CN104434821A - Gabexate mesylate composition for injection and preparation method of gabexate mesylate composition - Google Patents
Gabexate mesylate composition for injection and preparation method of gabexate mesylate composition Download PDFInfo
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- CN104434821A CN104434821A CN201410755480.2A CN201410755480A CN104434821A CN 104434821 A CN104434821 A CN 104434821A CN 201410755480 A CN201410755480 A CN 201410755480A CN 104434821 A CN104434821 A CN 104434821A
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Abstract
The invention discloses a gabexate mesylate composition for injection and a preparation method of the gabexate mesylate composition. Each unit dose of the gabexate mesylate composition for injection comprises 0.1g of gabexate mesylate, 0.2g of mannitol and a pharmaceutically acceptable acetic acid-sodium acetate buffer salt. The composition is stable in quality in the preparation process, low in content of related substances, simple in prescription, low in cost and suitable for industrialized mass production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of gabexate mesylate for injection composition and method of making the same.
Background technology
The chemical name of gabexate mesilate is p-(6-guanidine hexylyloxy) ethyl benzoate mesylate, and molecular formula is C16H23N3O4CH4O3S, and molecular weight is 417.48.
Gabexate mesilate be the seventies Japan development a kind of non-peptide albuminoid hydrolase inhibitor, 1978 by the production and sales of Japanese little Ye pharmaceutical industries company, trade name FOY.It is little that gabexate mesilate has molecular weight, the feature of non-immunogenicity.The activity of the protease such as trypsin, kallikrein, plasmin, thrombin can be suppressed, thus suppress the pathophysiological change that these enzymes cause.Be used for the treatment of acute mild (edema type) pancreatitis, also can be used for the auxiliary treatment of Acute haemorrhagic-necrotizing pancreatitis.
Gabexate mesilate is soluble in water, but unstable, and facile hydrolysis becomes ethylparaben, and also unstable in strong acid, alkaline aqueous solution, ester linkage breaking open loop, easily causes adverse effect to patient.For this reason, many producers add pharmaceutic adjuvant to improve the stability of injection in Gabexate of methane-sulfonic acid injection, but effect is not fine, and current commercialized product mostly is lyophilized formulations.
Japan Patent JPS60255723 discloses a kind of preparation method of gabexate mesilate freeze-drying prods, and product prepared by the method has good heat stability and dissolubility.The method, in freezing dry process, adopts secondary lyophilizing, by freeze-drying prods quick freezing to less than-25 DEG C, then at-2 DEG C ~ 18 DEG C heat dryings, at least 30 minutes are maintained, then, product is frozen to less than-25 DEG C again, carries out vacuum drying at much lower pressure.The production time of this freeze-drying prods is longer, and complex operation adds production cost.
Japan Patent JPS63270623 (A) discloses a kind of preparation method of gabexate mesilate freeze-drying prods.The water-miscible organic solvent (ethanol, methanol, acetone etc.) of 0.5% ~ 10% is added in gabexate mesilate solution, lyophilization again after stirring, the method can make the nearly half of cryodesiccated time shorten, but as a kind of product of drug administration by injection, add organic solvent in preparation process and there is safety aspect problem.
CN101455647A discloses a kind of Gabexate mesylate freeze-drying preparation for Injection and preparation method thereof, mannitol is added water for injection to dissolve, after adding gabexate mesilate mix homogeneously again, lyophilized formulations is made in lyophilizing, and wherein the ratio of gabexate mesilate and mannitol is 1: 1-2, PH4.5.The prescription of this invention is simple, and freeze drying process is common method, but this freeze-drying prods long-term storage less stable.
CN102526017A discloses the preparation method of a kind of Gabexate mesilate pharmaceutical composition and lyophilized injectable powder thereof, described Gabexate mesilate pharmaceutical composition comprises gabexate mesilate, vitamin C and glycine, and 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 composition and method of making the same.The method adopts two step dosing methods in preparation process, first dissolves adjuvant mannitol, adds medicinal charcoal, high temperature adsorption, add principal agent gabexate mesilate, be prepared into lyophilized formulations after fine straining after filtration.Because the temperature in the method during medicinal charcoal absorption is 60 DEG C ~ 80 DEG C, after filtered while hot, namely add gabexate mesilate, after principal agent is dissolved, higher by temperature, cause gabexate mesilate to be hydrolyzed, make the related substance in finished product higher, product long-time stability are poor.
