CN104434821B - A kind of gabexate mesylate for injection compositions and preparation method thereof - Google Patents
A kind of gabexate mesylate for injection compositions and preparation method thereof Download PDFInfo
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- CN104434821B CN104434821B CN201410755480.2A CN201410755480A CN104434821B CN 104434821 B CN104434821 B CN 104434821B CN 201410755480 A CN201410755480 A CN 201410755480A CN 104434821 B CN104434821 B CN 104434821B
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Abstract
The invention discloses a kind of gabexate mesylate for injection compositions and preparation method thereof.The described each unit dose of gabexate mesylate for injection compositions comprises gabexate mesilate 0.1g, mannitol 0.2g, pharmaceutically acceptable acetic acid sodium acetate buffer salt.Said composition is at preparation process steady quality, and relevant content of material is low, and prescription is simple, with low cost, is suitable for industrialized great production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of gabexate mesylate for injection compositions and system thereof
Preparation Method.
Background technology
The chemical name of gabexate mesilate is p-(6-guanidine hexylyloxy) ethyl benzoate mesylate, molecular formula
For C16H23N3O4 CH4O3S, molecular weight is 417.48.
Gabexate mesilate is the one non-peptide albuminoid hydrolase inhibitor that the seventies, Japan developed, 1978
By the production and sales of little Ye pharmaceutical industries company of Japan, trade name FOY.It is little that gabexate mesilate has molecular weight,
The feature of non-immunogenicity.The eggs such as trypsin, kallikrein, plasmin, thrombin can be suppressed
The activity of white enzyme, thus suppress the pathophysiological change that these enzymes are caused.For treating acute mild (edema
Type) pancreatitis it can also be used to Acute haemorrhagic-necrotizing pancreatitis auxiliary treatment.
Gabexate mesilate is soluble in water, but unstable, and facile hydrolysis becomes ethylparaben, by force
In acid, alkaline aqueous solution, also instability, ester linkage breaking open loop, easily causes adverse effect to patient.For
This, many producers add the pharmaceutic adjuvant stability with raising injection in Gabexate of methane-sulfonic acid injection, but
Be effect be not fine, current commercialized product mostly is lyophilized formulations.
Japan Patent JPS60255723 discloses the preparation method of a kind of gabexate mesilate freeze-drying prods, the party
Product prepared by method has good heat stability and dissolubility.The method, in freezing dry process, uses two
Secondary lyophilizing, will freeze-drying prods quick freezing to less than-25 DEG C, then at-2 DEG C～18 DEG C of heat dryings, dimension
Holding at least 30 minutes, then, product is frozen to less than-25 DEG C again, carries out vacuum at much lower pressure
It is dried.The production time of this freeze-drying prods is longer, and complex operation adds production cost.
Japan Patent JPS63270623 (A) discloses the preparation method of a kind of gabexate mesilate freeze-drying prods.
Water-miscible organic solvent (ethanol, methanol, the acetone of 0.5%～10% is added in gabexate mesilate solution
Deng), lyophilization again after stirring, the method can make the cryodesiccated time shorten nearly half, but conduct
The product of a kind of drug administration by injection, adds organic solvent and there is safety aspect problem in preparation process.
CN101455647A discloses a kind of Gabexate mesylate freeze-drying preparation for Injection and preparation method thereof, will
Mannitol adds water for injection and dissolves, and after adding gabexate mesilate mix homogeneously, lyophilized formulations is made in lyophilizing,
Wherein the ratio of gabexate mesilate and mannitol is 1: 1-2, PH4.5.The prescription of this invention is simple, lyophilizing
Method is common method, but this freeze-drying prods long-term storage less stable.
CN102526017A discloses the system of a kind of Gabexate mesilate pharmaceutical composition and lyophilized injectable powder thereof
Preparation Method, described Gabexate mesilate pharmaceutical composition includes gabexate mesilate, vitamin C and glycine,
Each composition weight number is: gabexate mesilate 50～200, vitamin C 200～900, glycine 200～
1200.The prescription of this lyophilized formulations is more complicated, and these all can increase the quality risk of gabexate mesilate injection.
