CN1481809A - Sodium bialginate for injection and its preparation method - Google Patents
Sodium bialginate for injection and its preparation method Download PDFInfo
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- CN1481809A CN1481809A CNA031276512A CN03127651A CN1481809A CN 1481809 A CN1481809 A CN 1481809A CN A031276512 A CNA031276512 A CN A031276512A CN 03127651 A CN03127651 A CN 03127651A CN 1481809 A CN1481809 A CN 1481809A
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- sodium sulfate
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Abstract
The present invention is one kind of freeze dried polysaccharide sulphate for injection, and each 1000 ampules of the injection contains polysaccharide sulphate 25-200 g and excipient 25-200 g. The injection preparation is prepared through advanced low temperature freeze drying process, and is stable in the preserving period and ever suitable for clinical application. The present invention has the functions of lowering blood viscosity, resisting blood coagulation, lowering blood fat, improving micro circulation, etc. and is used in preventing and treating ischemic cardiac and cerebral vascular diseases and hyperlipemia.
Description
Technical field
The present invention relates to a kind of freeze-dried type injection propylene glycol alginate sodium sulfate, belong to pharmaceutical product.
Background technology
Propylene glycol alginate sodium sulfate is to be basic material with the alginic acid, introduces effective group with chemical method and is synthesized into, and is acidic polysaccharose class medicine.Propylene glycol alginate sodium sulfate has strong dispersion and emulsion performance, and be not subject to the external factor influence, because of it has the characteristics of anionic polyelectrolyte fibre structure, along the chain charge concentration, under the effect of its electric repulsion, can make the cell surface increase repulsive force each other that is rich in negative charge, thus can impedance between the erythrocyte and the adhesion between erythrocyte and the blood vessel wall, have the hemorheological viscoelastic effect of improvement.In addition, propylene glycol alginate sodium sulfate can make the thrombin inactivation, prostaglandin (PG12) sample effects such as tool antithrombotic, reducing blood viscosity, fine motion vein spasmolytic, erythrocyte and platelet depolymerization.Propylene glycol alginate sodium sulfate also has the effect of obvious blood fat reducing, can suppress the generation and the development of atherosclerotic lesion, and peripheral blood vessel is had tangible dilating effect, and effectively microcirculation improvement suppresses the formation of thrombosis in the arteriovenous.Be mainly used in ischemic cerebrovascular clinically, as the control of diseases such as cerebral thrombosis, cerebral embolism, transient ischemic attack and cardiovascular disease and hypertension, hyperlipoproteinemia, coronary heart disease, angina pectoris.Also can be used for treating disseminated inravascular coagulation, chronic glomerulonephritis and hemorrhagic fever etc.
The preparation that with the propylene glycol alginate sodium sulfate is raw material at present has propylene glycol alginate sodium sulfate tablet, alginate diester sodium injection etc., has been subjected to the welcome of extensive patients since the clinical use deeply.By clinical observation, though that propylene glycol alginate sodium sulfate tablet is taken is more convenient, be subjected to the influence of factors such as disintegrate, first pass effect because of it, its bioavailability is lower; The alginate diester sodium injection though bioavailability is higher, curative effect is very fast, because of it needs high temperature sterilize in making production process, can make the degraded of part active component, causes appearance luster to change, and is unstable in storage life, thereby directly affects the treatment.
Summary of the invention
The objective of the invention is provides a kind of stable performance at above-mentioned deficiency, safe and reliable, clinical lyophilized injectable powder injection propylene glycol alginate sodium sulfate easy to use.
Contain propylene glycol alginate sodium sulfate, excipient (skeleton agent) in the injection propylene glycol alginate sodium sulfate of the present invention, the weight proportion that contains described each composition in wherein per 1000 bottles is:
Propylene glycol alginate sodium sulfate 25-200 gram
Excipient 200-25 gram.
Above-mentioned excipient (skeleton agent) is selected from: sodium chloride, mannitol, Dextran 40 etc.
