CN103173493A - Preparation containing recombinant adenovirus - Google Patents
Preparation containing recombinant adenovirus Download PDFInfo
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- CN103173493A CN103173493A CN201310053079XA CN201310053079A CN103173493A CN 103173493 A CN103173493 A CN 103173493A CN 201310053079X A CN201310053079X A CN 201310053079XA CN 201310053079 A CN201310053079 A CN 201310053079A CN 103173493 A CN103173493 A CN 103173493A
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- recombinant adenovirus
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- adenovirus
- damping fluid
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Abstract
The invention relates to a preparation containing recombinant adenovirus. The preparation consists of the recombinant adenovirus, buffer liquid or a buffer system and a protective agent, wherein the buffer liquid or buffer system is any of Tris-HCl buffer liquid, disodium hydrogen phosphate-citric acid buffer liquid and arginine-hydrochloric acid, and the protective agent is selected from propylene glycol, polyethylene glycol 400 and dimethyl sulfoxide. The preparation disclosed by the invention has the outstanding advantages that the ingredients are simple, divalent cationic salts and nonionic surfactants, such as MgCl2 and tween 80, are not contained, however, the adenovirus can be excellently conserved at the temperature of 2-8 DEG C even room temperature and is enabled to have good stability, and the like.
Description
Technical field
The present invention relates to recombinant adenovirus, relate in particular to a kind of preparation that contains recombinant adenovirus.
Background technology
The fundamental principle of selecting according to regulation auxiliary material in " notice that requires about issue pharmaceutical chemicals injection and polycomponent Biochemical Drugs injection basic fundamental " (state's food medicine prison is annotated [2008] No. 7) of State Food and Drug Administration issue: under the prerequisite of satisfying the demand, the kind of injection auxiliary material used and consumption should be the least possible.Recombinant adenovirus can kept under its stable prerequisite as clinical medicine, requires in principle pharmaceutical adjunct kind and consumption more few better.
In the prior art of having reported, US Patent No. 2006/0205080A1 discloses a kind of Tris-HCl of comprising, MgCl
2, glycine and be selected from the composition of the aqueous cosolvent of propylene glycol, DMSO, PEG, sucrose, glycerine, tetrahydrofuran (THF), glycol ether, said preparation can be 2～8 ℃ of activity that keep preferably adenovirus, but the component in said composition is more, cause products production comparatively complicated, even strengthen the security risks of gene therapy medicament.
In addition, Chinese patent CN101163794A discloses a kind of adenovirus composition, said composition comprises adenovirus particles and can keep pH at damping fluid and the glycerine of 8.0-9.6, has the simple advantage of component, but its prolonged preservation adenovirus stable undesirable under 2～8 ℃ of conditions.
Summary of the invention
The object of the present invention is to provide a kind of preparation that contains recombinant adenovirus, the protective material of inactivation forms said preparation by comprising recombinant adenovirus, damping fluid or buffer system, prevention adenovirus generation physics or chemical transformation, and described damping fluid or buffer system are selected from any or its combination of Tris-HCl damping fluid, Lin acid hydrogen Er Na – citrate buffer solution, arginine-hydrochloric acid; Be suitable for any or its combination that protective material of the present invention is selected from propylene glycol, poly(oxyethylene glycol) 400 or dimethyl sulfoxide (DMSO).
Further, the pH of described damping fluid or buffer system is 7.4-8.6.
Further, described damping fluid or buffer system are arginine-hydrochloride buffer.
Further, described damping fluid or buffer system are the Tris-HCl damping fluid.
Further, described damping fluid or buffer system are Lin acid hydrogen Er Na – citrate buffer solution.
Further, described polyol is propylene glycol, and further, in preparation of the present invention, the concentration of propylene glycol is 5-20w/v%, is preferably 10-20w/v%.
The present invention can according to the needs of stable maintenance adenovirus activity, adjust and select required buffer concentration.In preparation of the present invention, the concentration of damping fluid is 10-100mM, and described damping fluid is selected from any of Tris-HCl damping fluid, Lin acid hydrogen Er Na – citrate buffer solution, arginine-hydrochloric acid.Such selection can obtain gratifying saving result.
Preparation of the present invention is comprised of recombinant adenovirus, 10-50mM damping fluid and 10% propylene glycol, and pH is 7.8; Described damping fluid is selected from any of Tris-HCl damping fluid, Lin acid hydrogen Er Na – citrate buffer solution, arginine-hydrochloric acid.