CN103211774A discloses a kind of gabexate mesylate for injection compositions and preparation method thereof.The party
Method uses two step dosing methods in preparation process, first dissolves adjuvant mannitol, adds medicinal charcoal, high temperature adsorption,
Add principal agent gabexate mesilate after filtration, after fine straining, be prepared as lyophilized formulations.Owing in the method, medicinal charcoal is inhaled
Temperature time attached is 60 DEG C～80 DEG C, i.e. adds gabexate mesilate after filtered while hot so that after principal agent dissolves,
Higher by temperature, cause gabexate mesilate to hydrolyze, make that finished product has related substance higher, product is steady in a long-term
Property is poor.
In order to reduce injection quality risk, the requirement having related substance to control injection is more and more higher.Injection
Gabexate mesilate national drug standards WS1-(X-323)-2004Z, not about known impurities in its check item
The control of related substance is had with other.And the gabexate mesylate for injection national drug standards of follow-up promulgation
WS1-(X-323)-2004Z-2011, then adds known impurities ethylparaben in its check item, with
And other are about the control requirement of material, limit standard is 0.5% and 1.0% respectively.This target level of product quality
Improve, formulation and technology is proposed requirements at the higher level.
Prior art or employing secondary lyophilizing, or the two step dosing methods of employing so that production operation is loaded down with trivial details, during lyophilizing
Between longer, add production cost, and some finished product long-time stability be bad, relevant levels of substance is higher；
Or in prescription, add organic solvent, or add some adjuvants with pharmacologically active, this can increase injection
Hidden danger of quality, more considerably increases the risk of drug safety on Clinical practice.Along with what product quality was required
More and more higher, in the urgent need to exploitation, a kind of preparation technology is simple, is suitable for industrialized large-scaled production, low production cost,
Most importantly the relevant levels of substance of medicine is low, quality stability good, and the mesylate for injection of drug safety adds shellfish
Ester compositions and preparation technology thereof.
Summary of the invention
Object of the present invention is to provide a kind of gabexate mesylate for injection compositions, the compositions of the present invention
Relevant levels of substance is low, steady quality, and preparation technology is simple, and production cost is low.Solve prior art to exist
Defect.
The present inventor finds after research, and gabexate mesilate has instability under facile hydrolysis, hot conditions
Feature, the most sensitive to pH value, pH value change has also resulted in the most greatly related substance and has raised.In order to solve injection
With gabexate mesilate compositions i.e. freeze-dried powder in the unstability of preparation process, cause having related substance to raise
Problem, through numerous studies and scientific experiments, finds, by adding buffer salt in prescription, to control principal agent and add
The pH value of solution front and back, provides stable pH environment for principal agent gabexate mesilate, can effectively reduce first
The hydrolysis in preparation process of the sulfonic acid gabexate.Principal agent is molten simultaneously join during use lower temperature, it is possible in case
Only principal agent hydrolysis.It addition, control the maximum temperature of goods when pre-freeze speed and redrying in freeze-drying process,
Moisture content of finished products can be controlled at reduced levels, thus reduce the product hydrolysis in storage period, and add buffering
Ensure after salt that product long-term storage is stable, thus complete the present invention.
Specifically, in research process, the present inventor is by the most repeatedly debugging and measuring gabexate mesilate
Add the pH value of solution before and after dissolving, find, when the pH of solution controls in 4.4～4.8 before and after dissolving, to freeze
Finished product after Gan is possible not only to meet (the gabexate mesylate for injection national drug mark of acidity requirements in finished product standard
Quasi-WS1The detection method of-(X-323)-2004Z-2011 regulation acidity is: finished product one bottle, fills jetting 10ml,
After dissolving, pH value should be 4.0～5.0), and principal agent gabexate mesilate during drug solution preparing can be reduced
Hydrolysis, also can make relevant thing control at reduced levels.Control solution before and after gabexate mesilate addition is dissolved
PH value can realize by adding buffer salt and pH adjusting agent.By such medicinal buffer salts numerous are sieved
Choosing, final choice acetic acid and sodium acetate buffer salt.During preparing gabexate mesylate for injection compositions,
Before adding gabexate mesilate, first add a certain amount of solid sodium acetate in the solution, then use acetum
The pH of regulation solution, the pH making solution is 4.4～4.8, after adding gabexate mesilate dissolving, if
PH is the most within the range, it is also possible to acetic acid or sodium acetate solution regulation, makes the pH of medicinal liquid be maintained at 4.4～4.8.