In order to reduce injection quality risk, the requirement controlled injection related substance is more and more higher.Gabexate mesylate for injection national drug standards WS
1-(X-323)-2004Z, not about the control of known impurities with other related substances in its check item.And the gabexate mesylate for injection national drug standards WS of follow-up promulgation
1-(X-323)-2004Z-2011, then adds known impurities ethylparaben in its check item, and the control overflow of other related substances, and limit standard is 0.5% and 1.0% respectively.The raising of this target level of product quality, proposes requirements at the higher level to formulation and technology.
Prior art or the lyophilizing of employing secondary, or the two step dosing methods of employing, make production operation loaded down with trivial details, freeze-drying time is longer, adds production cost, and the finished product long-time stability had are bad, and related substance level is higher; Or organic solvent is added in prescription, or add the adjuvant that some have pharmacologically active, this can increase the hidden danger of quality of injection, on Clinical practice, more considerably increase the risk of drug safety.More and more higher along with what require product quality, simple in the urgent need to developing a kind of preparation technology, be suitable for industrialized great production, low production cost, most importantly medicine related substance level is low, quality stability good, the gabexate mesylate for injection compositions of drug safety and preparation technology thereof.
Summary of the invention
The object of the present invention is to provide a kind of gabexate mesylate for injection compositions, compositions related substance level of the present invention be low, steady quality, preparation technology is simple, and production cost is low.Solve the defect that prior art exists.
The present inventor finds after research, the feature that gabexate mesilate is unstable under having facile hydrolysis, hot conditions, also responsive to pH value, and pH value change too greatly also can cause related substance to raise.In order to solve gabexate mesylate for injection compositions and the freeze-dried powder unstability in preparation process, cause the problem that related substance raises, through large quantity research and scientific experiments, find by adding buffer salt in prescription, control the pH value that principal agent adds front and back solution, for principal agent gabexate mesilate provides stable pH environment, the hydrolysis of gabexate mesilate in preparation process effectively can be reduced.Principal agent molten joining in process adopt lower temperature simultaneously, principal agent also can be prevented to be hydrolyzed.In addition, in freeze-drying process, control the maximum temperature of goods when pre-freeze speed and redrying, moisture content of finished products can be controlled at reduced levels, thus reduce the hydrolysis of product in storage period, and ensure after adding buffer salt that product long-term storage is stablized, thus complete the present invention.
Specifically, in research process, the present inventor adds by repeatedly repeatedly debugging and measuring gabexate mesilate the pH value dissolving front and back solution, find that the pH of solution before and after dissolving controls 4.4 ~ 4.8 time, the finished product after lyophilizing not only can meet acidity requirements (gabexate mesylate for injection national drug standards WS in finished product standard
1the detection method of-(X-323)-2004Z-2011 regulation acidity is: finished product one bottle, filling jetting 10ml, after dissolving, pH value should be 4.0 ~ 5.0), and the hydrolysis of principal agent gabexate mesilate in drug solution preparing process can be reduced, relevant thing also can be made to control at reduced levels.Control gabexate mesilate add dissolve before and after the pH value of solution can by adding buffer salt and pH adjusting agent realizes.By screening such medicinal buffer salt numerous, final choice acetic acid and sodium acetate buffer salt.In the process preparing gabexate mesylate for injection compositions, before adding gabexate mesilate, first add a certain amount of solid sodium acetate in the solution, the pH of solution is regulated again with acetum, the pH making solution is 4.4 ~ 4.8, after adding gabexate mesilate dissolving, if pH is not within the scope of this, also can regulate by acetic acid or sodium acetate solution, make the pH of medicinal liquid remain on 4.4 ~ 4.8.
