic filtration is carried out in mistake
Integrity of filtration membranes detection should all be carried out before and after filter；
Step 5：Sterile filling
According to intermediates content measurement result, filling center loading amount is calculated：
Specification 40mg：
Specification 125mg：
Specification 500mg：
Control loading amount precision is ± 3% progress liquid packing and partly jumps a queue；Answer timely casual inspection filling in pouring process
Loading amount；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 is to -45 DEG C, plate layer temperature is raised to -15 DEG C rapidly,
1h is kept the temperature, then plate layer temperature is dropped to -45 DEG C, keeps the temperature 2h；
2. primary drying：- 15 DEG C of 40mg specifications and 125mg specification arranging plate layers temperature, then heating-up time 120min is protected
Temperature heat preservation 2h or more to after observing the disappearance of product ice crystal can carry out parsing-desiccation；500mg specification arranging plate layers temperature -15
DEG C, heating-up time 120min, parsing-desiccation can be carried out by then keeping the temperature to after observing the disappearance of product ice crystal heat preservation 3h or more；
3. parsing-desiccation：Heating-up time 120min is set, continues 3~7h after heat preservation to 30 DEG C of product temperature again, 500mg specifications are protected
Continue 5~10h again after temperature to 30 DEG C of product temperature；
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 6 hours it is filling, partly jump a queue, be transferred in freeze dryer.
In the above-mentioned technical solutions, in the primary drying of step 6, total soaking time of 40mg specifications and 125mg specifications is
16h~18h；Total soaking time of 500mg specifications is 30h~32h.
In the above-mentioned technical solutions, lactose meets injection stage lactose standard.
In the above-mentioned technical solutions, in step 6, heating-up time 120min, heat preservation to 30 DEG C of product temperature are set in parsing-desiccation
Continue 5h again afterwards, 500mg specifications continue 8h again after keeping the temperature to 30 DEG C of product temperature.
The invention has the advantages that：
(1) borosilicate cillin bottle during injection bottle of the present invention uses, can ensure that product quality, and when storage does not generate impurity, keeps away
Exempt to generate glass flake；
(2) present invention is by using the technique of multigelation, and good product quality, product stability is good, it is single it is miscellaneous, it is total it is miscellaneous compared with
It is few.
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.
Methylprednisolone sodium succinate for injection, it is characterised in that：When for 40mg gauge hypodermic Urbason Solubiles,
Recipe ingredient is：
When for 125mg gauge hypodermic Urbason Solubiles, recipe ingredient is：
When for 500mg gauge hypodermic Urbason Solubiles, recipe ingredient is：
The method for preparing the methylprednisolone sodium succinate for injection, includes the following steps：
Step 1：Bottle, plug and aluminium lid pre-treatment
1. injection bottle：By wash bottle post SOP cleanings, drying and sterilizing, it is placed under B grades of environment under A grades of laminar flows, confirmatory inspection
Particulate matter and visible foreign matters are surveyed, it is spare；Injection bottle is middle borosilicate cillin bottle；
2. rubber plug：It cleaned, sterilized, dried by rubber plug cleaning post SOP, confirmatory detection particulate matter and rubber plug
Loss on drying controls rubber plug loss on drying≤0.5%, spare；
3. aluminium-plastic combined cover：It is spare after being sterilized by aluminium-plastic combined cover sterilizing post SOP；
Step 2：It is molten to match
1. 10%NaOH solution is prepared：A certain amount of sodium hydroxide is weighed, adds appropriate water for injection with obtained a concentration of
10% NaOH solution is cooled to room temperature spare；
2. drug solution preparing：Water for injection is cooled to 15 DEG C~25 DEG C, weighs 70% formula ratio cooling water for injection and is placed in and matches
In flow container, formula ratio sodium dihydrogen phosphate, Anhydrous Disodium Phosphate, the lactose for being only applicable to 40mg specifications is added, stirring and dissolving is extremely
Clarification, adds formula ratio Methylprednisolone succinate and is uniformly dispersed；10%NaOH solution tune pH is slowly added under stirring
Value to solution is clarified, and makes solution final ph in 7.6~7.8 ranges；It is finally weighed surely with water for injection to formula total amount；
Step 3：Depyrogenation and decarbonization filtering
0.1% 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
It stores 24 hours at room temperature；
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；The filter membrane of aseptic filtration is carried out in mistake
Integrity of filtration membranes detection should all be carried out before and after filter；
Step 5：Sterile filling
According to intermediates content measurement result, filling center loading amount is calculated：
Specification 40mg：
Specification 125mg：
Specification 500mg：
Control loading amount precision is ± 3% progress liquid packing and partly jumps a queue；Answer timely casual inspection filling in pouring process
Loading amount；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 is to -45 DEG C, plate layer temperature is raised to -15 DEG C rapidly,
1h is kept the temperature, then plate layer temperature is dropped to -45 DEG C, keeps the temperature 2h；
2. primary drying：- 15 DEG C of 40mg specifications and 125mg specification arranging plate layers temperature, then heating-up time 120min is protected
Temperature heat preservation 2h or more to after observing the disappearance of product ice crystal can carry out parsing-desiccation；500mg specification arranging plate layers temperature -15
DEG C, heating-up time 120min, parsing-desiccation can be carried out by then keeping the temperature to after observing the disappearance of product ice crystal heat preservation 3h or more；
3. parsing-desiccation：Heating-up time 120min is set, continues 3~7h after heat preservation to 30 DEG C of product temperature again, 500mg specifications are protected
Continue 5~10h again after temperature to 30 DEG C of product temperature；
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 6 hours it is filling, partly jump a queue, be transferred in freeze dryer.