Also gabexate mesilate hydrolysis can be affected, it is therefore desirable to control moisture in dried frozen aquatic products due to the moisture in finished product
It is kept low, through the further investigation to lyophilizing parameter, finds to slow down speed during pre-freeze, work as lyophilizing
After the temperature of product is rapidly achieved 0 DEG C, then products temperature is made to be reduced to-15 DEG C through 30min～1h, to improve
Efficiency during follow-up redrying.Meanwhile, during redrying, goods need to be made to be warming up to 35 DEG C, and keep 4h～
5.5h.This freeze-drying process can make have related substance not increase in freeze-drying prods, can make product water simultaneously
Divide and be kept low.When using the gabexate mesylate for injection national drug standards
When the method for WS1-(X-323)-2004Z-2011 defined detects, its loss on drying can control below 0.5%
(standard is 1.0%).
For realizing the purpose of the present invention, it is provided that following embodiment:
In one embodiment, a kind of gabexate mesylate for injection compositions of the present invention, per unit preparation by
Gabexate mesilate 0.1g, mannitol 0.2g and pharmaceutically acceptable Acetic acid-sodium acetate buffer salt composition, its
It is characterised by per unit preparation that the amount of sodium acetate added as solid is 0.002g～0.02g.
In the above-described embodiment, the gabexate mesilate compositions of the present invention, the amount of described addition sodium acetate is excellent
Elect 0.004g～0.016g as.
In the above-described embodiment, the gabexate mesilate compositions of the present invention, described compositions is in preparation process
Before and after the addition of middle gabexate mesilate, the pH of solution is 4.4～4.8.
In another embodiment, the purpose of the present invention additionally provides a kind of injection first preparing the invention described above
The method of sulfonic acid gabexate compositions, comprises the following steps:
1) water for injection is cooled to 15 DEG C ± 2 DEG C, takes the water for injection after the cooling of recipe quantity about 80%, adds
The mannitol of recipe quantity, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving becomes solution, molten with acetic acid
The pH of liquid regulation solution is 4.4～4.8；
2) adding the gabexate mesilate of recipe quantity in upper step gained solution, stirring and dissolving becomes medicinal liquid, measures medicine
The pH of liquid, if it is necessary, the pH by sodium acetate solution or acetum regulation medicinal liquid is 4.4～4.8, adds
Surplus water for injection, constant volume；
3) in terms of g/ml, in medicinal liquid, add the medicinal charcoal of 0.05%～0.1%, stir 20～30 minutes, slightly
The de-charcoal of filter, then cross 0.45 μm and the microporous filter membrane of 0.22 μm or filter element respectively, fine straining is degerming；
4) detect product index in the middle of degerming rear medicinal liquid, by every bottle of 0.1g Han gabexate mesilate, by liquid medicine filling in
In 7ml cillin bottle, every bottle of about 2.0ml, the cillin bottle goods of canned medicinal liquid are put in freeze drying box,
Lyophilization, is dried after terminating, vacuum tamponade, outlet Zha Gai, and lamp inspection gets product.
In above-mentioned another embodiment, the method for the present invention, wherein, and described lyophilization, farther include
Lower step:
1) by goods (i.e. the cillin bottle of liquid drug) quick freezing to 0 DEG C, then cooling 30min～1h
Product is made to be chilled to-15 DEG C, then quick freezing to less than-40 DEG C, make goods keep 3h below-40 DEG C；
2) cold-trap refrigeration, evacuation, vacuum degree control between 20 handkerchiefs～35 handkerchiefs, then heat drying；
3), when being dried, first allow goods be rapidly heated-15 DEG C, then control programming rate, carry out temperature programming,
Heat up 5 DEG C every time, until products temperature reaches 15 DEG C, temperature-rise period keeps flaggy temperature and goods temperature
Degree difference 10 DEG C～15 DEG C；
4) it is rapidly heated, makes products temperature reach 35 DEG C, and keep 4h～5.5h, complete lyophilization.