Lin of the present invention acid hydrogen Er Na – citric acid and arginine-hydrochloride buffer not only have good shock absorption, also adenovirus are had to a certain degree provide protection.
It is simple that preparation of the present invention has component, do not contain divalent cation salt and nonionogenic tenside, as MgCl
2With tween-80 etc., also can be 2～8 ℃ of fine preservation adenovirus of room temperature even, and make it have the outstanding advantages such as satisfactory stability.
Preparation of the present invention is mainly used in the recombinant adenovirus of preserving gene therapy, also can be applicable to preserve the recombinant adenovirus of any wild-type adenovirus or other purposes.Specifically, comprise replication-defective adenoviral or replication competent adenovirus that all utilize recombinant DNA technology to build, and all human or animals' wild-type adenovirus or its sudden change adenovirus.
Adopt the ratio (being specific activity) of the virion number of the virus titer value of international TCID50 method calibrating and ultraviolet method calibrating to estimate the stability of recombinant adenovirus of the present invention.
The present invention adopts the TCID50 method to measure the recombinant adenovirus titre, its principle is: will infect 293 cells through the viral sample of serial dilution, the cell hole of some amount that each extent of dilution infects was cultivated 10 days, examine under a microscope the cell situation in each cell hole, statistics sick cell hole, utilize the TCID50 calculation formula, calculate virus titer.
TCID50/ml=10
-[-L-d(s-0.5)]+b
Wherein, L: be minimum dilution logarithm; D: poor for dilution between logarithm; S: be the positive boring ratio rate of pathology sum; B: be the virus inoculation amount, be scaled the logarithm of the multiple of every ml volumes.
The present invention adopts the granule number of spectrophotometry adenovirus, and its principle is: in theory, the composition of wild-type 5 type adenovirus is 87% protein and 13%DNA.Therefore, the concentration of adenovirus particles can directly be measured with ultraviolet spectrophotometer.The tryptophane of protein and tyrosine residues have uv-absorbing at the 277nm place, and double-stranded linear DNA has obtained the maximum absorption at 260nm.This law adopts and to contain the 0.1%SDS(sodium lauryl sulphate) the preparation damping fluid, viral capsid is resolved into protein and DNA, the recycling double-stranded linear DNA has obtained the maximum absorption at the 260nm place, when washing agent is arranged, granule density and 260nm light absorption value are proportional, measure the absorbance of trial-product with spectrophotometer in the 260nm place, adopt formula (1AU=1.1 * 10
12VP/mL) calculate the virion number.The scope of application of Test Virus granule number is trial-product virion number 〉=2 * 10
11VP/mL.
The final judge index of recombinant adenovirus stability of the present invention is, according to the viral specific activity that detects gained virus titer and granule number calculating gained, i.e. viral specific activity=virus titer/virion number * 100%.
National drug food Surveillance Authority (SFDA) is regulation in " people's gene treatment research and quality of the pharmaceutical preparations control techniques governing principle ", and clinical recombinant adenovirus specific activity should be higher than 3.3%; Zhang Xiaozhi etc. (" Chinese Medical Journal ",, the 84th the 10th phase of volume in 2004) mention in " quality controls of recombinant adenovirus clinical grade gene therapy goods ", and when estimating adenovirus preparation stable, in preparation, the specific activity of adenovirus should be greater than 3.3%.”
Except as otherwise noted, percentage composition of the present invention is the bulking value percentage composition.
The preparation method of recombinant adenovirus of the present invention can adopt this area common recombinant adenovirus preparation method gained, in general comprises cell recovery, seed cell preparation, virus infection, amplification, lysis, clarification filtration, the concentrated processes such as liquid, stoste preparation of changing
The preparation method of recombinant adenovirus toxin preparation of the present invention can adopt this area usually to prepare the method for recombinant adenovirus, in general comprise the steps: with stoste change liquid, detectable level, with the pharmaceutical adjunct of the good concentration of proportioning dilute, degerming, packing obtain finished product.
Another object of the present invention is to provide the recombinant adenovirus toxin preparation for the preparation of the application in gene therapy medicament.
Compared with prior art, recombinant adenovirus toxin preparation of the present invention has following advantage:
Recombinant adenovirus toxin preparation of the present invention not only can fine preservation recombinant adenovirus activity, effectively prevent gathering or the division of adenovirus, and component is simple, do not contain divalent cation salt, as MgCl
2, be beneficial to production and the clinical use of recombinant adenovirus.Thereby recombinant adenovirus toxin preparation of the present invention not only can well be preserved recombinant adenovirus and other adenovirus thereof, also has the production control of being easy to and industrialization, low cost of manufacture, the higher advantage such as better of preparation security.Preparation of the present invention has outstanding advantage in the preservation of recombinant adenovirus.
