CN106038497A - Medicine composition and preparation of gabexate mesylate and preparation method thereof - Google Patents
Medicine composition and preparation of gabexate mesylate and preparation method thereof Download PDFInfo
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- CN106038497A CN106038497A CN201610679384.3A CN201610679384A CN106038497A CN 106038497 A CN106038497 A CN 106038497A CN 201610679384 A CN201610679384 A CN 201610679384A CN 106038497 A CN106038497 A CN 106038497A
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/0012—Galenical forms characterised by the site of application
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Abstract
The invention relates to the field of medicine preparations and especially relates to a medicine composition and a preparation of gabexate mesylate and a preparation method thereof. In the invention, only are the gabexate mesylate, mannitol, acetic acid and water for injection are employed, wherein the usage amount of the mannitol is reduced, so that freeze-drying time is reduced and the cost is reduced. The preparation method has good stability and is suitable for industrial production. The product is less in side effects and has stable quality.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly to pharmaceutical composition, preparation and the preparation thereof of gabexate mesilate
Method.
Background technology
Gabexate is the inhibitor of a kind of non-peptide albuminoid, can suppress trypsin, swash and eliminate release enzyme, plasmin
The activity of the protease such as enzyme, thrombin, thus prevent the pathophysiological change that these enzymes are caused.At zoopery impatient property pancreas
Adenitis, can suppress the trypsin of activation, alleviate injury of pancreas, and serum amylase, lipase active and blood urea nitrogen raise simultaneously
Situation is also obviously improved.For acute mild (edema type) pancreatitic treatment it can also be used to Acute haemorrhagic-necrotizing pancreatitis
Auxiliary treatment.
Gabexate mesilate (gabexate mesylate), chemical entitled 4-(6-guanidine radicals hexylyloxy) ethyl benzoate
Mesylate, be Japan little Ye company develop non-peptides egg from hydrolase inhibitor, nineteen eighty-three first Japan list, exist
The listing of multiple countries, China produces in approval in 1992.
Gabexate mesilate is ester type compound, is degraded into 6-guanidine radicals caproic acid and P-hydroxybenzoic acid second in a heated condition
Ester.According to documents and materials, ethylparaben is the raw material in gabexate mesilate building-up process, be reaction is completed after
The control of retained material.The relevant gabexate mesilate data provided according to Japanese health ministry website shows, gabexate mesilate exists
6-guanidine radicals caproic acid mesylate and ethylparaben just it is decomposed into when boiling water water-bath is heated more than 16 hours.At present
There are the open methanesulfonic acid pharmaceutical composition of technology and the preparation method of lyophilized injectable powder thereof, prescription adds vitamin C, glycine
And dextran, this prescription is complicated, and cost is high, adds technique manufacture difficulty.Technology is also had to disclose a kind of injection first sulphur
Acid gabexate compositions and preparation method thereof, prescription is simple, but the large usage quantity of adjuvant in prescription, waste production cost.
Summary of the invention
In view of this, the present invention provides the pharmaceutical composition of a kind of gabexate mesilate, preparation and preparation method thereof.This
The bright medicine providing a kind of new gabexate mesylate for injection and freeze drying process, only used added methanesulfonic acid shellfish in medicine
Ester, mannitol and acetic acid and water for injection, mannitol consumption reduces, and freeze-drying time shortens.Cost reduces.The side that the present invention provides
Method good stability, is suitable for industrialized production, product few side effects, steady quality.
In order to realize foregoing invention purpose, the present invention provides techniques below scheme:
The invention provides the pharmaceutical composition of a kind of gabexate mesilate, including gabexate mesilate and sugar alcohols thing
Matter；Described gabexate mesilate is 100:(50～150 with the mass ratio of described sugar alcohols material).
In some specific embodiments of the present invention, described sugar alcohols material include mannitol, sorbitol, glucose,
A kind of or both mixture above in dextran.
Present invention also offers a kind of gabexate mesilate lyophilized injectable powder, its raw material include described pharmaceutical composition and
Pharmaceutically acceptable adjuvant.