Specifically, the gabexate mesylate for injection compositions of the present invention, can realize by below scheme.
The gabexate mesylate for injection compositions of the present invention, per unit preparation is by gabexate mesilate 0.1g, sweet
Dew alcohol 0.2g and pharmaceutically acceptable Acetic acid-sodium acetate buffer salt composition, wherein, conduct in per unit preparation
The amount of the sodium acetate that solid adds is 0.002g～0.02g, preferably 0.004g～0.016g, in preparation process,
Before and after gabexate mesilate addition dissolving, the pH of solution is 4.4～4.8, and said composition prepares by the following method,
The method comprises the following steps:
1) water for injection that consumption is gabexate mesilate 20 times amount is cooled to 15 DEG C ± 2 DEG C, the amount of taking about 80%
Cooling after water for injection, add the mannitol of recipe quantity, stirring and dissolving, add recipe quantity acetic acid
Sodium, stirring and dissolving becomes solution, adds acetum and adjusts pH to be 4.4～4.8；
2) adding the gabexate mesilate of recipe quantity in upper step solution, stirring and dissolving becomes medicinal liquid, measures medicinal liquid pH,
If it is necessary, the pH by sodium acetate solution or acetum regulation medicinal liquid is 4.4～4.8, add
The surplus water for injection of step, constant volume；
3) in terms of g/ml, medicinal liquid adds the medicinal charcoal of 0.05%～0.1%, stirs 20～30 minutes, coarse filtration
De-charcoal, then cross 0.45 μm and the microporous filter membrane of 0.22 μm or filter element respectively, fine straining is degerming；
4) degerming rear medicinal liquid (middle product) index is detected, by every bottle of 0.1g Han gabexate mesilate, by liquid medicine filling
In 7ml cillin bottle, every bottle of about 2.0ml, the cillin bottle goods of liquid drug are put in freeze drying box,
Lyophilization；
5) by goods (cillin bottle of the most canned medicinal liquid) quick freezing to 0 DEG C, then cooling 30min～1h,
Goods are made to be chilled to-15 DEG C, then quick freezing to less than-40 DEG C, make goods keep 3h below-40 DEG C；
6) cold-trap refrigeration, evacuation, vacuum degree control between 20 handkerchiefs～35 handkerchiefs, heats, is dried；
7), when being dried, first goods are rapidly heated to-15 DEG C, then control programming rate, carry out temperature programming, often
Secondary intensification 5 DEG C, until products temperature reaches 15 DEG C, keeps flaggy temperature to differ with products temperature in temperature-rise period
10 DEG C～15 DEG C；
8) it is rapidly heated again, makes products temperature reach 35 DEG C, and keep 4h～5.5h, be dried after terminating, Vacuum Pressure
Plug, outlet Zha Gai, lamp inspection, get product.
Gabexate mesylate for injection of the present invention and preparation method thereof has the advantages that and advantage:
1) the gabexate mesylate for injection prescription of the present invention is simple, in addition to mannitol, only used acetic acid-acetic acid
Sodium buffer salt, low production cost.It addition, Acetic acid-sodium acetate is buffer salt conventional in injection, nothing
Pharmacological action, safety is good, reduces the security risk of this product.
2), before and after owing to adding dissolve at gabexate mesilate, solution ph is kept to exist by adding buffer salt
4.4-4.8, and control temperature at about 15 DEG C, in the range of this temperature with pH, can at utmost subtract
The hydrolysis of few principal agent gabexate mesilate, thus reduce the content having related substance in finished product.
3) maximum temperature of goods when pre-freeze speed and redrying is controlled when lyophilizing, can be by moisture content of finished products control
At reduced levels, hydrolyze in storage period reducing product, thus reduce and have related substance, add addition acetic acid
Buffer salt, pH stable, show through study on the stability test in long-term 3 years, product quality change is little,
Product Safety is good.
Detailed description of the invention
Following example are for the invention will be further described and understands, but do not limit the model of the present invention with this
Enclose.