Further, in the primary drying of step 6, total soaking time of 40mg specifications and 125mg specifications be 16h~
18h；Total soaking time of 500mg specifications is 30h~32h.
Still further, lactose meets injection stage lactose standard.
Still further, in step 6, heating-up time 120min is set in parsing-desiccation, is held again after heat preservation to 30 DEG C of product temperature
Continuous 5h, 500mg specifications continue 8h again after keeping the temperature to 30 DEG C of product temperature.
Embodiment
Methylprednisolone sodium succinate for injection, is 40mg gauge hypodermic Urbason Solubiles, and recipe ingredient is：Amber
Amber acid methylprednisolone 5.075g, sodium dihydrogen phosphate 0.16g, Anhydrous Disodium Phosphate 1.746g, lactose 2.5g, sodium hydroxide are suitable
Amount adjusts PH to 7.6, water for injection is weighed surely to 100ml.
The method for preparing the methylprednisolone sodium succinate for injection, includes the following steps：
Step 1：Bottle, plug and aluminium lid pre-treatment
Step 2：It is molten to match
1. 10%NaOH solution is prepared：A certain amount of sodium hydroxide is weighed, adds appropriate water for injection with obtained a concentration of
10% NaOH solution is cooled to room temperature spare；
2. drug solution preparing：Water for injection is cooled to 15 DEG C~25 DEG C, weighs 70% formula ratio cooling water for injection and is placed in and matches
In flow container, formula ratio sodium dihydrogen phosphate, Anhydrous Disodium Phosphate, the lactose for being only applicable to 40mg specifications is added, stirring and dissolving is extremely
Clarification, adds formula ratio Methylprednisolone succinate and is uniformly dispersed；10%NaOH solution tune pH is slowly added under stirring
Value to solution is clarified, and makes solution final ph in 7.6~7.8 ranges；It is finally weighed surely with water for injection to formula total amount；
Step 3：Depyrogenation and decarbonization filtering
Step 4：Aseptic filtration
Step 5：Sterile filling
According to intermediates content measurement result, filling center loading amount is calculated：
Specification 40mg：
Control loading amount precision is ± 3% progress liquid packing and partly jumps a queue；Answer timely casual inspection filling in pouring process
Loading amount；In the case where A grades of laminar flows are protected, the liquid dispensed is sent into freeze dryer immediately；
Step 6：Freeze-drying
The parameters of freeze-drying process of 40mg specifications is shown in Table 1.
The parameters of freeze-drying process of 1 40mg specifications of table
The sample that different in moisture is obtained by different lyophilized techniques, investigates its stability, it is best to filter out stability
Sample, while determining the freeze-drying curve of this product.Moisture is weighed by loss on drying.Product is stablized in order to investigate loss on drying
Property influence, the satisfactory embodiment 2 of loss on drying, embodiment 3 and 4 sample of embodiment be put into 60 DEG C and investigate 10 by the present invention
Related substance is detected after it, testing result is shown in Table 2.
