CN103830166A - Preparation method of hypertonic resuscitation fluid and application thereof - Google Patents
Preparation method of hypertonic resuscitation fluid and application thereof Download PDFInfo
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- CN103830166A CN103830166A CN201210477240.1A CN201210477240A CN103830166A CN 103830166 A CN103830166 A CN 103830166A CN 201210477240 A CN201210477240 A CN 201210477240A CN 103830166 A CN103830166 A CN 103830166A
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Abstract
The invention relates to a preparation method of a hypertonic sodium chloride dextran 70 resuscitation fluid and application of the hypertonic resuscitation fluid. Specifically, further improvement is made to the existing preparation technology of hypertonic resuscitation fluids by the invention, the technological steps are simplified, and the technical parameters are optimized, so that the hypertonic sodium chloride dextran 70 resuscitation fluid product with more stable quality and lower cost can be prepared.
Description
Technical field
The present invention relates to a kind of preparation method of high-exudation anabiotic liquid and the application of this high-exudation anabiotic liquid, the invention provides specifically a kind of preparation method of hypertonic sodium chloride dextran 70 resuscitation fluids and the application of this high-exudation anabiotic liquid.
Background technology
Hemorrhagic shock (hemorrhagic shock, be called for short HS) be a kind of common shock, causing that because losing blood circulation volume die-offs, be often secondary to wound or other diseases, is the one of hypovolemic shock (hypovolemic shock).That hemorrhagic shock often occurs in is hemorrhage after wound, digestive tract hemorrhage, postoperative hemorrhage or dysfunction of blood coagulation.In treatment hemorrhagic shock, need to use resuscitation fluid or plasma substitute.The high-exudation anabiotic liquid of indication of the present invention is the aqueous solution for injection of hypertonic sodium chloride dextran 70(7.5%NaCl and 6% macrodex), this product is one of widely used resuscitation fluid clinically at present.
Dextran is first to be found with a kind of form of microniological proudcts by Louis Pasteur, it is a kind of macromolecule glucose polymer, at present both at home and abroad mainly ferment after sucrose and synthesize by Leuconostoc mesenteroides, due to the glucose molecule number difference of polymerization, and the product of generation different molecular weight has high molecular dextran (mean molecule quantity 100,000-200,000), medium molecular dextran (mean molecule quantity 60,000-80,000), low molecular dextran (mean molecule quantity 20,000-40,000) and Dextran 10 (mean molecule quantity 10,000-20,000).Its medicinal function of the product of different molecular weight is different.Low, Dextran 10, can improve microcirculation, erythrocyte aggregation and thrombosis etc. in prevention or elimination blood vessel, for microcirculation disturbance, disseminated inravascular coagulation, angina pectoris, acute myocardial infarction and other peripheral vascular diseases etc. due to various shocks, aspect medicinal, it is used as antithrombotic (antiplatelet) to reduce blood stickiness.Medium molecular dextran, main as blood plasma substitute, specifically as the resuscitation fluid in treatment hemorrhagic shock, traumatic shock and burn shock process, these class colloid goods can imitate the function of plasma protein that suitable osmotic pressure is provided, and recover simultaneously and maintain the composition that oozes such as basic in blood vessel.The mean molecule quantity of macrodex is about 70 000, belongs to medium molecular dextran.Low, Dextran 10 also has expanding blood volume effect, but effect is of short duration compared with medium molecular dextran, and while using as resuscitation fluid compared with side effect such as macrodex more easily cause allergic reaction.
