CN102031246B - Preparation containing recombinant adenoviruses - Google Patents
Preparation containing recombinant adenoviruses Download PDFInfo
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- CN102031246B CN102031246B CN 200910167813 CN200910167813A CN102031246B CN 102031246 B CN102031246 B CN 102031246B CN 200910167813 CN200910167813 CN 200910167813 CN 200910167813 A CN200910167813 A CN 200910167813A CN 102031246 B CN102031246 B CN 102031246B
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Abstract
The invention relates to a preparation containing recombinant adenoviruses. The preparation consists of the recombinant adenoviruses, buffer solution or a buffer system and a protective agent, wherein the buffer solution or the buffer system is selected from any one of Tris-HCl buffer solution, disodium hydrogen phosphate-citric acid buffer solution and arginine-hydrochloric acid; and the protective agent is selected from propylene glycol, polyethylene glycol 400 or dimethyl sulfoxide. The preparation has simple components, does not contain bivalent cationic salt or nonionic surfactant such as MgCl2 and Tween-80 and the like, can well store the adenoviruses at the temperature of between 2 and 8 DEG C and even room temperature, and has 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 for use according to regulation auxiliary material in " notice that requires about issue pharmaceutical chemicals injection and the biochemical medicine injection basic fundamental of polycomponent " (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 the used auxiliary material of injection and consumption should be the least possible.Recombinant adenovirus can kept under its stable prerequisite as clinical medicine, requires pharmaceutical adjunct kind and consumption more few more good in principle.
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 adenovirus preferably, but the component in the 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, form by the protective material of inactivation by comprising recombinant adenovirus, damping fluid or buffer system, prevention adenovirus generation physics or chemical transformation for said preparation, and described damping fluid or buffer system are selected from any or its combination of Tris-HCl damping fluid, Sodium phosphate dibasic-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 Sodium phosphate dibasic-citrate buffer solution.
Further, described polyol is propylene glycol, and further, the concentration of propylene glycol is 5-20w/v% in the preparation of the present invention, is preferably 10-20w/v%.
The present invention can adjust and select required buffer concentration according to the needs of stable maintenance adenovirus activity.The concentration of damping fluid is 10-100mM in the preparation of the present invention, and described damping fluid is selected from any of Tris-HCl damping fluid, Sodium phosphate dibasic-citrate buffer solution, arginine-hydrochloric acid.Such selection can obtain gratifying saving result.
Preparation of the present invention is made up 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, Sodium phosphate dibasic-citrate buffer solution, arginine-hydrochloric acid.
Sodium phosphate dibasic-citric acid of the present invention 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 ℃ even the fine preservation adenovirus of room temperature, and make it have 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 make up, 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: be dilution poor between the 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 spectrophotometry to detect the granule number of 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 the preparation damping fluid that contains 0.1%SDS (sodium lauryl sulphate), 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, with the absorbance of spectrophotometer in 260nm place mensuration trial-product, 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 detecting the viral specific activity that gained virus titer and granule number calculate 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 ", 2004, the 84th the volume the 10th phase), in " control of recombinant adenovirus clinical grade gene therapy Products Quality ", mention, the evaluation adenovirus preparation stable the time, the specific activity of adenovirus should be greater than 3.3% in the preparation.”
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, concentrates the processes such as liquid, stoste preparation of changing
The preparation method of recombinant adenovirus toxin preparation of the present invention can adopt this area to prepare the method for recombinant adenovirus usually, 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 the 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, prevent gathering or the division of adenovirus effectively, 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
Specify the present invention below with reference to embodiment, embodiments of the invention only are used for explanation technical scheme of the present invention, are not to further restriction of the present invention.
Embodiment 1pH value is to the influence of recombinant adenovirus stability in the preparation
In order to study the pH value to the influence of recombinant adenovirus stability in the 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, and the pH value is to the influence of recombinant adenovirus stability in the preparation.
The contriver has studied the influence of pH value to recombinant adenovirus stability by detecting virus titer (TCID50/mL) and the specific activity of recombinant adenovirus in the preparation, the results are shown in Table 1.
Table 1pH value is to the influence of recombinant adenovirus stability in the preparation
Annotate: preparation consist of 10mMTris+10% propylene glycol (w/v), regulate pH with HCl.