In some specific embodiments of the present invention, described pharmaceutically acceptable adjuvant includes activated carbon, pH regulator
Agent and water for injection；Described pH adjusting agent includes a kind of or both mixing above in sulfurous acid, phosphoric acid, nitrous acid, acetic acid
Thing.
In some specific embodiments of the present invention, in terms of g/mL, its raw material before lyophilizing described sugar alcohols material with
The mass volume ratio of medicinal liquid is 2.5%～7.5%.
Present invention also offers the preparation method of described gabexate mesilate lyophilized injectable powder, comprise the steps:
Step 1: the water for injection of the sugar alcohols material and recipe quantity 80% that take recipe quantity mixes, adds activated carbon adsorption
After, mix with the gabexate mesilate of recipe quantity, regulate pH value, add the water for injection of surplus, prepare medicinal liquid, fill；
Step 2: lyophilization, the full plug of pressure, rolls lid；
Described lyophilization includes the first lyophilization, the second lyophilization and the 3rd lyophilization；
Described first lyophilization is: be cooled to-45 DEG C～-35 DEG C, is incubated 2h；
Described second lyophilization is: under conditions of vacuum 10Pa～30Pa, temperature rises to-14 DEG C, is incubated 9h；
Described 3rd lyophilization is: be warming up to 35 DEG C, is incubated 4h.
In some specific embodiments of the present invention, in terms of g/mL, described sugar alcohols material and the quality of described medicinal liquid
Volume ratio is 2.5%～7.5%.
In some specific embodiments of the present invention, in terms of g/mL, described sugar alcohols material and the quality of described medicinal liquid
Volume ratio is 4%～5%.
In some specific embodiments of the present invention, in terms of g/mL, described activated carbon and the quality volume of described medicinal liquid
Ratio is 0.01%～0.1%.
In some specific embodiments of the present invention, described pH value is 4.0～5.0；The pH regulator of described regulation pH value
Agent is a kind of or both mixture above in sulfurous acid, phosphoric acid, nitrous acid or acetic acid.
The invention provides drug regimen and the freeze drying process of a kind of new gabexate mesylate for injection.The present invention uses
Only having used gabexate mesilate, mannitol and acetic acid and water for injection, mannitol consumption reduces, and freeze-drying time shortens.Cost
Reduce.This method good stability, is suitable for industrialized production, product few side effects, steady quality.
Detailed description of the invention
The invention discloses the pharmaceutical composition of a kind of gabexate mesilate, preparation and preparation method thereof, art technology
Personnel can use for reference present disclosure, is suitably modified technological parameter and realizes.Special needs to be pointed out is, all similar replacements and changing
Dynamic apparent to those skilled in the art, they are considered as being included in the present invention.The method of the present invention and should
With being described by preferred embodiment, related personnel substantially can be without departing from present invention, spirit and scope
Method described herein and application it is modified or suitably changes and combine, realize and apply the technology of the present invention.
The scheme that the present invention provides is as follows:
Step 1, drug solution preparing: pick and place in ten thousand grades of districts and be cooled to room temperature and be about the fresh water for injection of total water consumption 80%, add
Enter the mannitol stirring and dissolving of recipe quantity, add activated carbon stirring and adsorbing 30 minutes, use titanium rod decarbonization filtering, add recipe quantity
Gabexate mesilate, stirring and dissolving；By acetum regulation solution ph to 4.0～5.0, add dosing water to full dose.
The cylindrical filter cartridge using filter sizes to be 0.45 μm carries out coarse filtration；The cylindrical filter cartridge using filter sizes to be 0.22 μm carries out degerming
Filter.Content, pH value and visible foreign matters are surveyed in sampling, control content range is labelled amount 95.0%～the 105.0% of middle product,
Qualified rear fill.
Step 2, fill: environment cleanliness rank is 100 grades, local under ten thousand grades of environment, medicinal liquid section (separatory before filling the container
Device front end) carry out terminal cascade filtration through aperture 0.22 μm bellows filter element again, it is ensured that the aseptic and clarity of product.According to
Mesosome calculates loading amount containing surveying result, and fill, in 7ml cillin bottle, is the most partly jumped a queue after fill.