Because the moisture in finished product also can affect gabexate mesilate hydrolysis, therefore water tariff collection is needed to control in dried frozen aquatic products at reduced levels, through the further investigation to lyophilizing parameter, find speed when slowing down pre-freeze, after the temperature of freeze-drying prods reaches 0 DEG C fast, products temperature is made to be reduced to-15 DEG C through 30min ~ 1h again, to improve efficiency during follow-up redrying.Meanwhile, during redrying, goods need be made to be warming up to 35 DEG C, and to keep 4h ~ 5.5h.This freeze-drying process can make related substance in freeze-drying prods substantially not increase, and moisture content of finished products can be made to remain on reduced levels simultaneously.When detecting by the method for gabexate mesylate for injection national drug standards WS1-(X-323)-2004Z-2011 defined, its loss on drying can control below 0.5% (standard is 1.0%).
For realizing object of the present invention, provide following embodiment:
In one embodiment, a kind of gabexate mesylate for injection compositions of the present invention, per unit preparation is made up of gabexate mesilate 0.1g, mannitol 0.2g and pharmaceutically acceptable Acetic acid-sodium acetate buffer salt, it is characterized in that the amount of the sodium acetate added as solid in per unit preparation is 0.002g ~ 0.02g.
In the above-described embodiment, gabexate mesilate compositions of the present invention, described in add sodium acetate amount be preferably 0.004g ~ 0.016g.
In the above-described embodiment, gabexate mesilate compositions of the present invention, the pH that described compositions gabexate mesilate in preparation process adds front and back solution is 4.4 ~ 4.8.
In another embodiment, object of the present invention additionally provides a kind of method preparing the gabexate mesylate for injection compositions of the invention described above, comprises the following steps:
1) water for injection is cooled to 15 DEG C ± 2 DEG C, and get the cooled water for injection of recipe quantity about 80%, add the mannitol of recipe quantity, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving becomes solution, and the pH regulating solution with acetum is 4.4 ~ 4.8;
2) in upper step gained solution, add the gabexate mesilate of recipe quantity, stirring and dissolving becomes medicinal liquid, measures the pH of medicinal liquid, if necessary, regulates the pH of medicinal liquid to be 4.4 ~ 4.8, add surplus water for injection, standardize solution with sodium acetate solution or acetum;
3) in g/ml, add the medicinal charcoal of 0.05% ~ 0.1% in medicinal liquid, stir 20 ~ 30 minutes, coarse filtration takes off charcoal, then cross respectively 0.45 μm with the microporous filter membrane of 0.22 μm or filter element, fine straining is degerming;
4) product index in the middle of degerming rear medicinal liquid is detected, by every bottle containing gabexate mesilate 0.1g, by liquid medicine filling in 7ml cillin bottle, the cillin bottle goods of good for fill medicinal liquid are put in freeze drying box, lyophilization by every bottle of about 2.0ml, after drying terminates, vacuum tamponade, outlet Zha Gai, lamp inspection, gets product.
In another embodiment above-mentioned, method of the present invention, wherein, described lyophilization, comprises lower step further:
1) by goods (i.e. the cillin bottle of liquid drug) quick freezing to 0 DEG C, the 30min ~ 1h that then lowers the temperature makes product be chilled to-15 DEG C, then quick freezing is to less than-40 DEG C, makes goods keep 3h below-40 DEG C;
2) cold-trap refrigeration, evacuation, vacuum degree control between 20 handkerchief ~ 35 handkerchiefs, then heat drying;
3) during drying, first allow goods be rapidly heated-15 DEG C, then control programming rate, carry out temperature programming, each intensification 5 DEG C, until products temperature reaches 15 DEG C, keeps flaggy temperature to differ 10 DEG C ~ 15 DEG C with products temperature in temperature-rise period;
4) be rapidly heated, make products temperature reach 35 DEG C, and keep 4h ~ 5.5h, complete lyophilization.
Specifically, gabexate mesylate for injection compositions of the present invention, can realize by following scheme.