Another object of the present invention provides the preparation method of injection propylene glycol alginate sodium sulfate, and its preparation method comprises the steps:
(1) measures the water for injection of cumulative volume 80%, when pH value is higher than 5, is 10% hydrochloric acid solution, when pH value is lower than 3 is 4% sodium hydroxide solution, transfer pH value, add excipient (skeleton agent), be stirred to dissolving fully to 3-5 with concentration with concentration;
(2) take by weighing propylene glycol alginate sodium sulfate, account for the needle-use activated carbon of cumulative volume 0.1% weight, add in (1) gained solution, after being stirred to dissolving fully, benefit adds to the full amount of water for injection, when pH value is higher than 5, is 10% hydrochloric acid solution, when pH value is lower than 3 is 4% sodium hydroxide solution with concentration with concentration, transfer pH value to 3-5, after taking off charcoal,, get coarse filtration liquid with 0.45 μ m microporous membrane filtration;
(3) with (2) gained coarse filtration liquid with 0.22 μ m filtering with microporous membrane, fine straining liquid;
(4) (3) gained fine straining liquid bottled, partly fall to filling in, lyophilization 32-41 hour, pressing entirely, plug, gland got freeze-dried type injection propylene glycol alginate sodium sulfate.
Freeze drying process described in the preparation method of the present invention (4) is:
(1) cryogenic temperature-40 ℃--45 ℃, freezing 6-7 hour;
(2) sublimation temperature is sublimate into 30 ℃, 18-22 hour by-40 ℃ for the first time;
(3) sublimation temperature is sublimate into 38 ℃, 8-12 hour by 30 ℃ for the second time.
Injection propylene glycol alginate sodium sulfate of the present invention adopts advanced frozen drying technology to make lyophilized formulations, promptly overcome the lower shortcoming of tablet form product bioavailability, solved injection type product again and influenced by high temperature sterilize and unsettled shortcoming in easy to change, the storage life that causes.Show that through the high temperature contrast test under identical storage requirement, the lyophilised preparation of propylene glycol alginate sodium sulfate is more stable than its injection type product, is more suitable in clinical practice.Have effects such as blood viscosity lowering, anticoagulation, blood fat reducing, microcirculation improvement, be used for the control of the ischemic heart, cerebrovascular and hyperlipemia, have stable performance, safe and reliable, clinical advantage such as easy to use.
Test 1: the high temperature contrast test of injection propylene glycol alginate sodium sulfate
Test sample is placed in 60 ℃ the calorstat and placed 10 days, respectively at 0 day, 5 days, 10 days pick test, its result such as table 1.
Table 1 high temperature contrast test testing result
Content time dosage form, lot number weight average molecular weight and distribution character pH value thereof
(％)
Freeze-dried type 20,010,708 92.2 36580=10%≤17224≤10%=6914 white loose block 4.50 days
Injection 20,010,709 93.0 39580=10%≤16380≤10%=5342 colourless clear liquid 4.5
Freeze-dried type 20,010,708 91.8 39118=10%≤17539≤10%=6555 white loose block 4.55 days
The little yellow clear liquid 4.9 of injection 20,010,709 89.5 4989=10%≤15973≤10%=4312
The loose block of freeze-dried type 20,010,708 91.6 38911=10%≤17506≤10%=6367 off-white color 4.610 days
The yellow clear liquid 5.3 of injection 20,010,709 84.8 55128=10%≤15487≤10%=3216
Interpretation of result: can find out that from above result under identical storage requirement, lyophilised preparation is more stable, every index changes little, all the conformance with standard regulation; And the every index variation of injection type product is more obvious, and wherein content descends 7.4 percentage points, and color is by the colourless yellow that fades to, and pH value rises to 5.3 by 4.5, all exceeds the standard code scope.Weight average molecular weight also has bigger variation, small-molecule substance reduces gradually, and macromolecular substances increases gradually, shows that the temperature height is bigger to the property effect of propylene glycol alginate sodium sulfate, under identical storage requirement, the stability of lyophilised preparation will be considerably beyond the stability of injection type product.
Test 2: the hemolytic test of injection propylene glycol alginate sodium sulfate
(1) test objective: observe the injection propylene glycol alginate sodium sulfate man rabbit erythrocyte is had or not haemolysis and agglutination.
(2) test material:
Tried thing: injection propylene glycol alginate sodium sulfate, specification: 100mg.Lot number: 20020429-3.Provide by Jilin City Zhuoyikangna pharmaceutical Co., Ltd..Be mixed with 0.5mg/ml with normal saline, be equipped with test and use.