Step 3, lyophilization: be placed on freeze dryer dividing plate by fill certified products, be cooled to-40 DEG C, is incubated 2 hours；Will
Being evacuated to 10Pa～30pa in case, temperature rises to-14 DEG C from-40 DEG C, is incubated 9 hours；Temperature rises to 35 DEG C from-14 DEG C, protects
Temperature 4 hours, the full plug of pressure.
Step 4, roll lid: use antibiotic bottle rolling cap machine to roll lid in ten thousand grades of environment.
Step 1 employs mannitol, it is also possible to sorbitol, glucose, dextran etc., preferably mannitol, consumption exists
2.5%～7.5% (g/ml), preferably 4%～5%.
Activated carbon dosage in step 1 between 0.01%～0.1%, activated carbon when 0.01% to added methanesulfonic acid shellfish
The absorption of ester reaches 9.0%, therefore uses first by the method adding principal agent after activated carbon process adjuvant when preparation, to ensure
Finally finished satisfactory quality.
Adding acetic acid in step 1 is to make the pH value of medicinal liquid between 4.0～5.0.Also sulfurous acid, phosphoric acid, Asia can be used
Nitric acid etc., preferably acetic acid.
The invention provides drug regimen and the freeze drying process of a kind of new gabexate mesylate for injection.The present invention uses
Only having used gabexate mesilate, mannitol and acetic acid and water for injection, mannitol consumption reduces, and freeze-drying time shortens.Cost
Reduce.This method good stability, is suitable for industrialized production, product few side effects, steady quality.
A kind of examination used in the pharmaceutical composition of gabexate mesilate of present invention offer, preparation and preparation method thereof
Agent and raw material all can be buied by market.
Below in conjunction with embodiment, the present invention it is expanded on further:
Embodiment 1
Preparation technology:
1, pick and place and be cooled to room temperature fresh water for injection 1600ml, add mannitol 50g stirring and dissolving, add activated carbon
0.01% (w/v) stirring and adsorbing 30 minutes, uses titanium rod decarbonization filtering, adds the gabexate mesilate of 100g, stirring and dissolving；With
Acetum regulation solution ph is to 4.0～5.0, and benefit adds to the full amount of water for injection.The cartridge type using filter sizes to be 0.45 μm
Filter element carries out coarse filtration；The cylindrical filter cartridge using filter sizes to be 0.22 μm carries out aseptic filtration.Content, pH value and visible are surveyed in sampling
Foreign body, controls content range is labelled amount 95.0%～the 105.0% of middle product, qualified rear fill.
2. fill: environment cleanliness rank is 100 grades, local under ten thousand grades of environment, and medicinal liquid section before filling the container is (before liquor separator
End) carry out terminal cascade filtration through aperture 0.22 μm bellows filter element again, it is ensured that the aseptic and clarity of product.According to intermediate
Calculating loading amount containing surveying result, fill, in 7ml cillin bottle, is the most partly jumped a queue after fill.
3. lyophilization: be placed on freeze dryer dividing plate by fill certified products, is cooled to-40 DEG C, is incubated 2 hours；By in case
Being evacuated to 10Pa～30pa, temperature rises to-14 DEG C from-40 DEG C, is incubated 9 hours；Temperature rises to 35 DEG C from-14 DEG C, and insulation 4 is little
Time, the full plug of pressure.
Embodiment 2
Preparation technology:
1, pick and place and be cooled to room temperature fresh water for injection 1600ml, add mannitol 100g stirring and dissolving, add activated carbon
0.05% (w/v) stirring and adsorbing 30 minutes, uses titanium rod decarbonization filtering, adds the gabexate mesilate of 100g, stirring and dissolving；With
Acetum regulation solution ph is to 4.0～5.0, and benefit adds to the full amount of water for injection.The cartridge type using filter sizes to be 0.45 μm
Filter element carries out coarse filtration；The cylindrical filter cartridge using filter sizes to be 0.22 μm carries out aseptic filtration.Content, pH value and visible are surveyed in sampling
Foreign body, controls content range is labelled amount 95.0%～the 105.0% of middle product, qualified rear fill.