Though the preparation method of hypertonic sodium chloride dextran 70 resuscitation fluids has many pieces of bibliographical informations at present, wherein, applicant of the present invention just once disclosed a kind of preparation method in patent application 200410091454.0, but, in this production process, some difficult problem still could not solve, production technology still has the many places that can optimize, for example, in production process, need to use a large amount of activated carbon to remove the heat source substance such as tropina and metabolism residue thereof containing in dextran raw material, thereby increase the difficulty of the macrodex solution filter that original viscosity is larger, make technique become loaded down with trivial details, also increased accordingly cost, simultaneously a large amount of activated carbon and filtering technique repeatedly can reduce the content of macrodex greatly, reduce the quality of the product of producing, in addition, macrodex is easily degraded at high temperature, and the stability of macrodex affects the key factor of high-exudation anabiotic liquid drug quality exactly, in production, transportation, storage and use procedure, need to guarantee the least possible degraded of macrodex in high-exudation anabiotic liquid, there is as far as possible little variation in mean molecule quantity, but macrodex at high temperature dissolubility is just better, so in the whole engineering of preparing high-exudation anabiotic liquid, always need to operate under pyrosol environment.Therefore, inventor is again through long-term groping, after a large amount of practice and performing creative labour, further simplified this production technology, and optimized technological parameter, thereby produced the high-exudation anabiotic liquid product that quality is better and stable, cost is cheaper.
Summary of the invention
An object of the present invention is to provide a kind of preparation method of high-exudation anabiotic liquid.
A preparation method for hypertonic sodium chloride dextran 70 resuscitation fluids, comprises the following steps:
(1) sodium chloride of amount of calculation is added to dissolving tank, then add water for injection, be mixed with 7.5% sodium-chloride water solution, stirring and dissolving, is heated to 80 ℃, regulates pH4.8-5.5;
(2) add the macrodex of amount of calculation, be made into 6% macrodex solution; Stirring makes it to dissolve completely; Add needle-use activated carbon by dose volume 0.8%, keep fluid temperature near 85 ℃, pH4.8-5.5, stir 5 minutes; Use successively 1 μ m titanium rod filter and 0.2 μ m filter membrane, in 85 ℃ of insulation decarburization aseptic filtrations;
(3) regulate pH6.0-7.0, check the qualified rear fill of clarity;
(4) upper film, top plug, tamponade renovate, Zha Gai;
(5) 110 ℃, pressure sterilizing 15 minutes;
(6) lamp inspection, packing, warehouse-in.
Another object of the present invention is to provide high-exudation anabiotic liquid as the application in treatment preparation hemorrhagic shock, traumatic shock or burn shock medicine.
In this application, described resuscitation fluid using dosage is in the scope of 4～6ml/kg body weight; Described resuscitation fluid is infused in 5 minutes generally, not controlled when hemorrhage in treatment, by slower infusion velocity, infused in 10-20 minute.Adopt as above technical scheme, through experimental verification, the high-exudation anabiotic liquid providing of the present invention is successful in treatment traumatic hemorrhagic shock.
Compared with prior art, the present invention has following useful technique effect:
(1) by optimizing pH value and the temperature of solution in preparation process, increase the stability of macrodex, effectively suppressed the degradation reaction of raw material, made the molecular weight distribution of macrodex in product change reduction greatly, improved the quality of product;
(2) by optimizing pH value and the temperature of solution in preparation process, increase the dissolubility of macrodex, made solution be easy to filter, reduced the number of times filtering, simplified greatly preparation technology, reduced cost;
(3) by optimizing pH value and the temperature of solution in preparation process, strengthen the ability of the dissolubility of macrodex and the absorption impurity of active carbon, reduced the consumption of active carbon, be easy to the filtration in later stage, simplify preparation technology, when having reduced cost, improved the quality of product;
(4) by optimizing the addition of active carbon in preparation process, in the consumption that has reduced active carbon, strengthen it and gone deimpurity ability, also reduced the absorption to macrodex simultaneously, be easy to the filtration in later stage, simplify preparation technology, when having reduced cost, improved the quality of product;
(5) by optimizing pH value and the temperature of solution in preparation process, and the consumption of active carbon, the impurity such as the heat source substance in medicinal liquid are effectively removed, the temperature and time of pressure sterilizing is lowered, thereby further strengthen the stability of macrodex, effectively suppress the degradation reaction of raw material, made the molecular weight distribution of macrodex in product change reduction greatly, improved the quality of product;
(6) except as otherwise noted,, while the present invention relates to the percentage ratio between liquid and liquid, described percentage ratio is volume/volume percentage ratio; While the present invention relates to the percentage ratio between liquid and solid, described percentage ratio is volume/weight percentage ratio; While the present invention relates to the percentage ratio between solid and liquid, described percentage ratio is weight/volume percent; All the other are weight/percentage by weight.