The negative control thing: sodium chloride injection (normal saline), the 500ml/ bottle provides lot number by three nine-day periods after the winter solstice benefit people pharmaceutical Co. Ltd: 2001042903.
Animal: 1 of large ear rabbit, male, body weight 3kg, anti-medical group provides by the Shandong, Shandong, the quality certification number: Shandong kinoplaszm word 200008001.
(3) instrument: XLJ-II type centrifugal precipitation mechanism, Shanghai medical analytical factory.LSY type electric heating constant temperature water bath, Beijing Medical Equipment Plant.
(4) test method:
The preparation of 2% red blood cell suspension: get 1 of rabbit, cardiac puncture blood sampling 10ml puts into the triangular flask jolting 10 minutes that fills sterile glass beads, remove and defibrinate, make into defibrinated blood, put that an amount of normal saline of adding shakes up in the graduated centrifuge tube, centrifugal with 3000 rev/mins, each 10 minutes, abandoning supernatant, the cyclic washing several is till extremely centrifugal back supernatant is colourless, the gained erythrocyte is made into 2% red blood cell suspension with normal saline, is for experiment.
Hemolytic test: get 7 in test tube, pressing table 2 proportioning adds for reagent amount, 2% red cell suspension, normal saline and distilled water, gently behind the mixing, place and observe each pipe respectively in 37 ℃ of water-baths and have or not haemolysis and hemagglutination at 0.5,1.0,2.0,3.0,4.0 hour each pipe.
Table 2 injection propylene glycol alginate sodium sulfate is molten to test application of sample table
Test tubes number
Group
1234567 injection propylene glycol alginate sodium sulfate (ml) 0.1 0.2 0.2 0.4 0.5 00 normal saline (ml) 2.4 2.3 2.2 2.1 2.0 2.5 0
Distilled water (ml) 000000 2.52% red blood cell suspension (ml) 2.5 2.5 2.5 2.5 2.5 2.5 2.5 results judge: full haemolysis: the clear and bright redness of solution, it is residual that the pipe end does not have erythrocyte.
Part haemolysis: the clear and bright redness of solution or brown, the pipe end, have a small amount of erythrocyte residual.
No haemolysis: erythrocyte all sinks, the supernatant liquid achromatism and clarity.
Coagulation:, can not disperse after the jolting though red cell agglutination appears in haemolysis not.
(5) result: be shown in Table 3, except that the 7th arm (distilled water contrast) occurs the haemolysis, haemolysis or agglutination appear in each Guan Junwei for the reagent thing.
Table 3 injection propylene glycol alginate sodium sulfate result of the test
Test tubes observing time (h)
1 2 3 4 5 6 7
0.5 - - - - - - +
1.0 - - - - - - +
2.0 - - - - - - +
3.0 - - - - - - +
4.0 - - - - - - +
(6) conclusion: result of the test shows that the injection propylene glycol alginate sodium sulfate is no obvious haemolysis and hemagglutination generation in observing time.
Test 3: the sensitivity test of injection propylene glycol alginate sodium sulfate
(1) test objective: observe the injection propylene glycol alginate sodium sulfate Cavia porcellus is had or not sensitivity response, for data for clinical drug use provides test basis.
(2) test material:
Tried thing: injection propylene glycol alginate sodium sulfate, specification: 100mg.Lot number: 20020429-3.Provide by Jilin City Zhuoyikangna pharmaceutical Co., Ltd..Be mixed with 0.5mg/ml with normal saline, be equipped with test and use.
The negative control thing: sodium chloride injection (normal saline), the 500ml/ bottle provides lot number by three nine-day periods after the winter solstice benefit people pharmaceutical Co. Ltd: 2001042903.
Positive control: 5% ovalbumin normal saline solution, get fresh albumen under the aseptic condition, it is standby to be made into 5% concentration with normal saline.
Animal: Cavia porcellus, 18, body weight 250-300g, the male and female dual-purpose is provided by Jinan three nine-day periods after the winter solstice benefit people pharmaceutical Co. Ltd, the quality certification number: Shandong kinoplaszm word 200001012.