Gabexate mesylate for injection compositions of the present invention, per unit preparation is made up of gabexate mesilate 0.1g, mannitol 0.2g and pharmaceutically acceptable Acetic acid-sodium acetate buffer salt, wherein, the amount of the sodium acetate added as solid in per unit preparation is 0.002g ~ 0.02g, be preferably 0.004g ~ 0.016g, in preparation process, it is 4.4 ~ 4.8 that gabexate mesilate adds the pH dissolving front and back solution, said composition obtains by the following method, and the method comprises the following steps:
1) be that the water for injection of gabexate mesilate 20 times amount is cooled to 15 DEG C ± 2 DEG C by consumption, the cooled water for injection of the amount of taking about 80%, add the mannitol of recipe quantity, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving becomes solution, adds acetum and adjusts pH to be 4.4 ~ 4.8;
2) in upper step solution, add the gabexate mesilate of recipe quantity, stirring and dissolving becomes medicinal liquid, measures medicinal liquid pH, if necessary, regulates the pH of medicinal liquid to be 4.4 ~ 4.8, then add the surplus water for injection of step, standardize solution with sodium acetate solution or acetum;
3) in g/ml, add the medicinal charcoal of 0.05% ~ 0.1% in medicinal liquid, stir 20 ~ 30 minutes, coarse filtration takes off charcoal, then cross respectively 0.45 μm with the microporous filter membrane of 0.22 μm or filter element, fine straining is degerming;
4) detect degerming rear medicinal liquid (middle product) index, by every bottle containing gabexate mesilate 0.1g, by liquid medicine filling in 7ml cillin bottle, the cillin bottle goods of liquid drug are put in freeze drying box, lyophilization by every bottle of about 2.0ml;
5) by goods (i.e. the cillin bottle of the good medicinal liquid of fill), quick freezing is to 0 DEG C, and then lower the temperature 30min ~ 1h, make goods be chilled to-15 DEG C, then quick freezing is to less than-40 DEG C, makes goods keep 3h below-40 DEG C;
6) cold-trap refrigeration, evacuation, vacuum degree control, between 20 handkerchief ~ 35 handkerchiefs, heats, dry;
7) during drying, first goods are rapidly heated to-15 DEG C, then control programming rate, carry out temperature programming, each intensification 5 DEG C, until products temperature reaches 15 DEG C, keeps flaggy temperature to differ 10 DEG C ~ 15 DEG C with products temperature in temperature-rise period;
8) be rapidly heated again, make products temperature reach 35 DEG C, and keep 4h ~ 5.5h, after drying terminates, vacuum tamponade, outlet Zha Gai, lamp inspection, gets product.
Gabexate mesylate for injection of the present invention and preparation method thereof has following beneficial effect and advantage:
1) gabexate mesylate for injection prescription of the present invention is simple, except mannitol, only used Acetic acid-sodium acetate buffer salt, low production cost.In addition, Acetic acid-sodium acetate is buffer salt conventional in injection, and without pharmacological action, safety is good, reduces the security risk of this product.
2) front and back are dissolved owing to adding at gabexate mesilate, keep solution ph at 4.4-4.8 by adding buffer salt, and control temperature is at about 15 DEG C, within the scope of this temperature and pH, at utmost can reduce the hydrolysis of principal agent gabexate mesilate, thus reduce the content of related substance in finished product.
3) maximum temperature of goods when pre-freeze speed and redrying is controlled when lyophilizing, can moisture content of finished products be controlled at reduced levels, be hydrolyzed in storage period to reduce product, thus reduction related substance, add and add acetate buffer salt, pH value is stablized, and shows through study on the stability test in long-term 3 years, product quality change is little, and Product Safety is good.
Detailed description of the invention
Following examples for the invention will be further described and understand, but do not limit scope of the present invention with this.