Embodiment 1 gabexate mesylate for injection and preparation thereof
Prescription (in terms of 1000 bottles):
Preparation technology is as follows:
1) water for injection is cooled to 13 DEG C, takes the water for injection after recipe quantity about 80% cooling, adds recipe quantity
Mannitol, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving, adjust pH to be 4.4 with acetum；
2) gabexate mesilate of recipe quantity, stirring and dissolving are added.Measure medicinal liquid pH, if it is necessary, use vinegar
Acid sodium solution or acetum adjust pH to be 4.4.Surplus water for injection, constant volume is added according to recipe quantity；
3) in terms of g/ml, adding the medicinal charcoal of 0.05%, stir 20 minutes, coarse filtration takes off charcoal.Mistake the most respectively
0.45 μm and the microporous filter membrane of 0.22 μm, fine straining is degerming；
4) detection filtrate in the middle of product index, according to its content, fill in 7ml cillin bottle, every bottle of 2.0ml
Left and right, the cillin bottle of canned medicinal liquid is put in freeze drying box, lyophilization；
5) by goods (cillin bottle of the most canned medicinal liquid, the most same) quick freezing to 0 DEG C, then 30min
Goods are made to be chilled to-15 DEG C, then quick freezing to less than-40 DEG C, make goods keep 3h below-40 DEG C；
6) cold-trap refrigeration, evacuation, vacuum degree control is between 20 handkerchiefs～35 handkerchiefs.Heating, starts to be dried；
7), when being dried, first allow goods be rapidly heated-15 DEG C, then control programming rate, carry out temperature programming.
Heat up 5 DEG C every time, until products temperature reaches 15 DEG C, temperature-rise period keeps flaggy temperature and products temperature phase
Differ from 10 DEG C～15 DEG C；
8) it is rapidly heated, makes products temperature reach 35 DEG C, and keep 4h, be dried after terminating, vacuum tamponade,
Outlet Zha Gai, lamp inspection, get product.
Embodiment 2 gabexate mesylate for injection and preparation thereof
Prescription (in terms of 1000 bottles):
Preparation technology is as follows:
1) water for injection is cooled to 17 DEG C, takes the water for injection after recipe quantity about 80% cooling, adds recipe quantity manna
Alcohol, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving, adjust pH to be 4.8 with acetum；
2) add the gabexate mesilate of recipe quantity, stirring and dissolving, measure medicinal liquid pH, if it is necessary, use acetic acid
Sodium solution or acetum adjust pH to be 4.8, add surplus water for injection, constant volume according to recipe quantity；
3) in terms of g/ml, adding the medicinal charcoal of 0.1%, stir 30 minutes, coarse filtration takes off charcoal, then crosses 0.45 μm respectively
With the filter element of 0.22 μm, fine straining is degerming；
4) detection filtrate in the middle of product index, according to its content, fill in 7ml cillin bottle, every bottle of about 2.0ml.
Canned medicinal liquid is put in freeze drying box, lyophilization；
5) by goods quick freezing to 0 DEG C, then 1h makes goods be chilled to-15 DEG C, then quick freezing to-40 DEG C with
Under, make goods keep 3h below-40 DEG C；
6) cold-trap refrigeration, evacuation, vacuum degree control, between 20 handkerchiefs～35 handkerchiefs, heats, starts to be dried；
7), when being dried, first allow goods be rapidly heated-15 DEG C, then control programming rate, carry out temperature programming, often
Secondary intensification 5 DEG C, until products temperature reaches 15 DEG C, keeps flaggy temperature and products temperature in temperature-rise period
Differ 10 DEG C～15 DEG C；
8) it is rapidly heated, makes products temperature reach 35 DEG C, and keep 5.5h, be dried after terminating, vacuum tamponade, go out
Case Zha Gai, lamp inspection, get product.