(3) animal feeding environment:
SPF Animal Lab, the quality certification number: Shandong rotating ring word 200001002, temperature 20-24 ℃, humidity 40-70%, wind speed 0.1-0.2m/ second, air-flow 〉=28 time/time.
The cage tool: Wu County logical peace medical experiment instrument factory is produced, the quality certification number: moving (cage) 94005 of Soviet Union.
Feedstuff: Shandong Province's Experimental Animal Center provides, the quality certification number: the moving word 200001001 of raising in Shandong.
(4) test method:
Get 18 of Cavia porcelluss, be divided into negative control group (normal saline), positive controls (ovalbumin) and medicine group at random, 6 every group.The corresponding medicinal liquid 0.5ml/ of each treated animal every other day lumbar injection, continuous 3 times.Only get 3 corresponding medicinal liquid 1ml/ of Cavia porcellus intravenous injection for every group for the first time injecting back 14 days and 21 days respectively, observe injection and respectively organize Cavia porcellus in back 15 minutes and have or not anaphylaxis.
The result judges: according to the Pharmacopoeia of the People's Republic of China (2000 editions, two ones) regulation, observe after the administration that Cavia porcellus has or not anaphylaxis in 15 minutes, if any two or more person in perpendicular hair, dyspnea, sneeze, retch or the phenomenon such as cough 3, or one of sound of vomiting sound, tic, collapse or phenomena of mortality person is arranged, should be judged to the positive.
(5) result: Cavia porcellus 14 days and intravenous injection in 21 days after the administration first time are only tried thing 1ml/, phenomenon such as perpendicular hair, dyspnea, sneeze, retch all occur or cough 3, sound of vomiting sound, tic, collapse or death etc. do not appear yet, with the negative control group zero difference.The positive control treated animal symptoms such as astasia, tic, dyspnea all occur behind 14 days and intravenous injection in 21 days 5% ovalbumin normal saline solution after the administration first time, 6 Cavia porcelluss are all dead in 4 minutes after administration.
(6) conclusion: according to the Pharmacopoeia of the People's Republic of China (2000 editions, two ones) regulation, the result is negative for injection propylene glycol alginate sodium sulfate hypersensitive test.
Test 4: the vein irritating test of injection propylene glycol alginate sodium sulfate
(1) test objective: observe the stimulation of intravenous drip injection propylene glycol alginate sodium sulfate to large ear rabbit blood vessel (vein).
(2) test material:
Tried thing: injection propylene glycol alginate sodium sulfate, specification: 100mg.Lot number: 20020429-3.Provide by Jilin City Zhuoyikangna pharmaceutical Co., Ltd..Be mixed with 0.5mg/ml with normal saline, be equipped with test and use.
The negative control thing: sodium chloride injection (normal saline), the 500ml/ bottle is provided by three nine-day periods after the winter solstice benefit people pharmaceutical Co. Ltd, carries lot number: 2001042903.
Animal: 6 of large ear rabbits, the male and female dual-purpose, body weight 2.0-2.5kg, anti-medical group provides by the Shandong, Shandong, the quality certification number: Shandong kinoplaszm word 200008001.
(3) test method: 6 of rabbit are divided into injection propylene glycol alginate sodium sulfate administration group and sodium chloride injection matched group at random by body weight, 3 every group.Animal is fixed in the rabbit hutch, the corresponding medicinal liquid of left side auricular vein drop, the drop amount is 15ml/kg, drip velocity 1ml/ minute.Instil every day 1 time, for three days on end.During the instillation and after instiling, note observing the instillation position and have or not stimulations such as redness.,, cut the left side rabbit ear and draw materials after 24 hours in the last administration, carry out histopathologic examination from inserting needle position proximal part 1cm place with sacrifice of animal.
(4) result:
Perusal: during each instillation the and the back of instiling is observed, and is subjected to the reagent thing group rabbit ear position irritant reaction such as tangible vasodilation, hyperemia, heating not occur, compares no significant difference with matched group.