2. fill: environment cleanliness rank is 100 grades, local under ten thousand grades of environment, and medicinal liquid section before filling the container is (before liquor separator
End) carry out terminal cascade filtration through aperture 0.22 μm bellows filter element again, it is ensured that the aseptic and clarity of product.According to intermediate
Calculating loading amount containing surveying result, fill, in 7ml cillin bottle, is the most partly jumped a queue after fill.
3. lyophilization: be placed on freeze dryer dividing plate by fill certified products, is cooled to-35 DEG C, is incubated 2.5 hours；By case
Inside being evacuated to 10Pa～30pa, temperature rises to-14 DEG C from-35 DEG C, is incubated 9 hours；Temperature rises to 35 DEG C from-14 DEG C, is incubated 4
Hour, the full plug of pressure.
Embodiment 3
Preparation technology:
1, pick and place and be cooled to room temperature fresh water for injection 1600ml, add mannitol 150g stirring and dissolving, add activated carbon
0.1% (w/v) stirring and adsorbing 30 minutes, uses titanium rod decarbonization filtering, adds the gabexate mesilate of 100g, stirring and dissolving；With
Acetum regulation solution ph is to 4.0～5.0, and benefit adds to the full amount of water for injection.The cartridge type using filter sizes to be 0.45 μm
Filter element carries out coarse filtration；The cylindrical filter cartridge using filter sizes to be 0.22 μm carries out aseptic filtration.Content, pH value and visible are surveyed in sampling
Foreign body, controls content range is labelled amount 95.0%～the 105.0% of middle product, qualified rear fill.
2. fill: environment cleanliness rank is 100 grades, local under ten thousand grades of environment, and medicinal liquid section before filling the container is (before liquor separator
End) carry out terminal cascade filtration through aperture 0.22 μm bellows filter element again, it is ensured that the aseptic and clarity of product.According to intermediate
Calculating loading amount containing surveying result, fill, in 7ml cillin bottle, is the most partly jumped a queue after fill.
3. lyophilization: be placed on freeze dryer dividing plate by fill certified products, is cooled to-45 DEG C, is incubated 1.5 hours；By case
Inside being evacuated to 10Pa～30pa, temperature rises to-14 DEG C from-45 DEG C, is incubated 9 hours；Temperature rises to 35 DEG C from-14 DEG C, is incubated 4
Hour, the full plug of pressure.
Embodiment 4 quality determination
Example 1～3 prepare sample, carry out correlated quality mensuration:
1 three embodiment testing result summary sheets of table
Result shows, three above embodiment result after quality testing all meets regulation, stable content, and solution is clarified.
Compatibility mechanism is studied: the clinical usage and dosage of gabexate mesylate for injection is: this medicine is intended for intravenous drip and uses,
100mg every time, treatment starts 3 days every consumption per day 300mg, and symptom changes 100mg/ day into after alleviating, the 6-10 days course for the treatment of, first with 5ml
Water for injection inject fill in gabexate freeze-dried powder bottle, to be dissolved after i.e. distinguish decant(-ation) in 5% glucose solution and woods grignard
In liquid 500ml, for intravenous drip.Dropping speed is unsuitable too fast, within should controlling 1mg/kg/h, no more than 2.5mg/kg/
h。
The sample of Example 1 preparation, simulation clinical typical concentrations preparation compatibility liquid, by the medicinal liquid after compatibility at room temperature
Place 0,1,2,4,8,12h, observe the character of compatibility liquid, pH value, known impurities, single largest impurity, total impurities and content
Change, the result that content calculates by 0h, based on 100%, the results are shown in Table 2:
The compatibility stability result of table 2 transfusion
From the above results, gabexate mesylate for injection, in 5% glucose solution and ringer's solution, is put through room temperature
Put 1,2,4,8, after 12h compared with 0h, steady quality, each check item, all within critical field, can meet Clinical practice.
Example 2, embodiment 3 carry out above-mentioned experiment, the experimental result phase of the sample that experimental result is prepared with embodiment 1
Closely, without significant difference (P ＞ 0.05).