Testing result is investigated in influence of 2 loss on drying of table to product quality
Find out from testing result, after high temperature 10 days, loss on drying is increased, and during storage may be prompted
Because rubber plug moisture is into the growth for causing finished product loss on drying, therefore the initial loss on drying of the present invention should be less than commercially available product；Implement
2 loss on drying of example is larger, and methylprednisolone amplification of dissociating after high temperature 10 days is larger, prompts the product to moisture-sensitive, dry to lose
The smaller quality of weight is more stable；With 4 loss on drying of embodiment 0.6% or so, dry than commercially available product methylprednisolone loses embodiment 3
It is small to weigh 0.9%；Meanwhile the lyophilized technique of embodiment 3 takes short, low energy consumption, and therefore, embodiment 3 is 40mg gauge hypodermic first
The best lyophilized technique of prednisolone sodium succinate, lyophilization cycle are about 26.5h.
The impurity content of Urbason Solubile is as follows：
Impurity C
Chemical name：(EZ) the pregnant steroid -1,4,17 (20) of -6 Alpha-Methyl of -11 β, 20- dihydroxy-triolefin -3- ketone -21- aldehyde
Structural formula：
Or (Z)-isomers
Molecular formula：C22H28O4
Molecular weight：356.46
Impurity D
Chemical name：4- [(- 6 pregnant steroid -1,4- diene -17- bases of Alpha-Methyl -3,20- dioxies of 11 β, 21- dihydroxy) oxygen] -
4- ketobutyric acids
Structural formula：
Molecular formula：C26H34O8
Molecular weight：474.54
Impurity E
Chemical name：4- [(- 6 pregnant steroid -4- alkene -21- bases of Alpha-Methyl -3,20- dioxies of 11 β, 17- dihydroxy) oxygen] -4- oxygen
For butyric acid
Structural formula：
Molecular formula：C26H34O8
Molecular weight：474.54
Methylprednisolone sodium succinate for injection, is 125mg gauge hypodermic Urbason Solubiles, and recipe ingredient is：
Methylprednisolone succinate 21.15g, sodium dihydrogen phosphate 0.213g, Anhydrous Disodium Phosphate 2.32g, Sodium hydroxide q.s. adjust PH
It is weighed surely to 200ml to 7.7, water for injection.
The method for preparing the methylprednisolone sodium succinate for injection, includes the following steps：
Step 1：Bottle, plug and aluminium lid pre-treatment
Step 2：It is molten to match
1. 10%NaOH solution is prepared：A certain amount of sodium hydroxide is weighed, adds appropriate water for injection with obtained a concentration of
10% NaOH solution is cooled to room temperature spare；
2. drug solution preparing：Water for injection is cooled to 15 DEG C~25 DEG C, weighs 70% formula ratio cooling water for injection and is placed in and matches
In flow container, formula ratio sodium dihydrogen phosphate, Anhydrous Disodium Phosphate, the lactose for being only applicable to 40mg specifications is added, stirring and dissolving is extremely
Clarification, adds formula ratio Methylprednisolone succinate and is uniformly dispersed；10%NaOH solution tune pH is slowly added under stirring
Value to solution is clarified, and makes solution final ph in 7.6~7.8 ranges；It is finally weighed surely with water for injection to formula total amount；
Step 3：Depyrogenation and decarbonization filtering
Step 4：Aseptic filtration
Step 5：Sterile filling
According to intermediates content measurement result, filling center loading amount is calculated：
Specification 40mg：
Control loading amount precision is ± 3% progress liquid packing and partly jumps a queue；Answer timely casual inspection filling in pouring process
Loading amount；In the case where A grades of laminar flows are protected, the liquid dispensed is sent into freeze dryer immediately；
Step 6：Freeze-drying
The parameters of freeze-drying process of 125mg specifications is shown in Table 3.
The parameters of freeze-drying process of 3 125mg specifications of table
The sample that different in moisture is obtained by different lyophilized techniques, investigates its stability, it is best to filter out stability
Sample, while determining the freeze-drying curve of this product；Moisture is weighed by loss on drying；Product is stablized in order to investigate loss on drying
Property influence, the satisfactory embodiment 6 of loss on drying, embodiment 7 and 8 sample of embodiment be put into 60 DEG C and investigate 10 by the present invention
Related substance is detected after it, testing result is shown in Table 4.