Histopathologic examination: matched group censorship specimen organizational structure is normal, and auricular vein is not seen expansion, and vascular endothelial cell do not see yet and increase and change such as arrangement disorder, and blood vessel wall does not have and thickens and pathomorphology such as inflammation changes; Be subjected to reagent thing group censorship specimen organizational structure normal, vascular endothelial cell does not see and increases and change such as arrangement disorder that auricular vein is not seen expansion yet, and blood vessel wall does not have and thickens and pathomorphism such as inflammation changes, with matched group no significant difference (omission of pathology photo) relatively.
(5) conclusion: the intravenous drip of injection propylene glycol alginate sodium sulfate does not have obvious vascular stimulation effect.
Test 5: the medicine stability test of injection propylene glycol alginate sodium sulfate
(1) instrument and material:
High pressure liquid chromatograph (U.S.), and gel column (300 * 7.8mm), SYSTEMRI-150 differential detector (U.S. TSP company), GPC software (Beijing Long Zhida company).
Constant incubator: upright crane board electro-heating standing-temperature cultivator, Weifang, Shandong Medical Treatment Equipment Co., Ltd.
Growth cabinet (illumination 45001x) model LRH-250-GS, Guangdong medical apparatus and instruments factory.
The standard polysaccharide is purchased in the biochemical chamber of Chinese biological goods calibrating.
Other reagent is analytical pure.
(2) accelerated tests:
The investigation method:
With sample, in 40 ℃ ± 2 ℃ constant incubators, placed 6 months, respectively at 0,1,2,3, June, the variation of its discriminating, character, alginate diester sodium content, weight average molecular weight and molecular weight distribution was investigated in sampling.
The lot number 20010708-1 of sample source Jilin City Zhuoyikangna pharmaceutical Co., Ltd., 20010708-2,20010708-3
The investigation project is undertaken by method under " quality standard " item, and weight average molecular weight and distribution thereof are undertaken by the distribution and the assay method of two polysaccharide molecular weights of Chinese Pharmacopoeia.The results are shown in Table 4,5,6.
35047=10%≤16980≤10%=5373 white loose block 4.5 was qualified 4.5 qualified June 90.6 for the block piece of the block piece of 0 month 92.2 36582=10% of lot number 20010708-1 table 4 40 ℃ ± 2 ℃ accelerated test testing result time content (%) weight average molecular weight and distribution proterties PH clarity the color of the solution thereof≤17224≤10%=6914 white loose 4.5 34913=10% in qualified January 91.4≤16922≤10%=5350 white loose block 4.5 34794=10% in qualified February 92.3≤16946≤10%=5396 white loose 4.5 34779=10% in qualified March 91.8≤16816≤10%=5311 white loose block
Content RSD%=0.58 weight average molecular weight RSD%=0.88
The result: as can be seen from Table 4, the color of this product character, PH, clarity, solution all meets the requirements, and content and weight average molecular weight RSD% be all less than 5%, promptly changes not obviously, and product is stable.
34645=10%≤16794≤10%=5311 white loose block 4.5 was qualified 4.5 qualified June 90.6 for the block piece of the block piece of 0 month 91.8 37942=10% of lot number 20010708-2 table 5 40 ℃ ± 2 ℃ accelerated test testing result time content (%) weight average molecular weight and distribution proterties PH clarity the color of the solution thereof≤17233≤10%=6611 white loose 4.5 34631=10% in qualified January 91.0≤16815≤10%=5331 white loose block 4.5 34928=10% in qualified February 90.8≤16973≤10%=5435 white loose 4.5 35077=10% in qualified March 91.4≤17011≤10%=5377 white loose block
Content RSD%=0.42 weight average molecular weight RSD%=0.76
Conclusion: as can be seen from Table 5, the color of this product character, PH, clarity, solution all meets the requirements, and content weight average molecular weight RSD% is all less than 5%, promptly changes not obviously, and product is stable.
The block piece of 34660=10% white loose block 4.5 35047=10% white loose in qualified February 92.8 in the block piece of 0 month 93.4 38488=10% white loose of 40 ℃ ± 2 ℃ accelerated test testing result time content of lot number 20010708-3 table 6 (%) weight average molecular weight proterties PH clarity the color of the solution 4.5 qualified January 93.6 4.5 qualified March 92.0,35182=10% white loose block 4.5 34557=10% white loose block 4.5 in qualified June 92.4 was qualified
Content RSD%=0.57 weight average molecular weight RSD%=0.96
Conclusion: as can be seen from Table 6, the color of this product character, PH, clarity, solution all meets and will show, content and weight average molecular weight RSD% promptly change and fail to understand that product is stable all less than 5%.