The preparation of embodiment 3 gabexate mesylate for injection
Prescription (in terms of 1000 bottles):
Preparation technology is as follows:
1) water for injection is cooled to 15 DEG C, takes the water for injection after recipe quantity about 80% cooling, adds recipe quantity manna
Alcohol, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving, adjust pH to be 4.5 with acetum；
2) gabexate mesilate of recipe quantity, stirring and dissolving are added.Measure medicinal liquid pH, if it is necessary, use acetic acid
Sodium solution or acetum adjust pH to be 4.5, add surplus water for injection, constant volume according to recipe quantity；
3) in terms of g/ml, adding the medicinal charcoal of 0.07%, stir 24 minutes, coarse filtration takes off charcoal, then crosses 0.45 μm respectively
With the filter element of 0.22 μm, fine straining is degerming；
4) detection filtrate in the middle of product index, according to its content, fill in 7ml cillin bottle, every bottle of about 2.0ml,
Canned medicinal liquid is put in freeze drying box, lyophilization；
5) by goods quick freezing to 0 DEG C, then 40min makes goods be chilled to-15 DEG C, then quick freezing to-40 DEG C
Hereinafter, goods are made to keep 3h below-40 DEG C；
6) cold-trap refrigeration, evacuation, vacuum degree control is between 20 handkerchiefs～35 handkerchiefs.Heating, starts to be dried；
7), when being dried, first allow goods be rapidly heated-15 DEG C, then control programming rate, carry out temperature programming, often
Secondary intensification 5 DEG C, until products temperature reaches 15 DEG C.Temperature-rise period keep flaggy temperature differ with products temperature
10 DEG C～15 DEG C；
8) it is rapidly heated, makes products temperature reach 35 DEG C, and keep 4.5h, after lyophilizing terminates, vacuum tamponade, go out
Case Zha Gai, lamp inspection, get product.
The preparation of embodiment 4 gabexate mesylate for injection
Prescription (in terms of 1000 bottles):
Preparation technology is as follows:
1) water for injection is cooled to 16 DEG C, takes the water for injection after recipe quantity about 80% cooling, adds recipe quantity sweet
Dew alcohol, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving, with acetum tune pH be
4.7；
2) add the gabexate mesilate of recipe quantity, stirring and dissolving, measure medicinal liquid pH, if it is necessary, use acetic acid
Sodium solution or acetum adjust pH to be 4.7, add surplus water for injection, constant volume according to recipe quantity；
3) in terms of g/ml, adding the medicinal charcoal of 0.08%, stir 27 minutes, coarse filtration takes off charcoal, then crosses 0.45 μm respectively
With the microporous filter membrane of 0.22 μm, fine straining is degerming；
4) detection filtrate in the middle of product index, according to its content, fill in 7ml cillin bottle, every bottle of 2.0ml left side
The right side, canned medicinal liquid is put in freeze drying box, lyophilization；
5) by goods quick freezing to 0 DEG C, then 50min makes goods be chilled to-15 DEG C, then quick freezing to-40 DEG C
Hereinafter, goods are made to keep 3h below-40 DEG C；
6) cold-trap refrigeration, evacuation, vacuum degree control, between 20 handkerchiefs～35 handkerchiefs, heats, starts to be dried；
7), when being dried, first allow goods be rapidly heated-15 DEG C, then control programming rate, carry out temperature programming.
Heat up 5 DEG C every time, until products temperature reaches 15 DEG C, temperature-rise period keeps flaggy temperature and goods
Temperature difference 10 DEG C～15 DEG C；
8) it is rapidly heated, makes products temperature reach 35 DEG C, and keep 5h, be dried after terminating, vacuum tamponade, go out
Case Zha Gai, lamp inspection, get product.
Comparative example 1
It is prepared gabexate mesylate for injection by the method for CN101455647A embodiment 1, draws in full
Enter reference.
Comparative example 2
It is prepared gabexate mesylate for injection by the method for CN103211774A embodiment 1, introduces in full
Reference.
Stability Determination
The freeze-drying prods that above example 1-4 is obtained, and the freeze-drying prods of comparative example 1 and comparative example 2 presses
Test according to gabexate mesylate for injection national drug standards WS1-(X-323)-2004Z-2011, measure
The quality index such as their acidity, ethylparaben and relevant content of material, the results are shown in Table 1.
Table 1 gabexate mesylate for injection assay
The result of table 1 shows: the lyophilizing sample of embodiment 1～4, and the lyophilizing sample of comparative example 1, comparative example 2, i.e. injection
The quality of gabexate mesilate compositions all meets drug standard requirement, but the lyophilizing sample of comparative example 1 and comparative example 2, and it is to hydroxyl
Yl benzoic acid ethyl ester with about levels of substance apparently higher than the lyophilizing sample of embodiment of the present invention 1-4.
