CN1318090C - Medicine composition for improving stability of human urine kininogenase - Google Patents
Medicine composition for improving stability of human urine kininogenase Download PDFInfo
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- CN1318090C CN1318090C CNB2004100960604A CN200410096060A CN1318090C CN 1318090 C CN1318090 C CN 1318090C CN B2004100960604 A CNB2004100960604 A CN B2004100960604A CN 200410096060 A CN200410096060 A CN 200410096060A CN 1318090 C CN1318090 C CN 1318090C
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- urinary kallidinogenase
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Abstract
The present invention discloses a medical composition for enhancing the stability of kininogenase bioactivity of human urine. The medical composition is prepared from one or some of mannitol, dextran, hydrolyzed gelatin and trisodium citrate dihydrate which are prepared into water solution. During clinical application, the freeze-dried powder of the kininogenase of human urine is dissolved by the water solution, and is dissolved in large liquid, and thus, the reduction of the kininogenase activity of the human urine in the water solution can be obviously postponed.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, particularly in order to improve the pharmaceutical composition of biochemical drug Human Urinary Kallidinogenase biological activity stability.
Background technology
Human Urinary Kallidinogenase (Human Urinary Kallidinogenase) extracts purified protease from Urina Hominis, have blood vessel dilating, prevent effect such as thrombosis.The applicant's patent application formerly " application of 02116783.4 Human Urinary Kallidinogenase in preparation treatment and prevention of brain infraction medicine " discloses its a kind of medical usage.The Human Urinary Kallidinogenase is made generally in lyophilized injectable powder, with a small amount of isosmotic solution it is dissolved earlier during clinical practice, is diluted in big liquid medium-sized vein infusion such as sodium chloride solution, glucose solution then.Because the Human Urinary Kallidinogenase is a kind of proteolytic enzyme, in process, be easy to take place reduction of medicine biological activity even inefficacy with its lyophilized powder dissolving and molten National People's Congress liquid.When its through dilution, when being present in the aqueous solution that is mixed with, be easy to also take place that the medicine biological activity reduces even lost efficacy with low concentration.Even the method for end user's urinary kallidinogenase takes promptly to join promptly the mode of using, promptly joining fast usefulness clinically at present, still be difficult to avoid the inefficacy and the waste of medicine.This characteristic of Human Urinary Kallidinogenase may be affected the treatment to patient adversely.Because can not before each medication, all carry out the activity monitoring, when invalid case occurring, be difficult to judge to be the incompatibility of the property of medicine, or be to use the medicine that lost efficacy.
Summary of the invention
The technical problem to be solved in the present invention is, overcomes the problem of Human Urinary Kallidinogenase's lyophilized powder easy inactivation when being made into aqueous solution, improves its stability.Particularly adopt form with addition of thing.
The technical scheme that the present invention solves above technical problem is; choose and to shield to Human Urinary Kallidinogenase's activity, not produce antagonism, can do intravenous material with Human Urinary Kallidinogenase's pharmacological action; be mixed with aqueous solution; when clinical practice in order to dissolving Human Urinary Kallidinogenase lyophilized powder, molten again National People's Congress liquid medium-sized vein infusion.
Mannitol, dextran, gelatin hydrolysate and sodium citrate can be arranged the material that Human Urinary Kallidinogenase's activity shields.Can be a kind of or formulated in combination Human Urinary Kallidinogenase's stabiliser solution of any multiple material with it.Preferably use the combination of its 2～3 kinds of materials.
Above-mentioned stabilizing agent preferred compositions and proportioning be,
Optimization formula one: 1.5 parts in mannitol, 1 part of gelatin hydrolysate, 1 part of sodium citrate.I.e. " mannitol: gelatin hydrolysate: sodium citrate=1.5: 1: 1 ".
Optimization formula two: 1 part in 1.5 parts in mannitol, dextran 1 part, sodium citrate.I.e. " mannitol: dextran: sodium citrate=1.5: 1: 1 ".
Optimization formula three: 1.5 parts in mannitol, 1 part of sodium citrate.I.e. " mannitol: sodium citrate=1.5: 1 ".
Above stabilizing agent mixes the back and regulates pH value to 6～7 respectively with water for injection dissolving, and adding water for injection to concentration again is 2.0～3.5%, and it is standby to be distributed into 5 milliliters of ampoules.During clinical practice,, add again and do the defeated people of vein in National People's Congress's liquid with stabiliser solution dissolving Human Urinary Kallidinogenase lyophilized powder.The each application dose of Human Urinary Kallidinogenase is 0.05～0.5pNAU.The consumption of stabilizing agent is according to how many decisions of infusion solutions, and one 5 milliliters of stabiliser solutions are used in general per 100 milliliters of transfusions.