The specific embodiment
[0010]
illustrate the present invention below with reference to embodiment, embodiments of the invention are only for technical scheme of the present invention is described, and non-limiting essence of the present invention.
embodiment 1the preparation method of high-exudation anabiotic liquid provided by the present invention
1. preparation:
(1) water for injection preparation
?obtain fresh sterile, the pyrogen-free water for injection dosing water as this product using deionized water as water source through ultimate ultrafiltration.
(2) processing of inner packaging material and production environment
A. wash bottle: it is qualified that control antibiotic glass bottle rinses to clarity with deionized water and water for injection, for subsequent use after dry sterilization.
B. plug, film and aluminium lid: process routinely sterilizing for subsequent use.
C. active carbon: dry roasting 2 hours of 180 ℃ of high temperature are for subsequent use.
D. workshop: production and processing pipeline, sheet frame, germ tight filter, process routinely routine disinfection between subpackage except Mycoderma and purifying garment etc.
2. the preparation method of hypertonic sodium chloride dextran 70 resuscitation fluids, comprises the following steps:
(1) sodium chloride of amount of calculation is added to dissolving tank, then add water for injection, be mixed with 7.5% sodium-chloride water solution, stirring and dissolving, is heated to 80 ℃, regulates pH4.8-5.5;
(2) add the macrodex of amount of calculation, be made into 6% macrodex solution; Stirring makes it to dissolve completely; Add needle-use activated carbon by dose volume 0.8%, keep fluid temperature near 85 ℃, pH4.8-5.5, stir 5 minutes; Use successively 1 μ m titanium rod filter and 0.2 μ m filter membrane, in 85 ℃ of insulation decarburization aseptic filtrations;
(3) regulate pH6.0-7.0, check the qualified rear fill of clarity;
(4) upper film, top plug, tamponade renovate, Zha Gai;
(5) 110 ℃, pressure sterilizing 15 minutes;
(6) lamp inspection, packing, warehouse-in.
test case 1
This test case is used for illustrating pH value and the impact of heating-up temperature on macrodex stability of solution in step (1) and (2) in the preparation process of embodiment, wherein only changes corresponding pH value and temperature in step.Method of testing: prepare a collection of sample according to step (1) and (2) in the preparation process of embodiment, relative molecular mass and relative molecular mass measure of spread method (" Chinese Pharmacopoeia " the appendix V H of version II portion in 2000) according to polysaccharide are measured, and measurement result is in table 1.
Table 1
Test case 1 result shows, under the pH value and heating-up temperature of the selected solution of preparation method of the present invention, the average weight-molecular mass of macrodex approaches 70 000 most, and its average weight-molecular mass distributes also the narrowest, and under this condition, macrodex is more stable.
test case 2
This test case is used for illustrating the pH value of solution, the impact of the ability of temperature on impurity such as the heat source substances containing in activated carbon adsorption macrodex raw material, and the impact of absorption on raw material macrodex.Method of testing: prepare a collection of sample according to step (1) and (2) in the preparation process of embodiment, wherein only change corresponding pH value and temperature in step, test according to the method described in " Chinese Pharmacopoeia " version II portion in 2000 after sampling.Wherein the measurement result of particulate matter is take the result that whether meets " Chinese Pharmacopoeia " appendix IX C of version II portion in 2000 regulation as criterion.This measurement result is in table 2.