Conclusion: investigate the result according to 6 months accelerated tests and show that pilot scale 3 batch samples front and back change not obvious, interpret sample is stable.
(3) long term test
The investigation method:
With this lot number is 20010708-1,20010708-2, and the test product of 20010708-3 was placed 12 months in 25 ℃ ± 2 ℃ constant incubators are medium-term and long-term, and sampling regularly detects the variation of color, weight average molecular weight and the PH of character, discriminating, content, clarity, solution.
Investigate index and undertaken by " quality standard ", weight average molecular weight is undertaken by the distribution and the assay method of two polysaccharide molecular weights of Chinese Pharmacopoeia version in 2000,10000-25000 dalton; Molecular weight distribution is greater than 50000, less than 10%; Less than 3000 less than 10%.The results are shown in Table 7,8,9.
The color of 25 ℃ ± 2 ℃ long term test testing result time discriminating content (%) weight average molecular weight of lot number 20010708-1 table 7 and distribution character PH clarity solution thereof
The block piece of (1) 92.2 36582=10%≤17224≤10%=6914 white loose 4.5 qualified 0 month
(2)
4.4 qualified March of (1) 91.6 34681=10%≤16782≤10%=5311 white loose block
(2)
4.4 qualified June of the block piece of (1) 92.0 34749=10%≤16751≤10%=5243 white loose
(2)
(1) 91.4 34779=10%≤16870≤10%=5373 white loose block, 4.5 qualified JIUYUE
(2)
(1) 91.8 35914=10%≤16502≤10%=6284 white loose block, 4.3 qualified Decembers
(2)
Content RSD%=0.31 weight average molecular weight RSD%=0.26
Differentiate that item meets the requirements
Conclusion: as can be seen from Table 7, the color of this product character, discriminating, PH, clarity, solution has no significant change, alginate diester sodium content RSD% and weight average molecular weight RSD% illustrate that all less than 5% this product placement front and back variation in 12 months is not obvious, and this product is stable.
The color of 25 ℃ ± 2 ℃ long term test testing result time discriminating content (%) weight average molecular weight of lot number 20010708-2 table 8 and distribution character PH clarity solution thereof
The block piece of (1) 91.8 37942=10%≤17233≤10%=6611 white loose 4.5 qualified 0 month
(2)
4.5 qualified March of (1) 92.0 34779=10%≤16826≤10%=5331 white loose block
(2)
4.4 qualified June of the block piece of (1) 91.0 34498=10%≤16669≤10%=5248 white loose
(2)
(1) 91.4 34719=10%≤16770≤10%=5282 white loose block, 4.4 qualified JIUYUE
(2)
(1) 90.8 35639=10%≤16611≤10%=6645 white loose block, 4.3 qualified Decembers
(2)
Content RSD%=1.97 weight average molecular weight RSD%=0.99
Differentiate that item meets the requirements
Conclusion: as can be seen from Table 8, the color of this product character, discriminating, PH, clarity, solution all meets the requirements, and propylene glycol alginate sodium sulfate RSD% and weight average molecular weight RSD% be all less than 5%, illustrates that this product placed 1 year, changes not obviously, and this product is stablized.
The color of 25 ℃ ± 2 ℃ long term test testing result time discriminating content (%) weight average molecular weight of lot number 20010708-3 table 9 and distribution character PH clarity solution thereof
The block piece of (1) 93.4 38488=10%≤17399≤10%=6507 white loose 4.2 qualified 0 month
(2)
4.3 qualified March of (1) 92.8 35333=10%≤16992≤10%=5331 white loose block
(2)
4.2 qualified June of the block piece of (1) 93.0 34631=10%≤16795≤10%=5373 white loose
(2)
(1) 92.4 35047=10%≤16846≤10%=5268 white loose block, 4.1 qualified JIUYUE
(2)
(1) 92.2 37098=10%≤17134≤10%=6644 white loose block, 4.2 qualified Decembers
(2)
Content RSD%=0.40 weight average molecular weight RSD%=1.10
Differentiate that item meets the requirements
Conclusion: as can be seen from Table 9, the color of this product character, discriminating, PH, clarity, solution meets the requirements, and alginate diester sodium content RSD% and weight average molecular weight RSD% are all less than 5%, and it is not obvious to illustrate that this product front and back change, and this product is stable.