Experiment shows, uses stabiliser solution dissolving Human Urinary Kallidinogenase lyophilized powder of the present invention, adds in National People's Congress's liquid again, and this aqueous solution places two days later that tiring of Human Urinary Kallidinogenase still can remain on more than 95%.And the Human Urinary Kallidinogenase's lyophilized powder molten National People's Congress liquid that does not use stabiliser solution is after one day, and it is tired and just reduces to below 92%; Through two days, tire and just reduce to below 81%, lose use value.
The specific embodiment
The invention will be further described by the following examples.
Embodiment 1～5
According to the form below institute number of columns takes by weighing each stabilizing agent raw material respectively.Unit of weight is a milligram.
Preparation method: take by weighing each medicinal stabilizing agent by listed kind and weight in the table, add the dissolving of injection water respectively, mix the back and regulate pH value to 6～7, add water for injection to 5000 milliliter again, filter membrane aseptic filtration is sub-packed in 1000 ampoules, moist heat sterilization behind the sealing by fusing.
The experiment of embodiment 6 stabilities of solution
Get one of 0.5pNAU Human Urinary Kallidinogenase lyophilized injectable powder, add 5 milliliters of stabiliser solution dissolvings by the preparation of embodiment 1～5 method, annotate in 100 milliliter of 0.9% sodium chloride solution of people and shake up, 20 ℃ of placements, observe cosmetic variation, sampling and measuring pH value, residual activity at 1,6,12,24,36,48 hour respectively, the results are shown in Table 1～5.
Other gets a 0.5pNAU Human Urinary Kallidinogenase freeze-dried powder, with 5 milliliter of 0.9% sodium chloride solution dissolving, annotate again in people 100ml 0.9% sodium chloride solution and shake up, 20 ℃ of placements, observe cosmetic variation, sampling and measuring pH value, residual activity in contrast at 1,6,12,24,36,48 hour respectively, the results are shown in Table 6.
Table 1 Human Urinary Kallidinogenase adds behind embodiment 1 stabilizing agent stability test result in the sodium chloride infusion solutions
| Sample time (h) | 0 | ?1 | ?6 | ?1?2 | ?24 | ?36 | ?48 |
| Outward appearance | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| PH value | 6.6 | ?6.5 | ?6.5 | ?6.5 | ?6.5 | ?6.5 | ?6.5 |
| Residual activity (%) | 100 | ?100 | ?99.2 | ?99.1 | ?98.3 | ?97.5 | ?96.2 |
Table 2 Human Urinary Kallidinogenase adds behind embodiment 2 stabilizing agents stability test result in the sodium chloride infusion solutions
| Sample time (h) | 0 | ?1 | ?6 | ?12 | ?24 | ?36 | ?48 |
| Outward appearance | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| PH value | 6.6 | ?6.5 | ?6.5 | ?6.5 | ?6.5 | ?6.5 | ?6.5 |
| Residual activity (%) | 100 | ?100 | ?98.9 | ?99.1 | ?98.0 | ?97.2 | ?95.5 |
Table 3 Human Urinary Kallidinogenase adds behind embodiment 3 stabilizing agents stability test result in the sodium chloride infusion solutions
| Sample time (h) | 0 | ?1 | ?6 | ?12 | ?24 | ?36 | ?48 |
| Outward appearance | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| PH value | 6.6 | ?6.5 | ?6.5 | ?6.5 | ?6.5 | ?6.5 | ?6.5 |
| Residual activity (%) | 100 | ?99.8 | ?98.2 | ?98.1 | ?97.7 | ?97.0 | ?95.2 |
Table 4 Human Urinary Kallidinogenase adds behind embodiment 4 stabilizing agents stability test result in the sodium chloride infusion solutions
| Sample time (h) | 0 | ?1 | ?6 | ?12 | ?24 | ?36 | ?48 |
| Outward appearance | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| PH value | 6.6 | ?6.5 | ?6.5 | ?6.5 | ?6.5 | ?6.5 | ?6.5 |
| Residual activity (%) | 100 | ?99.5 | ?97.9 | ?97.1 | ?96.7 | ?95.5 | ?94.2 |
Table 5 Human Urinary Kallidinogenase adds behind embodiment 5 stabilizing agents stability test result in the sodium chloride infusion solutions
| Sample time (h) | 0 | ?1 | ?6 | ?12 | ?24 | ?36 | ?48 |
| Outward appearance | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| PH value | 6.6 | ?6.5 | ?6.5 | ?6.5 | ?6.5 | ?6.5 | ?6.5 |
| Residual activity (%) | 100 | ?99.9 | ?98.6 | ?98.2 | ?97.3 | ?96.5 | ?94.8 |
Table 6 Human Urinary Kallidinogenase does not add stabilizing agent stability test result in the sodium chloride infusion solutions
| Sample time (h) | 0 | ?1 | ?6 | ?12 | ?24 | ?36 | ?48 |
| Outward appearance | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| PH value | 6.6 | ?6.5 | ?6.5 | ?6.5 | ?6.5 | ?6.5 | ?6.5 |
| Residual activity (%) | 100 | ?98.8 | ?96.6 | ?94.1 | ?90.3 | ?89.6 | ?82.2 |
This experimental result shows, the Human Urinary Kallidinogenase with stabiliser solution dissolving back in the sodium chloride transfusion through still using two days later, only can not preserve 12 hours effectively and do not add stabilizing agent.