Table 2
Test case 2 results show, under the pH value and heating-up temperature of the selected solution of preparation method of the present invention, in the impurity such as the heat source substance of active carbon in effective removal medicinal liquid, have reduced the absorption to effective ingredient macrodex.
test case 3
The impact of the stability of the temperature and time that this test case is used for illustrating pressure sterilizing on macrodex.Prepare a batch sample according to the step in the preparation process of embodiment, wherein only change the temperature and time of pressure sterilizing, sample thief 1 ml adds mobile phase to 10 ml, shake up, relative molecular mass and relative molecular mass measure of spread method (" Chinese Pharmacopoeia " the appendix V H of version II portion in 2000) according to polysaccharide are measured, and measurement result is in table 3.
Table 3
Test case 3 results demonstrations, under the temperature and time of the selected pressure sterilizing of preparation method of the present invention, the degree that the molecular weight of macrodex reduces is minimum, and under this condition, macrodex is more stable.
comparative example 1the preparation method of disclosed a kind of high-exudation anabiotic liquid in patent application 200410091454.0
1. preparation:
(1) water for injection preparation
Obtain fresh sterile, the pyrogen-free water for injection dosing water as this product using deionized water as water source through ultimate ultrafiltration.
(2) processing of inner packaging material and production environment
A. wash bottle: it is qualified that control antibiotic glass bottle rinses to clarity with deionized water and water for injection, for subsequent use after dry sterilization.
B. plug, film and aluminium lid: process routinely sterilizing for subsequent use.
C. active carbon: dry roasting 2 hours of 180 ℃ of high temperature are for subsequent use.
D. workshop: production and processing pipeline, sheet frame, germ tight filter, process routinely routine disinfection between subpackage except Mycoderma and purifying garment etc.
2. preparation process:
(1) water for injection is added to dissolving tank, add the macrodex of amount of calculation, squeeze into dense preparing tank, squeeze into again appropriate water for injection to dissolving tank, be made into 10% concentrated solution, boil 5 minutes, make it to dissolve completely, add needle-use activated carbon to dissolve by dose volume 2%, stirring is boiled 30 minutes, through clarification, use 1 μ m titanium rod filter to filter, shift in solution to the first dilute preparing tank, add to the full amount of water for injection, add 7.5% sodium chloride, add needle-use activated carbon by rare part long-pending 1%, stir 20 minutes;
(2) macrodex and sodium chloride content, pH value, pyrogen in mensuration the first dilute preparing tank, making macrodex concentration is 6%, sodium chloride concentration is 7.5%, as undesirable, finely tunes until qualified;
(3) by qualified solution in the first dilute preparing tank through clarification, use 1 μ m titanium rod filter to filter, shift in solution to the second dilute preparing tank, use 0.45 μ m filter membrane and 0.2 μ m filter element aseptic filtration 15 minutes, check the qualified rear fill of clarity;
(4) upper film, top plug, tamponade renovate, Zha Gai;
(5) 118 ℃, sterilizing in 20 minutes;
(6) lamp inspection, packing, warehouse-in.
test case 4
This test case is used for illustrating quality and the long-time stability impact on obtained product of preparation method that embodiment and comparative example provide.The result criterion of method of testing and particulate matter is identical with test case 1,2, and measurement result is in table 4.
Table 4
Test case 4 results show, adopt prepared hypertonic sodium chloride dextran 70 resuscitation fluids out of preparation method provided by the present invention, the molecular weight of effective ingredient macrodex and be distributed in preparation process and long-term process of preserving in the change of molecular weight all less, and impurity content is few compared with comparative example, illustrate that the prepared hypertonic sodium chloride dextran 70 resuscitation fluid quality out of preparation method provided by the present invention are high and stable.
Claims (2)
1. a preparation method for hypertonic sodium chloride dextran 70 resuscitation fluids, comprises the following steps:
(1) sodium chloride of amount of calculation is added to dissolving tank, then add water for injection, be mixed with 7.5% sodium-chloride water solution, stirring and dissolving, is heated to 80 ℃, regulates pH4.8-5.5;
(2) add the macrodex of amount of calculation, be made into 6% macrodex solution; Stirring makes it to dissolve completely; Add needle-use activated carbon by dose volume 0.8%, keep fluid temperature near 85 ℃, pH4.8-5.5, stir 5 minutes; Use successively 1 μ m titanium rod filter and 0.2 μ m filter membrane, in 85 ℃ of insulation decarburization aseptic filtrations;
(3) regulate pH6.0-7.0, check the qualified rear fill of clarity;
(4) upper film, top plug, tamponade renovate, Zha Gai;
(5) 110 ℃, pressure sterilizing 15 minutes;
(6) lamp inspection, packing, warehouse-in.