Testing result is investigated in influence of 4 loss on drying of table to product quality
Find out from testing result, after high temperature 10 days, loss on drying is increased, and during storage may be prompted
Because rubber plug moisture is into the growth for causing finished product loss on drying, therefore the initial loss on drying of the present invention should be less than commercially available product；Implement
7 loss on drying of example is larger, and methylprednisolone amplification of dissociating after high temperature 10 days is larger, prompts the product to moisture-sensitive, dry to lose
The smaller quality of weight is more stable；With 8 loss on drying of embodiment 0.6% or so, dry than commercially available product methylprednisolone loses embodiment 6
It is small to weigh 0.9%；Meanwhile the lyophilized technique of embodiment 8 takes short, low energy consumption, and therefore, embodiment 8 is best lyophilized technique, freeze-drying
Period is about 29h.
The formula and preparation process of 500mg gauge hypodermic Urbason Solubiles are sprinkled with 125mg gauge hypodermics first
Nylon sodium succinate.
Product prepared by three specifications meets quality standard draft regulation.
Methylprednisolone sodium succinate for injection of the present invention is detected
1, the related substance detection of methylprednisolone sodium succinate for injection of the present invention
With the methylprednisolone sodium succinate for injection quality standard draft drafted to sample made from embodiment 3 and embodiment 8
Product and original grind commercially available product and carry out full inspection, and comparative study is carried out to related substance；Sample and city made from embodiment 3 and embodiment 8
The product of selling are carried out at the same time compatibility mechanism, and indices are met the requirements of the standard.
1) 40mg specifications preparation correlation properties
1. the leading indicator comparing result of the present invention and commercially available product
Sample：According to three batches of middle test agents of 40mg specifications made from embodiment 3, lot number is respectively 20160205,
20160207 and 20160209；
Commercially available product, lot number YO6677.
Compare leading indicator：Related substance
Investigation the results are shown in Table 5.
Comparing result of the table 5 in relation to substance
Conclusion：The impurity number of three batches of middle test agents of this product 40mg specifications, impurity position, the miscellaneous amount of each list and total miscellaneous amount are basic
Unanimously, and with the impurity of commercially available product it composes almost the same；As can be seen from the above table, the injection methylprednisolone of 40mg specifications of the present invention
Sodium succinate list is miscellaneous, total miscellaneous is respectively less than commercially available product；The related substance detection of each sample meets this product clearance quality standard draft
Regulation.
2. compatibility mechanism
The results showed：The methylprednisolone sodium succinate for injection of 40mg specifications of the present invention can with 5% glucose solution,
Physiological saline or the mixed liquor of 5% glucose and 0.45% sodium chloride carry out compatibility, the quality within 48 hours of the solution after preparation
Stablize, the fingers such as character, clarity of solution, basicity, free methylprednisolone, related substance, visible foreign matters, particulate matter and content
Mark meets mark regulation, and index variation tendency is consistent with commercially available product.
2) 125mg and 500mg specification preparation correlation properties
1. the leading indicator comparing result of the present invention and commercially available product
Sample：According to three batches of middle test agents of 125mg specifications made from embodiment 8, lot number is respectively 20160212,
20160214 and 20160216；
According to three batches of middle test agents of 500mg specifications made from embodiment 8, lot number is respectively 20160219,20160222 and
20160225；
500mg commercially available products, lot number Y02927.
Compare leading indicator：Related substance
Investigation the results are shown in Table 6.
Comparing result of the table 6 in relation to substance
Conclusion：This product 125mg specifications, the impurity number of test agent, impurity position, each list are miscellaneous in three batches of 500mg specifications
Amount and total miscellaneous amount are almost the same, and almost the same with the impurity of commercially available product spectrum；As can be seen from the above table, 125mg specifications of the present invention,
The methylprednisolone sodium succinate for injection lists of 500mg specifications is miscellaneous, total miscellaneous is respectively less than commercially available product；The related substance detection of each sample accords with
Close the regulation of this product clearance quality standard draft.
2. compatibility mechanism
Conclusion：The methylprednisolone sodium succinate for injection and 5% glucose water of 125mg specifications and 500mg specifications of the present invention
Solution, physiological saline or the mixed liquor of 5% glucose and 0.45% sodium chloride carry out compatibility, and the solution after preparation is within 48 hours
Stable quality, character, clarity of solution, basicity, free methylprednisolone, related substance, visible foreign matters, particulate matter and content
Etc. indexs meet mark regulation, index variation tendency is consistent with commercially available product.
