CN102973526B - Protective agent in people's antithrombase preparation freezing dry process - Google Patents
Protective agent in people's antithrombase preparation freezing dry process Download PDFInfo
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- CN102973526B CN102973526B CN201210584198.3A CN201210584198A CN102973526B CN 102973526 B CN102973526 B CN 102973526B CN 201210584198 A CN201210584198 A CN 201210584198A CN 102973526 B CN102973526 B CN 102973526B
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Abstract
The invention discloses a kind of people's antithrombase preparation freezing dry process protective agent, described protective agent is sucrose or aminoacid or its salt, and described aminoacid or its salt are lysine or its hydrochlorate, tyrosine or its salt, the one in aspartic acid or its salt.Test shows; as long as adding mass percentage concentration before the lyophilization of people's antithrombase preparation is 0.1%-0.8% sucrose or 0.2%-1.0% lysine or its hydrochlorate or 0.2%-1.0% tyrosine or its salt or 0.2%-1.0% aspartic acid or its salt, just can in freezing dry process the activity of available protecting antithrombase.
Description
Technical field
The present invention relates to technical field of pharmaceutical biotechnology, be people's antithrombase preparation freezing dry process, effectively can prevent the protective agent of main component antithrombase inactivation in preparation.Be specifically related to, in antithrombase preparation, add the one in sucrose or aminoacid or its salt, can available protecting antithrombin activity at freezing dry process (-40 DEG C to 30 DEG C), improve the productive rate of antithrombase preparation.
Background technology
People's antithrombase (antithrombin, AT) is a kind of strand α
2glycoprotein, mainly synthesizes in liver, and be made up of 423 aminoacid, average molecular is about 58.2kD(kilodalton), in normal plasma, content is about 150mg/l.Antithrombase can Trombin inhibiting, activation factor Ⅸ, Ⅹ, Ⅺ, the activity of Ⅻ, account for the 70-85% of plasma anticoagulant blood activity, in addition, it also has certain inhibitory action to fibrinolytic in blood, kassinin kinin, complement system, is a kind of multi-functional serpin.Human body antithrombin activity lacks, and thrombosis risk increases.Antithrombase lacks can divide congenital heredity and acquired shortage two type, it is a kind of autosomal dominant inherited disease that congenital antithrombin lacks, its antithrombin activity level is the 40-70% of normal person, wherein Symptomatic patient, and in American-European countries crowd, ratio is about 1/2000-1/5000; Acquired antithrombase deficiency disease can be brought out by disseminated inravascular coagulation (DIC), acute myeloid leukemia, nephrotic syndrome, hemolytic uremic syndrome, acute and chronic hepatopathy, enteritis, hemodialysis, diabetes etc.Antithrombase lacks patient, especially before and after During Pregnancy, childbirth or surgical operation, antithrombase preparation need be used to prevent or treat the formation of acute thrombus.So far, China does not have people's antithrombase preparation listing of molding, and makes this type of patient can not get effective treatment.
For the ease of the storage and transport of people's antithrombase preparation, it adopts injectable powder type usually, therefore, needs through freezing dry process in preparation process.But in whole freezing dry process, there is various stress, comprise low temperature stress, freezing stress (comprising the separation etc. of the formation of dendrite, ionic strength increase, pH change, phase) and drying stress (removing protein surface monolayer hydrone) etc., these stress normally directly or indirectly cause the factor of protein denaturation.People's antithrombase has bioactive albumen; in order to maintain its function; usually need to add a certain amount of protective agent at freezing dry process, but so far there are no about sucrose or lysine or tyrosine or aspartic acid are used for document and the patent report of people's antithrombase preparation freezing drying protective agent.
Summary of the invention
The object of the invention is the storage and transport for the ease of people's antithrombase preparation; improve in the freezing dry process of people's antithrombase preparation in prior art; produce the problem directly or indirectly causing protein denaturation, and the protective agent of antithrombase preparation in a kind of people's antithrombase preparation freezing dry process is provided.
Technical scheme of the present invention is:
Sucrose or aminoacid or its salt are used as the protective agent in people's antithrombase preparation freezing dry process; described aminoacid or its salt are lysine or its salt, tyrosine or its salt, aspartic acid or its salt; the one of above-mentioned substance is made solute deionized water to be mixed with solution and to obtain protective agent solution, add in people's antithrombase preparation before the lyophilization of people's antithrombase preparation.
Protective agent in above-mentioned people's antithrombase preparation freezing dry process, the mass percentage concentration of sucrose is 0.1-0.8%, the mass percentage concentration of lysine or its salt is 0.2-1.0%, the mass percentage concentration of tyrosine or its salt is 0.2-1.0%, the mass percentage concentration 0.2-1.0% of aspartic acid or its salt, described lysinate is lysine hydrochloride; After above-mentioned each mass percentage concentration is and adds protective agent, the concentration that each protective agent component is last in people's antithrombase preparation.
Beneficial effect of the present invention is:
Protective agent provided by the invention makes antithrombase preparation at freezing dry process (-40 DEG C to 30 DEG C); antithrombin activity loss reduces; the response rate reaches more than 86%; and lyophilizing outward appearance, the redissolution time, redissolve clarity can reach American Pharmacopeia the 32nd edition (United States Pharmacopeia32; and the standard of European Pharmacopoeia the 7th edition (European Pharmacopoeia7.0, EP7.0) USP32).0.1-0.8% sucrose is added at antithrombase preparation; 0.2-1.0% lysine or its hydrochlorate; 0.2-1.0% tyrosine or its salt, in 0.2-1.0% aspartic acid or its salt a kind of just can in freezing dry process the activity of available protecting antithrombase, improve the productive rate of antithrombase preparation.