2. the prepared high-exudation anabiotic liquid of high-exudation anabiotic liquid and preparation method thereof as claimed in claim 1 is as the application in treatment preparation hemorrhagic shock, traumatic shock or burn shock medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107375204A (en) * | 2017-07-25 | 2017-11-24 | 湖北多瑞药业有限公司 | Compound dextran 40 parenteral solution and its preparation method and application |
| CN109793755A (en) * | 2017-11-17 | 2019-05-24 | 中国人民解放军总医院 | A kind of resuscitation fluid and the preparation method and application thereof for treating seawater immersion wound |
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| US5443848A (en) * | 1991-05-31 | 1995-08-22 | Board Of Regents, The University Of Texas System | Hypertonic isochloremic formulations for treatment of hypovolemic and circulatory shock |
| CN1778312A (en) * | 2004-11-24 | 2006-05-31 | 中国人民解放军军事医学科学院野战输血研究所 | High-exudation anabiotic liquid, its preparation and use thereof |
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2012
- 2012-11-22 CN CN201210477240.1A patent/CN103830166B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5443848A (en) * | 1991-05-31 | 1995-08-22 | Board Of Regents, The University Of Texas System | Hypertonic isochloremic formulations for treatment of hypovolemic and circulatory shock |
| CN1778312A (en) * | 2004-11-24 | 2006-05-31 | 中国人民解放军军事医学科学院野战输血研究所 | High-exudation anabiotic liquid, its preparation and use thereof |
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| 何雪明等: "液体复苏在休克治疗中的研究进展", 《社区医学杂志》, vol. 9, no. 17, 30 September 2011 (2011-09-30), pages 16 - 18 * |
| 李涛等: "高渗氯化钠/右旋糖酐对失血性休克大鼠酸碱平衡的影响", 《局解手术学杂志》, vol. 17, no. 1, 31 December 2008 (2008-12-31), pages 8 - 9 * |
| 王德伟等: "高张盐右旋糖酐液对烧伤休克延迟复苏心肌功能的影响", 《第二军医大学学报》, vol. 18, no. 4, 31 August 1997 (1997-08-31), pages 346 - 348 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107375204A (en) * | 2017-07-25 | 2017-11-24 | 湖北多瑞药业有限公司 | Compound dextran 40 parenteral solution and its preparation method and application |
| CN109793755A (en) * | 2017-11-17 | 2019-05-24 | 中国人民解放军总医院 | A kind of resuscitation fluid and the preparation method and application thereof for treating seawater immersion wound |
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| CN103830166B (en) | 2015-07-15 |
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Address after: 101113 Beijing city Tongzhou District Zhangjiawan Town Guangyuan West Street No. 13 Applicant after: Beijing Sihuan Pharmaceutical Co., Ltd. Applicant after: Beijing Aohe Pharmaceutical Research Institute Co., Ltd. Address before: 101114 Beijing city Tongzhou District Zhangjiawan Town Qi Shanzhuang East Village Applicant before: Beijing Sihuan Pharmaceutical Co., Ltd. Applicant before: Beijing Aohe Pharmaceutical Research Institute Co., Ltd. |
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Effective date of registration: 20160219 Address after: Two road 100102 Beijing city Chaoyang District Wangjing Lizedong No. 1 Patentee after: China Resources Double-Crane Pharmaceutical Co., Ltd. Address before: 101113 Beijing city Tongzhou District Zhangjiawan Town Guangyuan West Street No. 13 Patentee before: Beijing Sihuan Pharmaceutical Co., Ltd. Patentee before: Beijing Aohe Pharmaceutical Research Institute Co., Ltd. |