Stability test:
The sample of embodiment 1～3 is positioned in right amount temperature 40 DEG C ± 2 DEG C, the calorstat of relative humidity 75% ± 5%
In, take sample detect respectively at January, February, March, 6 the end of month, the results are shown in Table 3:
Table 3 accelerated stability test result table
Safety testing:
Experiment material: embodiment 1～the gabexate mesilate lyophilized injectable powder of embodiment 3 preparation.
One, hypersensitive test
Experiment material: the gabexate mesilate lyophilized injectable powder of embodiment 1 preparation.
Cavia porcellus 24, is randomly divided into 4 groups, often group 6.1. (0.1g injects heavy dose of 6 of gabexate mesylate for injection group
5% glucose injection is moved into gabexate mesilate 6ml water for injection in 100ml, concentration: 1mg after fully dissolving:
1ml).2. low dose of 6 (concentration: the 0.5mg:1ml) of gabexate mesylate for injection group.3. 5% glucose injection matched group 6
Only, 4. 5% Ovum Gallus domesticus album normal saline positive controls 6.Gabexate mesylate for injection, 5% Ovum Gallus domesticus album normal saline, 5%
6 groups of glucose injection matched group, 4 groups equal the next day lumbar injection 1ml/ only, continuous 3 times, after final injection 10 days, by hind leg
Saphena only injects 2.0ml/ respectively, has useless pawl to scratch nose, sneeze, perpendicular hair, tic, dyspnea, defecation after observing injection
Incontinence, shock and death etc. are reacted.
Anaphylaxis evaluation methodology: calculate animal anaphylaxis progression by table 4 requirement.When the order of reaction is below 2 grades, then
Think qualified by the hypersensitive test of test product.It is shown in Table 4,5.
Table 4 Cavia porcellus anaphylaxis grading table
| The order of reaction | Reaction symptom |
| 0 | Non-evident sympton |
| 1 | The most slightly grab nose, tremble or erect hair |
| 2 | Have and cough several times, grab nose, tremble or erect hair |
| 3 | Have and repeatedly or continuously cough, with dyspnea or spasm, tic etc. |
| 4 | Spasm, tic, gatism, death |
Table 5 gabexate mesylate for injection Cavia porcellus anaphylaxis grade form
Experimental result
5% glucose injection matched group is administered 10 days in last and attacks, and Cavia porcellus is all normal, sends out without any anaphylaxis
Raw, the Ovum Gallus domesticus album normal saline group of 5% in last be administered 10 days attack Cavia porcellus first occur grabbing nose, tremble, perpendicular hair, breathe tired
Difficulty, tic, urinary incontinence, finally dead.Death mostly occurred in 2 minutes.Gabexate mesylate for injection last is administered 10 days
Attack all without any symptom, without anaphylaxis.
Conclusion: gabexate mesylate for injection Cavia porcellus hypersensitive test is negative.
Example 2, embodiment 3 carry out above-mentioned experiment, the experimental result phase of the sample that experimental result is prepared with embodiment 1
Closely, without significant difference (P ＞ 0.05).
Two, hemolytic test
The preparation of the red cell suspension of 1.2%: take Fresh rabbit blood 10ml, put in conical flask, be pre-placed steaming in bottle
The bead that distilled water is rinsed well shakes up removing fibrin, adds raw in then removing protein blood move into 10ml graduated centrifuge tube
Reason saline 10ml mixing, is centrifuged 10min, abandoning supernatant with 2000rpm, then uses 10ml normal saline flushing, and the most repeatedly 4
Secondary, till supernatant is colourless, by gained cell volume, become 2% red blood cell suspension with normal saline.
2. test procedure: dividing and take 7, test tube for 3 times, according to the form below ratio is sequentially added into 2% red cell suspension and normal saline,
(0.1g gabexate mesylate for injection 6ml water for injection moves into 5% after fully dissolving to be then respectively adding different amounts of medicinal liquid
Glucose injection in 100ml, concentration: 1mg:1ml), the 6th pipe only adds normal saline, for anhemolytic negative control pipe,
7th pipe adds the positive control pipe that distilled water is complete hemolysis.Each pipe shakes up gently, puts observation 4h, 1h in 37 DEG C of calorstats immediately
In observe once every 15min, after 1h, observed once every 1 hour, altogether 4h. observes each pipe with or without haemolysis, the results are shown in Table
6,7,8.