Embodiment 1 gabexate mesylate for injection and preparation thereof
Prescription (in 1000 bottles):
Preparation technology is as follows:
1) water for injection is cooled to 13 DEG C, gets the cooled water for injection of recipe quantity about 80%, adds recipe quantity mannitol, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving, adjusts pH to be 4.4 with acetum;
2) gabexate mesilate of recipe quantity is added, stirring and dissolving.Measure medicinal liquid pH, if necessary, adjust pH to be 4.4 with sodium acetate solution or acetum.Surplus water for injection is added, standardize solution according to recipe quantity;
3) in g/ml, add the medicinal charcoal of 0.05%, stir 20 minutes, coarse filtration takes off charcoal.Cross respectively again 0.45 μm with the microporous filter membrane of 0.22 μm, fine straining is degerming;
4) detect product index in the middle of filtrate, according to its content, fill in 7ml cillin bottle, every bottle of about 2.0ml, the cillin bottle of the good medicinal liquid of fill is put in freeze drying box, lyophilization;
5) by goods (i.e. the cillin bottle of the good medicinal liquid of fill, all same below), quick freezing is to 0 DEG C, and then 30min makes goods be chilled to-15 DEG C, then quick freezing is to less than-40 DEG C, makes goods keep 3h below-40 DEG C;
6) cold-trap refrigeration, evacuation, vacuum degree control is between 20 handkerchief ~ 35 handkerchiefs.Heating, starts dry;
7), during drying, first allow goods be rapidly heated-15 DEG C, then control programming rate, carry out temperature programming.Each intensification 5 DEG C, until products temperature reaches 15 DEG C, keeps flaggy temperature to differ 10 DEG C ~ 15 DEG C with products temperature in temperature-rise period;
8) be rapidly heated, make products temperature reach 35 DEG C, and keep 4h, after drying terminates, vacuum tamponade, outlet Zha Gai, lamp inspection, gets product.
Embodiment 2 gabexate mesylate for injection and preparation thereof
Prescription (in 1000 bottles):
Preparation technology is as follows:
1) water for injection is cooled to 17 DEG C, gets the cooled water for injection of recipe quantity about 80%, adds recipe quantity mannitol, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving, adjusts pH to be 4.8 with acetum;
2) add the gabexate mesilate of recipe quantity, stirring and dissolving, measure medicinal liquid pH, if necessary, adjust pH to be 4.8 with sodium acetate solution or acetum, add surplus water for injection according to recipe quantity, standardize solution;
3) in g/ml, add the medicinal charcoal of 0.1%, stir 30 minutes, coarse filtration takes off charcoal, then cross respectively 0.45 μm with the filter element of 0.22 μm, fine straining is degerming;
4) detect product index in the middle of filtrate, according to its content, fill in 7ml cillin bottle, every bottle of about 2.0ml.The medicinal liquid that fill is good 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 is to less than-40 DEG C, makes goods keep 3h below-40 DEG C;
6) cold-trap refrigeration, evacuation, vacuum degree control is between 20 handkerchief ~ 35 handkerchiefs, and heating, starts dry;
7) during drying, first allow goods be rapidly heated-15 DEG C, then control programming rate, carry out temperature programming, each intensification 5 DEG C, until products temperature reaches 15 DEG C, keeps flaggy temperature to differ 10 DEG C ~ 15 DEG C with products temperature in temperature-rise period;
8) be rapidly heated, make products temperature reach 35 DEG C, and keep 5.5h, after drying terminates, vacuum tamponade, outlet Zha Gai, lamp inspection, gets product.