Embodiment
Illustrate the present invention below with reference to embodiment, embodiments of the invention only are used for technical scheme of the present invention is described, are not to further restriction of the present invention.
The impact of embodiment 1pH value on recombinant adenovirus stability in preparation
In order to study the pH value to the impact of recombinant adenovirus stability in preparation, under 25 ℃ of conditions, we have studied in pH6.8～8.6 scopes, and the pH value was respectively 6.8,7.2,7.4,7.6,7.8,8.2,8.6 o'clock, the impact of pH value on recombinant adenovirus stability in preparation.
The contriver has studied the impact of pH value on recombinant adenovirus stability by detecting virus titer (TCID50/mL) and the specific activity of recombinant adenovirus in preparation, the results are shown in Table 1.
The impact of table 1pH value on recombinant adenovirus stability in preparation
Annotate: preparation consist of 10mMTris+10% propylene glycol (w/v), regulate pH with HCl.
By as seen from Table 1, lower than 7.4 o'clock, the recombinant adenovirus in preparation was more unstable at pH, and pH is too high, and pungency is larger.Therefore, preparation selection pH of the present invention is 7.4～8.6.Wherein pH value is 7.8 o'clock, adenovirus stable fine, and close to the pH value of human body, adverse drug reaction is less.
Embodiment 2MgCl
2Impact on recombinant adenovirus stability in preparation
In order to study MgCl
2On the impact of recombinant adenovirus stability in preparation, under 25 ℃ of conditions, the present invention adopts simultaneous test, has studied and has had MgCl in preparation
2Whether on the impact of recombinant adenovirus stability.Wherein, the experimental group preparation is recombinant adenovirus toxin preparation of the present invention, comprises recombinant adenovirus, Tris-HCl damping fluid and is selected from the protective materials such as propylene glycol, poly(oxyethylene glycol) 400, dimethyl sulfoxide (DMSO), does not contain MgCl in preparation
2The control group preparation also comprises MgCl in preparation except the recombinant adenovirus toxin preparation of the present invention that contains same composition and same amount
2
By detecting virus titer (TCID50/mL) and the specific activity of recombinant adenovirus in preparation, studied MgCl
2On the impact of recombinant adenovirus stability, composition and the result of study of preparation see Table 2.
Table 2MgCl
2Impact on recombinant adenovirus stability in preparation
Annotate: Tris concentration is 50mM, regulates pH78 with HCl; Each protectant percentage is w/v%.
By as seen from Table 2, recombinant adenovirus toxin preparation of the present invention with added MgCl
2Control formulation compare, under 25 ℃ of conditions, both the stability that keeps recombinant adenovirus is not had difference substantially.As everyone knows, as the medicine for treatment thing, the supplementary product kind that adds in preparation and consumption are more few better.As seen, simplification preparation of the present invention compared with prior art has advantage in the preservation of recombinant adenovirus.
Stability study under 25 ℃ of conditions of embodiment 3 recombinant adenovirus toxin preparation of the present invention
Under 25 ℃ of conditions, studied the stability of recombinant adenovirus in recombinant adenovirus toxin preparation of the present invention and prior art preparation (being the disclosed preparation of CN101163794A1).Wherein, the experimental group preparation is recombinant adenovirus toxin preparation of the present invention, comprises recombinant adenovirus, Tris-HCl damping fluid and is selected from the protective materials such as propylene glycol, poly(oxyethylene glycol) 400, dimethyl sulfoxide (DMSO), does not contain MgCl
2Control formulation is the disclosed preparation of CN101163794A1.
By detecting virus titer (TCID50/mL) and the specific activity of recombinant adenovirus in preparation, studied the stability under 25 ℃ of conditions of recombinant adenovirus toxin preparation of the present invention, composition and the detected result of preparation see Table 3.
Stability study under 25 ℃ of conditions of table 3 recombinant adenovirus toxin preparation of the present invention
Annotate: Tris concentration is 50mM, regulates pH78 with HCl, and each protectant percentage is w/v%.
By as seen from Table 3, compare with the control group preparation, recombinant adenovirus toxin preparation of the present invention has more excellent stability, under 25 ℃ of conditions, can preserve recombinant adenovirus 3 months, and specific activity is all more than 3.3%, and the specific activity of control group preparation is only 2.48%, lower than criterion of acceptability (specific activity of gene therapy recombinant adenovirus should be not less than 3.3%).