Table 6 gabexate mesylate for injection (embodiment 1) hemolytic test table
Table 7 gabexate mesylate for injection (embodiment 2) hemolytic test table
Table 8 gabexate mesylate for injection (embodiment 3) hemolytic test table
-represent not haemolysis+expression haemolysis
Experimental result result of the test such as table 3, shown in 4,5,1-6 test tube not haemolysis, without coacervation, No. 7 test tube is complete
Haemolysis.
Conclusion gabexate mesylate for injection is without haemolysis.
Three, vascular stimulation tests
Experiment material: the gabexate mesilate lyophilized injectable powder of embodiment 1 preparation.
Take rabbit 5, method for preparation of drug: 0.1g gabexate mesylate for injection 6ml water for injection moves after fully dissolving
In entering to 5% glucose injection to 100ml, left ear auricular vein injects 5% glucose injection 5ml/kg, and auris dextra ear edge is quiet
Moderate pulse slow injection injection gabexate mesilate 5ml/kg, every day 1 time, the same position auricular vein of rabbit is slowly injected, continuously
Inject 7 days, inject latter 24 hours, put to death 3 animals, take auricle formalin and fix, send pathological section (to take ear position for note
Penetrate the auricle near cardia below position).Residue animal last is observed 7 days after being administered again, then does and ibid process.
Experimental result: 5% glucose injection matched group, gabexate mesylate for injection are injected 7 days and recover 7 days, quiet
Vessel lumen is without substantially expansion, and endothelium is complete, and smooth muscle and adventitia are without thickening, and perivascular fibrous connective tissue soaks without inflammatory cell
Profit.Conclusion: gabexate mesylate for injection vascular stimulation safety experiment shows to meet regulation.
Example 2, embodiment 3 carry out above-mentioned experiment, the experimental result phase of the sample that experimental result is prepared with embodiment 1
Closely, without significant difference (P ＞ 0.05).
Four, muscular irritation test:
Experiment material: the gabexate mesilate lyophilized injectable powder of embodiment 1 preparation.
Take healthy rabbits 4, respectively at two lower limb quadriceps femoris around with aseptic manipulation injection injection added methanesulfonic acid
Shellfish ester (0.1g gabexate mesylate for injection 6ml water for injection move into after fully dissolving 5% glucose injection to 100ml)
Compare each 1ml with 5% glucose injection, inject latter 24 hours, put to death 3 animals, dissect and take out quadriceps femoris, longitudinally cut
Open, observe injection site irritant reaction, and fix with formalin, send pathological section.Residue animal is observed 7 days after being administered again,
Do again and ibid process.Pathological section test report and photo are attached.
Experimental result 5% glucose injection matched group and gabexate mesylate for injection group rabbit rhabdium row
Row are neat, clear in structure, and form is without exception, and muscle fiber is without pathological changes such as atrophy, degeneration, necrosis, and muscle fiber is interior and interstitial
All ooze out without edema, without cell infiltration, without proliferation of fibrous tissue.Conclusion: gabexate mesylate for injection to striped muscle without bright
Aobvious stimulation.
Table 9 injection is to rabbit intramuscular injection irritant reaction grade form
Rabbit intramuscular injection irritant reaction is marked by table 10 gabexate mesylate for injection
Conclusion: injection site has no obvious muscular irritation effect.
Example 2, embodiment 3 carry out above-mentioned experiment, the experimental result phase of the sample that experimental result is prepared with embodiment 1
Closely, without significant difference (P ＞ 0.05).
Conclusion gabexate mesylate for injection rabbit auricular vein is injected continuously and is not caused vascular stimulation reaction, injection first
The injection of sulfonic acid gabexate rabbit ear leg muscle does not causes muscular irritation reaction, Cavia porcellus hypersensitive test negative, and hemolytic test is negative.
Embodiment 5 comparative example
Take the embodiment of the present invention 1 to embodiment 3 preparation gabexate mesilate lyophilized injectable powder and presently commercially available product and
Method carries out contrast test: often group does 10 parallel tests.