The preparation of embodiment 3 gabexate mesylate for injection
Prescription (in 1000 bottles):
Preparation technology is as follows:
1) water for injection is cooled to 15 DEG C, gets the cooled water for injection of recipe quantity about 80%, adds recipe quantity mannitol, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving, adjusts pH to be 4.5 with acetum;
2) gabexate mesilate of recipe quantity is added, stirring and dissolving.Measure medicinal liquid pH, if necessary, adjust pH to be 4.5 with sodium acetate solution or acetum, add surplus water for injection according to recipe quantity, standardize solution;
3) in g/ml, add the medicinal charcoal of 0.07%, stir 24 minutes, coarse filtration takes off charcoal, then cross respectively 0.45 μm with the filter element of 0.22 μm, fine straining is degerming;
4) detect product index in the middle of filtrate, according to its content, fill in 7ml cillin bottle, every bottle of about 2.0ml, the medicinal liquid that fill is good 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 is to less than-40 DEG C, makes goods keep 3h below-40 DEG C;
6) cold-trap refrigeration, evacuation, vacuum degree control is between 20 handkerchief ~ 35 handkerchiefs.Heating, starts dry;
7) during drying, first allow goods be rapidly heated-15 DEG C, then control programming rate, carry out temperature programming, each intensification 5 DEG C, until products temperature reaches 15 DEG C.Flaggy temperature is kept to differ 10 DEG C ~ 15 DEG C with products temperature in temperature-rise period;
8) be rapidly heated, make products temperature reach 35 DEG C, and keep 4.5h, after lyophilizing terminates, vacuum tamponade, outlet Zha Gai, lamp inspection, gets product.
The preparation of embodiment 4 gabexate mesylate for injection
Prescription (in 1000 bottles):
Preparation technology is as follows:
1) water for injection is cooled to 16 DEG C, gets the cooled water for injection of recipe quantity about 80%, adds recipe quantity mannitol, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving, adjusts pH to be 4.7 with acetum;
2) add the gabexate mesilate of recipe quantity, stirring and dissolving, measure medicinal liquid pH, if necessary, adjust pH to be 4.7 with sodium acetate solution or acetum, add surplus water for injection according to recipe quantity, standardize solution;
3) in g/ml, add the medicinal charcoal of 0.08%, stir 27 minutes, coarse filtration takes off charcoal, then cross respectively 0.45 μm with the microporous filter membrane of 0.22 μm, fine straining is degerming;
4) detect product index in the middle of filtrate, according to its content, fill in 7ml cillin bottle, every bottle of about 2.0ml, the medicinal liquid that fill is good 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 is to less than-40 DEG C, makes goods keep 3h below-40 DEG C;
6) cold-trap refrigeration, evacuation, vacuum degree control is between 20 handkerchief ~ 35 handkerchiefs, and heating, starts dry;
7), during drying, first allow goods be rapidly heated-15 DEG C, then control programming rate, carry out temperature programming.Each intensification 5 DEG C, until products temperature reaches 15 DEG C, keeps flaggy temperature to differ 10 DEG C ~ 15 DEG C with products temperature in temperature-rise period;
8) be rapidly heated, make products temperature reach 35 DEG C, and keep 5h, after drying terminates, vacuum tamponade, outlet Zha Gai, lamp inspection, gets product.
Comparative example 1
Obtain gabexate mesylate for injection by the method preparation of CN101455647A embodiment 1, introduce reference in full.
Comparative example 2
Obtain gabexate mesylate for injection by the method preparation of CN103211774A embodiment 1, introduce reference in full.
Stability Determination
To the freeze-drying prods that above embodiment 1-4 obtains, and the freeze-drying prods of comparative example 1 and comparative example 2 is tested according to gabexate mesylate for injection national drug standards WS1-(X-323)-2004Z-2011, measure the quality index such as their acidity, ethylparaben and its related substances, 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 comparative example 1, comparative example 2 lyophilizing sample, namely the quality of gabexate mesylate for injection compositions all meets drug standard requirement, but the lyophilizing sample of comparative example 1 and comparative example 2, its ethylparaben and related substance level are apparently higher than the lyophilizing sample of embodiment of the present invention 1-4.
According to Chinese Pharmacopoeia version in 2010 two annex XIX C crude drug and pharmaceutical preparation stability test guideline, long-time stability investigation is carried out to the lyophilizing sample of the lyophilizing sample of the embodiment of the present invention 1 ~ 4 and comparative example 1, comparative example 2.
Get gabexate mesylate for injection compositions, place by commercially available back in room temperature, respectively at 0,3,6,9,12,18,24,36 sampling at the end of month, measure coherent detection project, result is as table 2.