Accompanying drawing explanation
Fig. 1 is antithrombase preparation freezing dry process temperature and time change curve.
Illustrate: in FIG abscissa represent freezing dry process time (hour, h), vertical coordinate represents the temperature (DEG C) in freezing dry process, curve representative along with the variations in temperature in the passing freezer dryer lyophilization casing of sublimation drying.
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the effect of protective agent of the present invention in antithrombase preparation freezing dry process is elaborated,
1. the extraction of antithrombase
CohnShi method blood products component I V precipitates, sodium citrate and NaCl solution 25 DEG C of condition extracting 60min, and extract 6000rmp pelleted by centrifugation 40min, gets supernatant; Supernatant 0.80 μm and 0.45 μm of membrane filtration, filtrate, through affinity chromatograph, obtains eluent, then through ultrafiltration desalination and concentrated, obtains antithrombase concentrate (>=6.0IU/mg).
2. add freeze drying protectant, prepare antithrombase lyophilized formulations
25-37 DEG C of condition, with deionized water, by mass percentage, compound concentration is sucrose or the lysine hydrochloride of 4-16%, or tyrosine, or aspartic acid solution, measures and uses the HCl of 0.1mol/L-1mol/L or NaOH solution to adjust pH to 6.0-7.5; Amount according to required protective agent final concentration and antithrombase concentrate adds protective agent,
Such as: needed for antithrombase preparation, sucrose protective agent final mass percentage concentration is 0.4%, preparation sucrose solution mass percentage concentration is 10%, the antithrombase quality of the pharmaceutical preparations is 200g, then take 8.3333g mass percentage concentration be 10% sucrose solution mix homogeneously with 200g antithrombase preparation;
Again such as: the whole mass percentage concentration of aspartic acid protective agent needed for antithrombase preparation is 0.8%; preparation aspartic acid solution quality percentage concentration is 6%; the antithrombase quality of the pharmaceutical preparations is 500g, then take 76.9231g mass percentage concentration be 6% aspartic acid solution mix homogeneously with 500g antithrombase preparation.Degerming, subpackage after protective agent adds ,-40 DEG C to 30 DEG C condition lyophilizations.
3. preparation shaping visual inspection after lyophilization
After lyophilization, antithrombase preparation shaping appearance results is in table 1.
Table 1 different protective agent antithrombase preparation shaping outward appearance
As seen from Table 1, add protectant preparation, after lyophilization, its shaping outward appearance is better.
4. preparation redissolution time and clarity observation after redissolving after lyophilization
Under room temperature condition, water for injection dissolves preparation, observes its redissolution time, and room temperature observes clarity after placing 20min, the results are shown in Table 2.
Table 2 different protective agent antithrombase preparation redissolution time and rear clarity of redissolving
As seen from Table 2, add protectant preparation, all can dissolve completely in 60 seconds, and after room temperature placement 20min, solution is clarified, and has graininess insoluble matter with protective agent blank, and protective agent energy available protecting antithrombase of the present invention is described.
5. antithrombin activity yield in preparation after lyophilization
Antithrombin activity in preparation before and after detection lyophilization.After lyophilization, antithrombin activity yield the results are shown in Table 3.
Antithrombin activity yield after the different protective agent lyophilization of table 3
As seen from Table 3, do not add protectant preparation, after lyophilization, antithrombin activity yield is no more than 75%, and adds protectant preparation, and antithrombin activity yield is not less than 86%, and the activity of protective agent energy available protecting antithrombase of the present invention is described.
In sum, the present invention is that the freezing dry process of antithrombase preparation provides effective protective agent.
Below invention has been described in conjunction with the embodiments.Protection scope of the present invention is not limited thereto, and any the art personnel are in the technical scope that the present invention discloses, and the simple change of the technical scheme obtained or equivalence are replaced and all fallen within the scope of protection of the present invention.
Claims (1)
1. aminoacid or the protectant purposes of its salt in preparation people antithrombase preparation freezing dry process; it is characterized in that: aminoacid or its salt are made solute deionized water and be mixed with solution and obtain protective agent solution; add before the lyophilization of people's antithrombase preparation in people's antithrombase preparation; described aminoacid or its salt are the one in aspartic acid or its salt; the mass percentage concentration of described Radix Asparagi aminoacid or its salt is 0.2%-1.0%; described mass percentage concentration for after adding protective agent, the concentration of protective agent in people's antithrombase preparation.
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| CN103893135B (en) * | 2014-03-28 | 2017-01-11 | 中国医学科学院输血研究所 | Lyophilized stabilizer composition of human plasma protein C and use of composition |
| CN110563835A (en) * | 2018-06-05 | 2019-12-13 | 内蒙古伊利实业集团股份有限公司 | Lactoferrin freeze-drying protective agent and application thereof |
| CN108949787A (en) * | 2018-07-05 | 2018-12-07 | 上海海洋大学 | A kind of goldfish Tgf2 transposase and its preparation and store method |
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Non-Patent Citations (2)
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| 人抗凝血酶III冻干保护剂的初步筛选;曹海军等;《中国输血杂志》;20101231;第23卷;第5页 * |
| 离子色谱法检测水果、饮品中的蔗糖、葡萄糖和果糖;张磊等;《食品科学》;20120425;第33卷(第8期);第160页第1.3栏 * |
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