The experiment of embodiment 7 stabilities of solution
Get one of 0.5pNAU Human Urinary Kallidinogenase lyophilized injectable powder, add 5 milliliters of stabiliser solution dissolvings by the preparation of embodiment 1～5 method, injecting 100 milliliter of 5% glucose isosmotic solution shakes up, 20 ℃ of placements, observe cosmetic variation, sampling and measuring pH value, residual activity at 1,6,12,24,36,48 hour respectively, the results are shown in Table 7～11.
Other gets a 0.5pNAU Human Urinary Kallidinogenase freeze-dried powder, with 5 milliliter of 5% glucose solution dissolving, reinject and shake up in 100ml 5% glucose solution, 20 ℃ of placements, observe cosmetic variation, sampling and measuring pH value, residual activity in contrast at 1,6,12,24,36,48 hour respectively, the results are shown in Table 12.
Table 7 Human Urinary Kallidinogenase adds behind embodiment 1 stabilizing agent stability test result in the glucose infusion solutions
| Sample time (h) | 0 | ?1 | 6 | 12 | 24 | 36 | 48 |
| Outward appearance | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| PH value | 6.3 | ?6.3 | ?6.4 | ?6.4 | ?6.4 | ?6.4 | ?6.4 |
| Residual activity (%) | 100 | ?99.7 | ?99.5 | ?99.3 | ?99.3 | ?97.9 | ?97.2 |
Table 8 Human Urinary Kallidinogenase adds behind embodiment 2 stabilizing agents stability test result in the glucose infusion solutions
| Sample time (h) | 0 | ?1 | ?6 | ?12 | ?24 | ?36 | ?48 |
| Outward appearance | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| PH value | 6.3 | ?6.3 | ?6.4 | ?6.4 | ?6.4 | ?6.4 | ?6.4 |
| Residual activity (%) | 100 | ?100 | ?99.6 | ?99.1 | ?98.8 | ?97.9 | ?96.2 |
Table 9 Human Urinary Kallidinogenase adds behind embodiment 3 stabilizing agents stability test result in the glucose infusion solutions
| Sample time (h) | 0 | ?1 | ?6 | ?12 | ?24 | ?36 | ?48 |
| Outward appearance | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| PH value | 6.3 | ?6.3 | ?6.4 | ?6.4 | ?6.4 | ?6.4 | ?6.4 |
| Residual activity (%) | 100 | ?99.5 | ?99.3 | ?98.8 | ?98.3 | ?97.1 | ?96.0 |
Table 10 Human Urinary Kallidinogenase adds behind embodiment 4 stabilizing agents stability test result in the glucose infusion solutions
| Sample time (h) | 0 | ?1 | ?6 | ?12 | ?24 | ?36 | ?48 |
| Outward appearance | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| PH value | 6.3 | ?6.3 | ?6.4 | ?6.4 | ?6.4 | ?6.4 | ?6.4 |
| Residual activity (%) | 100 | ?99.1 | ?98.7 | ?97.4 | ?95.1 | ?94.4 | ?94.2 |
Table 11 Human Urinary Kallidinogenase adds behind embodiment 5 stabilizing agents stability test result in the glucose infusion solutions
| Sample time (h) | 0 | ?1 | ?6 | ?12 | ?24 | ?36 | ?48 |
| Outward appearance | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| PH value | 6.3 | ?6.3 | ?6.4 | ?6.4 | ?6.4 | ?6.4 | ?6.4 |
| Residual activity (%) | 100 | ?99.4 | ?98.6 | ?97.1 | ?96.6 | ?95.0 | ?93.3 |
Table 12 Human Urinary Kallidinogenase does not add stabilizing agent stability test result in the glucose infusion solutions
| Sample time (h) | 0 | ?1 | ?6 | ?12 | ?24 | ?36 | ?48 |
| Outward appearance | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| PH value | 6.3 | ?6.3 | ?6.4 | ?6.4 | ?6.4 | ?6.4 | ?6.4 |
This experimental result shows, the Human Urinary Kallidinogenase with stabiliser solution dissolving back in glucose infusion liquid through still using two days later, only can not preserve 12 hours effectively and do not add stabilizing agent.