Table 2 gabexate mesylate for injection long-term stable experiment measurement result
Table 2 result shows, freeze-drying prods prepared by embodiment 1 ~ 4 is placed 36 months under long storage periods condition, and ethylparaben, related substance have a small amount of increase, and the change of other indexs is not obvious.And ethylparaben in the freeze-drying prods of comparative example 1-2 and its related substances increase obviously along with the prolongation of resting period, therefore, generally, gabexate mesylate for injection compositions of the present invention, related substance level is low, quality stability is good, and drug safety is good, is applicable to industrialized great production.
Claims (5)
1. a gabexate mesylate for injection compositions, per unit preparation is made up of gabexate mesilate 0.1g, mannitol 0.2g and pharmaceutically acceptable Acetic acid-sodium acetate buffer salt, wherein, the amount of the sodium acetate added as solid in per unit preparation is 0.002g ~ 0.02g.
2. compositions as claimed in claim 1, the amount of the described sodium acetate added as solid is 0.004g ~ 0.016g.
3. compositions as claimed in claim 1 or 2, the pH that described compositions gabexate mesilate in preparation process adds front and back solution is 4.4 ~ 4.8.
4. prepare a method for the arbitrary described gabexate mesylate for injection compositions of claims 1 to 3, comprise the following steps:
A) water for injection is cooled to 15 DEG C ± 2 DEG C, gets the cooled water for injection of recipe quantity about 80%, adds the mannitol of recipe quantity, stirring and dissolving, add the sodium acetate of recipe quantity, stirring and dissolving, and the pH regulating solution with acetum is 4.4 ~ 4.8;
B) in upper step gained solution, add the gabexate mesilate of recipe quantity, stirring and dissolving becomes medicinal liquid, measures the pH of medicinal liquid, if necessary, regulates the pH of medicinal liquid to be 4.4 ~ 4.8, add surplus water for injection, standardize solution with sodium acetate solution or acetum;
C) in g/ml, add the medicinal charcoal of 0.05% ~ 0.1% in medicinal liquid, stir 20 ~ 30 minutes, coarse filtration takes off charcoal, then cross respectively 0.45 μm with the microporous filter membrane of 0.22 μm or filter element, fine straining is degerming;
D) product index in the middle of degerming rear medicinal liquid is detected, by every bottle containing gabexate mesilate 0.1g, by liquid medicine filling in 7ml cillin bottle, the cillin bottle goods of good for fill medicinal liquid are put in freeze drying box, lyophilization by every bottle of about 2.0ml, after drying terminates, vacuum tamponade, outlet Zha Gai, lamp inspection, gets product.
5. method as claimed in claim 4, wherein, described lyophilization, comprises lower step further:
1) by goods quick freezing to 0 DEG C, the 30min ~ 1h that then lowers the temperature makes goods be chilled to-15 DEG C, then quick freezing is to less than-40 DEG C, makes goods keep 3h below-40 DEG C;
2) cold-trap refrigeration, evacuation, vacuum degree control between 20 handkerchief ~ 35 handkerchiefs, then heat drying;
3) during drying, first allow goods be rapidly heated-15 DEG C, then control programming rate, carry out temperature programming, each intensification 5 DEG C, until products temperature reaches 15 DEG C, keeps flaggy temperature to differ 10 DEG C ~ 15 DEG C with products temperature in temperature-rise period;
4) be rapidly heated, make products temperature reach 35 DEG C, and keep 4h ~ 5.5h, complete lyophilization.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106038497A (en) * | 2016-08-17 | 2016-10-26 | 甘肃成纪生物药业有限公司 | Medicine composition and preparation of gabexate mesylate and preparation method thereof |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103211774A (en) * | 2013-04-26 | 2013-07-24 | 成都苑东药业有限公司 | Gabexate mesylate composition for injection and preparation method thereof |
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2014
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103211774A (en) * | 2013-04-26 | 2013-07-24 | 成都苑东药业有限公司 | Gabexate mesylate composition for injection and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106038497A (en) * | 2016-08-17 | 2016-10-26 | 甘肃成纪生物药业有限公司 | Medicine composition and preparation of gabexate mesylate and preparation method thereof |
| 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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| CN104434821B (en) | 2016-11-02 |
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