2, methylprednisolone sodium succinate for injection Detection of Stability of the present invention
1) standard stability detects
Result and the commercially available product investigation that the standard stability trials that the present invention carries out are investigated the results are shown in Table 7.
The result that 7 standard stability trials of table are investigated
2) product stability detects in use
The result of product stability experiment investigation in 8 use of table
3, accelerated test
Accelerated test sample message is shown in Table 9, and test result is shown in Table 10~table 11.
9 accelerated test sample message of table
10 methylprednisolone sodium succinate for injection accelerated test result one of table
The related material result of 11 methylprednisolone sodium succinate for injection accelerated test of table two
In above table, "-" indicates that the impurity of impurity or impurity content less than 0.01% is not detected.
It is preferable, single miscellaneous and total miscellaneous less that stability of the present invention can be obtained by upper table 7- tables 11.
Zoopery
Methylprednisolone sodium succinate for injection is provided by Hubei people pharmaceutical Co. Ltd, non-clinical by Chengdu qi xanthate object
Research Co., Ltd completes the specific safety experimental study of 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 methylprednisolone sodium succinate for injection vascular stimulation tests, rabbit auricular vein control group, commercially available group and
Tested group occurs without congested, bleeding and degeneration necrosis phenomenon, also without pathologic lesion, shows injection methylprednisolone of the present invention
Sodium succinate (it is 20160611 sample that the present invention, which selects lot number) intravenously administrable does not generate stimulate the reaction to rabbit ear blood vessel；
(2) in methylprednisolone sodium succinate for injection muscle single-dose irritation test, the control of rabbit leg biceps muscle of thigh
Group, commercially available group and tested group occur without red and swollen, congested and degeneration necrosis phenomenon, also without pathologic lesion, show injection of the present invention
With Urbason Solubile (lot number 20160611) intramuscular single injection stimulate the reaction is not generated to rabbit biceps muscle of thigh；
(3) in methylprednisolone sodium succinate for injection muscle multiple dosing irritation test, the control of rabbit leg biceps muscle of thigh
Group occurs 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；7 days visible rabbit bicepss muscle of thigh of commercially available group of recovery become
Property, necrosis and cell infiltration；Show that methylprednisolone sodium succinate for injection of the present invention (lot number 20160611) is intramuscular repeatedly
Injection has certain irritation to rabbit biceps muscle of thigh, but has restorability；
(4) in the experiment of methylprednisolone sodium succinate for injection hemolytic, methylprednisolone sodium succinate for injection of the present invention (is criticized
Number for 20160611) it is test tube without haemolysis occur, red blood cell is dispersible after shaking, no coacervation；
(5) in methylprednisolone sodium succinate for injection whole body active sensitivity test, (instep is quiet when tested group of cavy excites
Arteries and veins is injected) do not occur systemic anaphylaxis, show that methylprednisolone sodium succinate for injection of the present invention (lot number 20160611) is right
Cavy does not generate predisposing medical conditions；
(6) in methylprednisolone sodium succinate for injection passive cutaneous anaphylaxis test, after cavy excitation, tested group of locus coeruleus is straight
Diameter, leachate the absorbance indifference compared with negative group, there were significant differences compared with positive group, shows that injection first of the present invention is sprinkled
Nylon sodium succinate (lot number 20160611) does not generate passive cutaneous anaphylaxis to cavy.