According to Chinese Pharmacopoeia two annex XIX C crude drug of version in 2010 and pharmaceutical preparation stability test guideline, to the present invention
The lyophilizing sample of the lyophilizing sample of embodiment 1～4 and comparative example 1, comparative example 2 carries out long-time stability investigation.
Take gabexate mesylate for injection compositions, place in room temperature by commercially available back, respectively at 0,3,6,
9,12,18,24,36 samplings at the end of month, are measured coherent detection project, result such as table 2.
Table 2 gabexate mesylate for injection long-term stable experiment measurement result
Table 2 result shows, the freeze-drying prods of embodiment 1～4 preparation places 36 under long-term storage requirement
Month, ethylparaben, there is related substance to have a small amount of increase, the change of other indexs is inconspicuous.And contrast
Ethylparaben in the freeze-drying prods of example 1-2 and about content of material along with the prolongation of resting period
And increase substantially, and therefore, generally, the gabexate mesylate for injection compositions of the present invention, relevant thing
Matter level is low, and quality stability is good, and drug safety is good, is suitable for industrialized great production.
Claims (1)
1. a gabexate mesylate for injection compositions, per unit preparation is by gabexate mesilate 0.1g, mannitol
0.2g and pharmaceutically acceptable Acetic acid-sodium acetate buffer salt composition, wherein, conduct in per unit preparation
The amount of the sodium acetate that solid adds is 0.004g～0.016g, described compositions methanesulfonic acid in preparation process
Before and after gabexate addition, the pH of solution is 4.4～4.8, and described compositions is prepared by following methods, the party
Method, comprises the following steps:
A) water for injection is cooled to 15 DEG C ± 2 DEG C, takes the water for injection after the cooling of recipe quantity about 80%, adds
The mannitol of recipe quantity, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving, use acetic acid
The pH of solution regulation solution is 4.4～4.8；
B) adding the gabexate mesilate of recipe quantity in upper step gained solution, stirring and dissolving becomes medicinal liquid, measures
The pH of medicinal liquid, if it is necessary, with sodium acetate solution or acetum regulate the pH of medicinal liquid be 4.4～
4.8, add surplus water for injection, constant volume；
C) in terms of g/ml, in medicinal liquid, add the medicinal charcoal of 0.05%～0.1%, stir 20～30 minutes, slightly
The de-charcoal of filter, then cross 0.45 μm and the microporous filter membrane of 0.22 μm or filter element respectively, fine straining is degerming；
D) product index in the middle of degerming rear medicinal liquid is detected, by every bottle of 0.1g Han gabexate mesilate, by liquid medicine filling
In 7ml cillin bottle, the cillin bottle goods of canned medicinal liquid are put freezing by every bottle of about 2.0ml
In drying baker, lyophilization, it is dried after terminating, vacuum tamponade, outlet Zha Gai, lamp inspection, to obtain final product
Finished product,
The described lyophilization of step d), farther includes lower step:
1) by goods quick freezing to 0 DEG C, then cooling 30min～1h makes goods be chilled to-15 DEG C, sooner
Speed is chilled to less than-40 DEG C, makes goods keep 3h below-40 DEG C；
2) cold-trap refrigeration, evacuation, vacuum degree control between 20 handkerchiefs～35 handkerchiefs, then heat drying；
3), when being dried, first allow goods be rapidly heated-15 DEG C, then control programming rate, carry out temperature programming,
Heat up 5 DEG C every time, until products temperature reaches 15 DEG C, temperature-rise period keeps flaggy temperature and products temperature phase
Differ from 10 DEG C～15 DEG C；
4) it is rapidly heated, makes products temperature reach 35 DEG C, and keep 4h～5.5h, complete lyophilization.
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| CN112101772A (en) * | 2020-09-10 | 2020-12-18 | 重庆华森制药股份有限公司 | Intelligent manufacturing system and method for six-ingredient nerve-soothing capsules |
| CN117643578A (en) * | 2023-11-24 | 2024-03-05 | 石家庄四药有限公司 | Gabexate mesylate freeze-dried preparation and preparation method thereof |
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