The impact of embodiment 4 buffer systems on recombinant adenovirus stability in preparation
Under 25 ℃ of conditions, the present invention has studied three kinds of buffer system (citric acid-Na
2HPO
4, Arg-HCl, Tris-HCl) on the impact of recombinant adenovirus stability in preparation.
By detecting virus titer (TCID50/mL) and the specific activity of recombinant adenovirus in preparation, studied the impact of buffer system on recombinant adenovirus preparation stability in preparation, composition and the result of study of preparation see Table 4.
By as seen from Table 4, under 25 ℃ of conditions, Tris-HCl, citric acid-Na
2HPO
4, the Arg-HCl buffer system can better keep the stability of recombinant adenovirus in preparation.
The impact of table 4 buffer system on recombinant adenovirus stability in preparation
Annotate: in the Tris-HCl damping fluid, Tris concentration is 50mM, regulates pH78 with HCl; Citric acid-Na
2HPO
4In damping fluid, citric acid concentration is 50mM, uses Na
2HPO
4Regulate pH78; In the Arg-HCl damping fluid, arginine concentration is 50mM, regulates pH78 with HCl; Each protectant percentage is w/v%.
Stability study under 4 ℃ of conditions of embodiment 5 recombinant adenovirus toxin preparation of the present invention
Under 4 ℃ of conditions, studied the stability of recombinant adenovirus in recombinant adenovirus toxin preparation of the present invention and prior art preparation (being the disclosed preparation of CN101163794A).Wherein, the experimental group preparation is recombinant adenovirus toxin preparation of the present invention, and the control group preparation is the prior art preparation.
By detecting virus titer (TCID50/mL) and the specific activity of recombinant adenovirus in preparation, studied the stability of recombinant adenovirus toxin preparation of the present invention under 4 ℃ of conditions, composition and the result of study of preparation see Table 5.
As shown in Table 5, compare with the control group preparation, under 4 ℃ of conditions, in recombinant adenovirus toxin preparation of the present invention, the stability of recombinant adenovirus is far above the stability of adenovirus in prior art.
In addition, table 5 data also show, in same buffer system, different protective materials are also variant to the stability influence of recombinant adenovirus, and the protective material preferred sequence is propylene glycol, poly(oxyethylene glycol) 400, methyl-sulphoxide, and relatively poor is glycerol.
The stability study of table 5 recombinant adenovirus toxin preparation of the present invention
Annotate: in the Tris-HCl damping fluid, Tris concentration is 50mM, regulates pH78 with HCl; Citric acid-Na
2HPO
4In damping fluid, citric acid concentration is 50mM, uses Na
2HPO
4Regulate pH78; In the Arg-HCl damping fluid, arginine concentration is 50mM, regulates pH78 with HCl; In Histidine-HCl damping fluid, histidine concentrations is 50mM, regulates pH78 with HCl; Each protectant percentage is w/v%.
The impact of embodiment 6 propylene glycol concentration on recombinant adenovirus stability in preparation
Under 25 ℃ of conditions, the present invention has studied the impact of propylene glycol concentration (5%, 10%, 15%, 20%) on recombinant adenovirus stability in preparation.By detecting virus titer (TCID50/mL) and the specific activity of recombinant adenovirus in preparation, studied the impact of propylene glycol concentration on recombinant adenovirus preparation stability in preparation, composition and the result of study of preparation see Table 6.
By as seen from Table 6, propylene glycol concentration and recombinant adenovirus stability are linear dependence substantially, and namely propylene glycol concentration is higher, and in preparation, the stability of recombinant adenovirus is better.And, when the concentration of propylene glycol is not less than 10w/v%, get final product the stability of recombinant adenovirus in fine preservation preparation.
The impact of table 6 propylene glycol concentration on recombinant adenovirus stability in preparation
Annotate: in the Tris-HCl damping fluid, Tris concentration is 50mM, regulates pH78 with HCl; Citric acid-Na
2HPO
4In damping fluid, citric acid concentration is 50mM, uses Na
2HPO
4Regulate pH78; In the Arg-HCl damping fluid, arginine concentration is 50mM, regulates pH78 with HCl; The percentage of propylene glycol is w/v%.
The impact of embodiment 7 buffer salinities on recombinant adenovirus stability in preparation
Under 25 ℃ of conditions, the present invention has studied the impact of buffer salinity (10mM, 50mM, 100mM) on recombinant adenovirus stability in preparation in the buffer system.