Matched group formula: gabexate mesilate is 100:200 with the mass ratio of mannitol；
Matched group preparation method: lyophilization is at-40 DEG C, pre-freeze starts evacuation after 4 hours, vacuum control 10～
Between 30 handkerchiefs, it is warming up to-20 DEG C, keeps 12h, be warming up to 0 DEG C, keep 2h, be warming up to 20 DEG C, keep 4h, and in lyophilization
During condenser temperature be maintained at-60 DEG C.
Result is as shown in table 11:
Table 11 comparative test result
As shown in Table 11, experimental group is compared with matched group, and gabexate mesilate is notable (P with the mass ratio of sugar alcohols material
＜ 0.05) decline, i.e. the addition of sugar alcohols material significantly reduces (P ＜ 0.05)；Freeze-drying time by 22h drop to 14.5～
15.5, there is pole significant difference (P ＜ 0.01)；Lab scale production cost is dropped to 1.5 ten thousand yuan by 20,000 yuan, has pole significant difference
(P ＜ 0.01).
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For Yuan, under the premise without departing from the principles of the invention, it is also possible to make some improvements and modifications, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (10)
1. the pharmaceutical composition of a gabexate mesilate, it is characterised in that include gabexate mesilate and sugar alcohols material；Institute
The mass ratio stating gabexate mesilate and described sugar alcohols material is 100:(50～150).
Pharmaceutical composition the most according to claim 1, it is characterised in that described sugar alcohols material includes mannitol, Pyrusussuriensis
A kind of or both mixture above in alcohol, glucose, dextran.
3. a gabexate mesilate lyophilized injectable powder, it is characterised in that its raw material includes medicine as claimed in claim 1 or 2
Compositions and pharmaceutically acceptable adjuvant.
Gabexate mesilate lyophilized injectable powder the most according to claim 3, it is characterised in that described pharmaceutically acceptable
Adjuvant includes activated carbon, pH adjusting agent and water for injection；Described pH adjusting agent includes in sulfurous acid, phosphoric acid, nitrous acid, acetic acid
A kind of or that both are above mixture.
5. according to the gabexate mesilate lyophilized injectable powder described in claim 3 or 4, it is characterised in that in terms of g/mL, its raw material
Before lyophilizing, described sugar alcohols material is 2.5%～7.5% with the mass volume ratio of medicinal liquid.
6., according to the preparation method of the gabexate mesilate lyophilized injectable powder described in any one of claim 3 to 5, its feature exists
In, comprise the steps:
Step 1: the water for injection of the sugar alcohols material and recipe quantity 80% that take recipe quantity mixes, after adding activated carbon adsorption, with
The gabexate mesilate mixing of recipe quantity, regulates pH value, adds the water for injection of surplus, prepare medicinal liquid, fill；
Step 2: lyophilization, the full plug of pressure, rolls lid；
Described lyophilization includes the first lyophilization, the second lyophilization and the 3rd lyophilization；
Described first lyophilization is: be cooled to-45 DEG C～-35 DEG C, is incubated 1.5～2.5h；
Described second lyophilization is: under conditions of vacuum 10Pa～30Pa, temperature rises to-14 DEG C, is incubated 9h；
Described 3rd lyophilization is: be warming up to 35 DEG C, is incubated 4h.
Preparation method the most according to claim 6, it is characterised in that in terms of g/mL, described sugar alcohols material and described medicine
The mass volume ratio of liquid is 2.5%～7.5%.
Preparation method the most according to claim 6, it is characterised in that in terms of g/mL, described sugar alcohols material and described medicine
The mass volume ratio of liquid is 4%～5%.
9. according to the preparation method described in any one of claim 6 to 8, it is characterised in that in terms of g/mL, described activated carbon and institute
The mass volume ratio stating medicinal liquid is 0.01%～0.1%.
10. according to the preparation method described in any one of claim 6 to 9, it is characterised in that described pH value is 4.0～5.0；Institute
The pH adjusting agent stating regulation pH value is a kind of or both mixture above in sulfurous acid, phosphoric acid, nitrous acid or acetic acid.
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