(5) conclusion
Show that from above-mentioned accelerated tests, long-term test results this product was placed 6 months under 40 ℃ ± 2 ℃ conditions, every index all meets the quality standard regulation, places for a long time 12 months, and every finger will all not have significant change.
The specific embodiment
Embodiment below in conjunction with the preparation of injection propylene glycol alginate sodium sulfate is further described the present invention.
Embodiment 1:
Each proportion of raw materials is:
Propylene glycol alginate sodium sulfate 200 grams
Sodium chloride 25 grams
Water for injection is made 1000 bottles for 2000 milliliters
Preparation method is as follows: getting 1600 milliliters of waters for injection, is that 10% hydrochloric acid solution or concentration are that 4% sodium hydroxide solution is transferred pH value to 4.5 with concentration, adds sodium chloride 25 grams, is stirred to dissolving fully; Get propylene glycol alginate sodium sulfate 200 grams, needle-use activated carbon 2 grams, add in the above-mentioned solution, after being stirred to dissolving fully, add water for injection to 2000 milliliter, with concentration is that 10% hydrochloric acid solution or concentration are that 4% sodium hydroxide solution is transferred pH value to 4.5, after taking off charcoal with reuse 0.22 μ m filtering with microporous membrane behind the 0.45 μ m microporous membrane filtration; With gained fine straining liquid bottling, false add plug, lyophilization 36 hours, wherein: cryogenic temperature-40 ℃, freezing 6 hours; Sublimation temperature is sublimate into 30 ℃, 20 hours by-40 ℃ for the first time; For the second time sublimation temperature is by 30-38 ℃, 10 hours; Press full plug, gland to get the injection propylene glycol alginate sodium sulfate afterwards.
The injection propylene glycol alginate sodium sulfate that present embodiment is made, specification: 100mg/ bottle; Usage and consumption: intravenous drip, the adult, by a 1-3mg/kg of body weight (50-100mg), maximum is no more than 150mg.Face with after before being dissolved among transfusion (normal saline or 5% glucose, the 6% hetastarch etc.) 500-1000ml dilution, slowly instil, 1 time on the one, 10-14 day is a course of treatment.
Embodiment 2:
Each proportion of raw materials is:
Propylene glycol alginate sodium sulfate 100 grams
Mannitol 50 grams
Water for injection is made 1000 bottles for 2000 milliliters
Preparation method is substantially the same manner as Example 1, lyophilization 37 hours, wherein: cryogenic temperature-40 ℃, freezing 7 hours; Sublimation temperature is sublimate into 30 ℃, 20 hours by-40 ℃ for the first time; For the second time sublimation temperature is by 30-38 ℃, 10 hours.
Embodiment 3:
Each proportion of raw materials is:
Propylene glycol alginate sodium sulfate 25 grams
Dextran 40 200 grams
Water for injection is made 1000 bottles for 2000 milliliters
Preparation method is substantially the same manner as Example 1, lyophilization 36 hours, wherein: cryogenic temperature-40 ℃, freezing 6 hours; Sublimation temperature is sublimate into 30 ℃, 20 hours by-40 ℃ for the first time; For the second time sublimation temperature is by 30-38 ℃, 10 hours.
The source of used supplementary material and quality standard are as follows among each embodiment:
Two ones of 95 years two the 4th two needle-use activated carbon Shanghai active carbon factories of Chinese Pharmacopoeia two Dextran 40 Shanghai of version in 2000 two water for injection Shandong Green Leaf Pharmaceutical Co., Ltd of grape sugar refinery Chinese Pharmacopoeia version in 2000 Chinese Pharmacopoeia version in 2000 of Chinese Pharmacopoeia two sweet mellow wine Jilins of version in 2000 Cornell medicine company limited company of fascicle sodium chloride Weihai Asia-Pacific pharmaceutcal corporation, Ltd Chinese Pharmacopoeias of quality standard PSS Dalian, supplementary material source beach subsidiary factory of Ao Sen pharmaceutical factory ministry of Health of China ministry standard versions in 2000
Claims (4)
1, a kind of injection propylene glycol alginate sodium sulfate is characterized in that containing propylene glycol alginate sodium sulfate, excipient, and the weight proportion that contains described each composition in wherein per 1000 bottles is:
Propylene glycol alginate sodium sulfate 25-200 gram
Excipient 200-25 gram.