By detecting virus titer (TCID50/mL) and the specific activity of recombinant adenovirus in preparation, studied the impact of buffer salinity on recombinant adenovirus preparation stability in preparation, composition and the result of study of preparation see Table 7.
The impact of table 7 buffer salinity on recombinant adenovirus stability in preparation
Annotate: pH78, the percentage of propylene glycol is w/v%.
By as seen from Table 7, in buffer system in citric acid concentration and preparation the stability of recombinant adenovirus be obvious linear relationship, the concentration of citric acid is higher, in preparation, the stability of recombinant adenovirus is better, when the concentration of citric acid in buffer system is not less than 50mM, get final product the stability of recombinant adenovirus in fine preservation preparation; In buffer system in arginine concentration and preparation the stability of recombinant adenovirus be obvious linear relationship, arginic concentration is higher, in preparation, the stability of recombinant adenovirus is better, when in buffer system, arginic concentration is not less than 50mM, get final product the stability of recombinant adenovirus in fine preservation preparation; In buffer system in the concentration of Tris and preparation the stable dependency of recombinant adenovirus not strong, when the concentration of Tris in buffer system was not less than 10mM, preparation of the present invention was under different Tris concentration, in preparation, the stability difference of recombinant adenovirus is little.
Embodiment 8 preparation of the present invention is preserved the impact of high density recombinant adenovirus stability
For test preparation of the present invention is preserved greater concn recombinant adenovirus stability, designed 2,4,6,8, six recombinant adenovirus concentration gradients of 10E12vp/mL, after sample preparation in 25 ℃ of preservations, detect virus titer and granule number respectively at sampling in 0,1,2,3 month, calculate specific activity, the results are shown in Table 8.
Table 8 preparation of the present invention is preserved the impact of high density recombinant adenovirus stability
Annotate: pH78, the percentage of propylene glycol is w/v%.
By as seen from Table 8, in three kinds of preparation damping fluids of the present invention, the stability of adenovirus and its concentration all are significant linear relationship, preparation of the present invention is preserved the following recombinant adenovirus of 2～6E12vp/mL concentration stability preferably, preserves the recombinant adenovirus of 8～10E12vp/mL concentration and also can keep the stability of 1～2 month 25 ℃ of conditions.
Claims (6)
1. preparation that contains recombinant adenovirus, described preparation is comprised of recombinant adenovirus, damping fluid and dimethyl sulfoxide (DMSO), wherein, described damping fluid is selected from any or its combination of Tris-HCl damping fluid, Sodium phosphate dibasic-citrate buffer solution, arginine-hydrochloride buffer.
2. preparation according to claim 1, the pH of described damping fluid is 7.4-8.6.
3. preparation according to claim 1, in described preparation, the concentration of dimethyl sulfoxide (DMSO) is 5-20w/v%.
4. preparation according to claim 3, in described preparation, the concentration of dimethyl sulfoxide (DMSO) is 10-20w/v%.
5. according to claim 1-4 described preparations of any one, the concentration of described damping fluid is 10-100mM.
6. preparation according to claim 5, described preparation is comprised of recombinant adenovirus, 50mM damping fluid and 10% dimethyl sulfoxide (DMSO), pH is 7.8, and wherein, described damping fluid is selected from any of Tris-HCl damping fluid, Sodium phosphate dibasic-citrate buffer solution, arginine-hydrochloride buffer.
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| CN201310053079.XA CN103173493B (en) | 2009-09-29 | 2009-09-29 | Preparation containing recombinant adenovirus |
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| CN201310053079.XA CN103173493B (en) | 2009-09-29 | 2009-09-29 | Preparation containing recombinant adenovirus |
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| CN 200910167813 Division CN102031246B (en) | 2009-09-29 | 2009-09-29 | Preparation containing recombinant adenoviruses |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1347450A (en) * | 1999-04-09 | 2002-05-01 | 阿文蒂斯药物股份有限公司 | Composition for preservation of infections recombinant adenoviruses |
| US20040033239A1 (en) * | 2001-03-06 | 2004-02-19 | Evans Robert K | Adenovirus formulations |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1347450A (en) * | 1999-04-09 | 2002-05-01 | 阿文蒂斯药物股份有限公司 | Composition for preservation of infections recombinant adenoviruses |
| US20040033239A1 (en) * | 2001-03-06 | 2004-02-19 | Evans Robert K | Adenovirus formulations |
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