Conclusion：In the methylprednisolone sodium succinate for injection specific safety experiment that lot number of the present invention is 20160611, blood
Pipe irritation test, muscle single-dose irritation test have no related stimulus, have no haemolysis and allergic reaction；Muscle is repeatedly given
Medicine irritation test shows that intramuscular multiple injection has certain irritation to rabbit biceps muscle of thigh, but has restorability；In conjunction with medicine
The points for attention of product specification：Intramuscular injection is only limitted to use when this approach being needed to be administered, and same position should be avoided to note repeatedly
It penetrates；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 (7)
1. methylprednisolone sodium succinate for injection, it is characterised in that：When for 40mg gauge hypodermic Urbason Solubiles, matching
Square group is divided into：
When for 125mg gauge hypodermic Urbason Solubiles, recipe ingredient is：
When for 500mg gauge hypodermic Urbason Solubiles, recipe ingredient is：
The method for preparing the methylprednisolone sodium succinate for injection, includes the following steps：
Step 1：Bottle, plug and aluminium lid pre-treatment
1. injection bottle：It by wash bottle post SOP cleanings, drying and sterilizing, is placed under B grades of environment under A grades of laminar flows, confirmatory detection is not
Dissolubility particle and visible foreign matters, it is spare；Injection bottle is middle borosilicate cillin bottle；
2. rubber plug：It cleaned, sterilized, dried by rubber plug cleaning post SOP, confirmatory detection particulate matter and rubber plug drying
Weightlessness controls rubber plug loss on drying≤0.5%, spare；
3. aluminium-plastic combined cover：It is spare after being sterilized by aluminium-plastic combined cover sterilizing post SOP；
Step 2：It is molten to match
1. 10%NaOH solution is prepared：A certain amount of sodium hydroxide is weighed, adds appropriate water for injection with obtained a concentration of 10%
NaOH solution is cooled to room temperature spare；
2. drug solution preparing：Water for injection is cooled to 15 DEG C~25 DEG C, weighs 70% formula ratio cooling water for injection and is placed in Agitation Tank
In, formula ratio sodium dihydrogen phosphate, Anhydrous Disodium Phosphate, the lactose for being only applicable to 40mg specifications is added, stirring and dissolving is extremely clarified,
Formula ratio Methylprednisolone succinate is added to be uniformly dispersed；10%NaOH solution tune pH value is slowly added under stirring to molten
Liquid is clarified, and makes solution final ph in 7.6~7.8 ranges；It is finally weighed surely with water for injection to formula total amount；
Step 3：Depyrogenation and decarbonization filtering
0.1% medical charcoal is added, stirs evenly rear standing adsorption and is not less than 30min, then carries out de- charcoal mistake with 0.22 μm of miillpore filter
Filter, obtains intermediate；Intermediate is sampled, is detected by intermediate quality standard；Intermediate can store 24 at room temperature
Hour；
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；Carry out the filter membrane of aseptic filtration before filtration
After should all carry out integrity of filtration membranes detection；
Step 5：Sterile filling
According to intermediates content measurement result, filling center loading amount is calculated：
Specification 40mg：
Specification 125mg：
Specification 500mg：
Control loading amount precision is ± 3% progress liquid packing and partly jumps a queue；The filling loading amount of timely casual inspection is answered in pouring process；
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 is to -45 DEG C, plate layer temperature is raised to -15 DEG C rapidly, is kept the temperature
1h, then plate layer temperature is dropped to -45 DEG C, keep the temperature 2h；
2. primary drying：- 15 DEG C, heating-up time 120min of 40mg specifications and 125mg specification arranging plate layers temperature, then keep the temperature to
Heat preservation 2h or more can carry out parsing-desiccation after observing the disappearance of product ice crystal；- 15 DEG C of 500mg specification arranging plate layers temperature rises
Warm time 120min, parsing-desiccation can be carried out by then keeping the temperature to after observing the disappearance of product ice crystal heat preservation 3h or more；
3. parsing-desiccation：Heating-up time 120min is set, continues 3~7h after heat preservation to 30 DEG C of product temperature again, 500mg specifications keep the temperature to
Continue 5~12h again after 30 DEG C of product temperature；
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. methylprednisolone sodium succinate for injection according to claim 1, it is characterised in that：In step 3, miillpore filter is
Polyether sulfone material miillpore filter；In step 4, miillpore filter is polyether sulfone material miillpore filter.
3. methylprednisolone sodium succinate for injection according to claim 2, it is characterised in that：In step 4, degerming is carried out
The filter membrane of filter before filtration after carry out integrity of filtration membranes detection.
4. methylprednisolone sodium succinate for injection according to claim 3, it is characterised in that：In step 5, in 6 hours
Complete it is filling, partly jump a queue, be transferred in freeze dryer.
5. methylprednisolone sodium succinate for injection according to claim 4, it is characterised in that：In the primary drying of step 6,
Total soaking time of 40mg specifications and 125mg specifications is 16h~18h；Total soaking time of 500mg specifications is 30h~32h.
6. methylprednisolone sodium succinate for injection according to claim 5, it is characterised in that：Lactose meets injection stage lactose
Standard.
7. methylprednisolone sodium succinate for injection according to claim 6, it is characterised in that：In step 6, in parsing-desiccation
Heating-up time 120min is set, continues 5h after heat preservation to 30 DEG C of product temperature again, 500mg specifications continue again after keeping the temperature to 30 DEG C of product temperature
8h。
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