Claims (3)
1. pharmaceutical composition that is used for improving the aqueous solution stability of human urine kininogenase is characterized in that it is that concentration by mannitol 1.5 weight portions, dextran 1 weight portion and sodium citrate 1 weight portion formulated in combination is the aqueous solution of 2.0-3.5%.
2. according to the pharmaceutical composition of claim 1, its PH is 6-7.
3. method for preparing according to the pharmaceutical composition of claim 1, it is characterized in that getting mannitol, dextran and sodium citrate respectively with the water for injection dissolving, mix, regulate PH to 6-7, add water for injection again to concentration 2.0-3.5%, packing sealing by fusing moist heat sterilization promptly.
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| CNB2004100960604A CN1318090C (en) | 2004-11-29 | 2004-11-29 | Medicine composition for improving stability of human urine kininogenase |
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| CNB2004100960604A CN1318090C (en) | 2004-11-29 | 2004-11-29 | Medicine composition for improving stability of human urine kininogenase |
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| CN1318090C true CN1318090C (en) | 2007-05-30 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104083756A (en) * | 2014-07-22 | 2014-10-08 | 张庆宇 | Auxiliary agent for stabilizing pharmaceutical composition and pharmaceutical composition containing auxiliary agent |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101879310A (en) * | 2010-06-13 | 2010-11-10 | 广东天普生化医药股份有限公司 | Application of human urinary kallidinogenase in preparing medicine for treating diabetic nephropathy |
| CN101879309A (en) * | 2010-06-13 | 2010-11-10 | 广东天普生化医药股份有限公司 | Application of human urinary kallidinogenase in preparing medicine for treating diabetic foot ulcers |
| CN107802827B (en) * | 2017-11-29 | 2019-01-22 | 广东天普生化医药股份有限公司 | A kind of recombination kallikrein freeze-dried powder preparation |
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| CN1072337A (en) * | 1992-11-23 | 1993-05-26 | 苏州制胶公司日用化工厂 | Skin care cream |
| CN1307905A (en) * | 2001-01-22 | 2001-08-15 | 长春长生基因药业股份有限公司 | Recombinant human interleukin-2 protectant |
| CN1365628A (en) * | 2001-08-31 | 2002-08-28 | 李致勋 | Health-care antisanility food and its preparing process |
| CN1380093A (en) * | 2002-04-30 | 2002-11-20 | 新疆医科大学 | Alcohol extraction method for extracting grape skin extract and its grape liver-nourishing capsule |
| CN1403156A (en) * | 2002-05-13 | 2003-03-19 | 广东天普生化医药股份有限公司 | Application of human urokininogenase in preparing medicine for preventing and treating cerebral infraction |
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- 2004-11-29 CN CNB2004100960604A patent/CN1318090C/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1072337A (en) * | 1992-11-23 | 1993-05-26 | 苏州制胶公司日用化工厂 | Skin care cream |
| CN1307905A (en) * | 2001-01-22 | 2001-08-15 | 长春长生基因药业股份有限公司 | Recombinant human interleukin-2 protectant |
| CN1365628A (en) * | 2001-08-31 | 2002-08-28 | 李致勋 | Health-care antisanility food and its preparing process |
| CN1380093A (en) * | 2002-04-30 | 2002-11-20 | 新疆医科大学 | Alcohol extraction method for extracting grape skin extract and its grape liver-nourishing capsule |
| CN1403156A (en) * | 2002-05-13 | 2003-03-19 | 广东天普生化医药股份有限公司 | Application of human urokininogenase in preparing medicine for preventing and treating cerebral infraction |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104083756A (en) * | 2014-07-22 | 2014-10-08 | 张庆宇 | Auxiliary agent for stabilizing pharmaceutical composition and pharmaceutical composition containing auxiliary agent |
| CN104083756B (en) * | 2014-07-22 | 2015-12-02 | 张庆宇 | A kind of adjuvant of stabilizing pharmaceutical composition and the pharmaceutical composition containing this adjuvant |
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| CN1634576A (en) | 2005-07-06 |
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