2, injection propylene glycol alginate sodium sulfate according to claim 1 is characterized in that excipient is selected from: sodium chloride, mannitol, Dextran 40.
3, the preparation method of claim 1 injection propylene glycol alginate sodium sulfate is characterized in that its preparation method comprises the steps:
(1) measures the water for injection of cumulative volume 80%, when pH value is higher than 5, is 10% hydrochloric acid solution, when pH value is lower than 3 is 4% sodium hydroxide solution, transfer pH value, add excipient, be stirred to dissolving fully to 3-5 with concentration with concentration;
(2) take by weighing propylene glycol alginate sodium sulfate, account for the needle-use activated carbon of cumulative volume 0.1% weight, add in (1) gained solution, after being stirred to dissolving fully, benefit adds to the full amount of water for injection, when pH value is higher than 5, is 10% hydrochloric acid solution, when pH value is lower than 3 is 4% sodium hydroxide solution with concentration with concentration, transfer pH value to 3-5, after taking off charcoal,, get coarse filtration liquid with 0.45 μ m microporous membrane filtration;
(3) with (2) gained coarse filtration liquid with 0.22 μ m filtering with microporous membrane, fine straining liquid;
(4) (3) gained fine straining liquid bottled, partly fall to filling in, lyophilization 32-41 hour, pressing entirely, plug, gland got the injection propylene glycol alginate sodium sulfate.
4, preparation method according to claim 3 is characterized in that its freeze drying process is:
(1) cryogenic temperature-40 ℃--45 ℃, freezing 6-7 hour;
(2) sublimation temperature is sublimate into 30 ℃, 18-22 hour by-40 ℃ for the first time;
(3) sublimation temperature is sublimate into 38 ℃, 8-12 hour by 30 ℃ for the second time.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03127651 CN1218704C (en) | 2003-07-29 | 2003-07-29 | Sodium bialginate for injection and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 03127651 CN1218704C (en) | 2003-07-29 | 2003-07-29 | Sodium bialginate for injection and its preparation method |
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| CN1481809A true CN1481809A (en) | 2004-03-17 |
| CN1218704C CN1218704C (en) | 2005-09-14 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102824357A (en) * | 2012-09-19 | 2012-12-19 | 天津市嵩锐医药科技有限公司 | Polysaccharide sulphate pharmaceutical compound for injection |
| CN103083261A (en) * | 2013-02-18 | 2013-05-08 | 青岛正大海尔制药有限公司 | Polysaccharide sulfate freeze-dried powder injection |
| CN104688766A (en) * | 2015-03-31 | 2015-06-10 | 山东北大高科华泰制药有限公司 | Alginic sodium diester powder-injection pharmaceutical composition for injection and preparation method thereof |
-
2003
- 2003-07-29 CN CN 03127651 patent/CN1218704C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102824357A (en) * | 2012-09-19 | 2012-12-19 | 天津市嵩锐医药科技有限公司 | Polysaccharide sulphate pharmaceutical compound for injection |
| CN103083261A (en) * | 2013-02-18 | 2013-05-08 | 青岛正大海尔制药有限公司 | Polysaccharide sulfate freeze-dried powder injection |
| CN103083261B (en) * | 2013-02-18 | 2014-03-19 | 青岛正大海尔制药有限公司 | Polysaccharide sulfate freeze-dried powder injection |
| CN104688766A (en) * | 2015-03-31 | 2015-06-10 | 山东北大高科华泰制药有限公司 | Alginic sodium diester powder-injection pharmaceutical composition for injection and preparation method thereof |
| CN104688766B (en) * | 2015-03-31 | 2018-06-01 | 山东北大高科华泰制药有限公司 | Polysaccharide sulphate for injection powder-injection pharmaceutical composition and preparation method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1218704C (en) | 2005-09-14 |
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