By table 1 as seen, be lower than at 7.4 o'clock at pH, the recombinant adenovirus in the preparation is unstable, and pH is too high, and pungency is bigger.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
2Influence to recombinant adenovirus stability in the preparation
In order to study MgCl
2To the influence of recombinant adenovirus stability in the preparation, under 25 ℃ of conditions, the present invention adopts simultaneous test, has studied to have MgCl in the preparation
2Whether to the influence 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 protective materials such as propylene glycol, poly(oxyethylene glycol) 400, dimethyl sulfoxide (DMSO), does not contain MgCl in the preparation
2The control group preparation also comprises MgCl in the 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 the preparation, studied MgCl
2To the influence of recombinant adenovirus stability, composition and the result of study of preparation see Table 2.
Table 2MgCl
2Influence to recombinant adenovirus stability in the preparation
Annotate: Tris concentration is 50mM, regulates pH7.8 with HCl; Each protectant percentage is w/v%.
By table 2 as seen, recombinant adenovirus toxin preparation of the present invention with added MgCl
2Control formulation compare, under 25 ℃ of conditions, the two does not have difference substantially to the stability that keeps recombinant adenovirus.As everyone knows, as the medicine for treatment thing, the supplementary product kind that adds in the preparation and consumption are more few more good.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 preparations of the present invention
Under 25 ℃ of conditions, studied the stability of recombinant adenovirus in recombinant adenovirus toxin preparation of the present invention and the 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 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 the 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 pH7.8 with HCl, and each protectant percentage is w/v%.
By table 3 as seen, 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 only is 2.48%, is lower than criterion of acceptability (specific activity of gene therapy recombinant adenovirus should be not less than 3.3%).
Embodiment 4 buffer systems are to the influence of recombinant adenovirus stability in the preparation
Under 25 ℃ of conditions, the present invention has studied three kinds of buffer system (citric acid-Na
2HPO
4, arginine-HCl, Tris-HCl) to the influence of recombinant adenovirus stability in the preparation.
By detecting virus titer (TCID50/mL) and the specific activity of recombinant adenovirus in the preparation, studied the influence of buffer system to recombinant adenovirus preparation stability in the preparation, composition and the result of study of preparation see Table 4.
By table 4 as seen, under 25 ℃ of conditions, Tris-HCl, citric acid-Na
2HPO
4, arginine-HCl buffer system can better keep the stability of recombinant adenovirus in the preparation.
Table 4 buffer system is to the influence of recombinant adenovirus stability in the preparation
Annotate: Tris concentration is 50mM in the Tris-HCl damping fluid, regulates pH7.8 with HCl; Citric acid-Na
2HPO
4Citric acid concentration is 50mM in the damping fluid, uses Na
2HPO
4Regulate pH7.8; Arginine concentration is 50mM in arginine-HCl damping fluid, regulates pH7.8 with HCl; Each protectant percentage is w/v%.
Stability study under 4 ℃ of conditions of embodiment 5 recombinant adenovirus toxin preparations of the present invention
Under 4 ℃ of conditions, studied the stability of recombinant adenovirus in recombinant adenovirus toxin preparation of the present invention and the 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 the 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, the stability of recombinant adenovirus is far above the stability of adenovirus in the prior art in the recombinant adenovirus toxin preparation of the present invention.
In addition, table 5 data show that also different protective materials are also variant to the stability influence of recombinant adenovirus in the same buffer system, and the protective material preferred sequence is propylene glycol, poly(oxyethylene glycol) 400, methyl-sulphoxide, and relatively poor is glycerol.
The research of table 5 recombinant adenovirus stability of formulation of the present invention
Annotate: Tris concentration is 50mM in the Tris-HCl damping fluid, regulates pH7.8 with HCl; Citric acid-Na
2HPO
4Citric acid concentration is 50mM in the damping fluid, uses Na
2HPO
4Regulate pH7.8; Arginine concentration is 50mM in arginine-HCl damping fluid, regulates pH7.8 with HCl; Histidine concentrations is 50mM in Histidine-HCl damping fluid, regulates pH7.8 with HCl; Each protectant percentage is w/v%.
Embodiment 6 propylene glycol concentration are to the influence of recombinant adenovirus stability in the preparation
Under 25 ℃ of conditions, the present invention has studied the influence of propylene glycol concentration (5%, 10%, 15%, 20%) to recombinant adenovirus stability in the preparation.By detecting virus titer (TCID50/mL) and the specific activity of recombinant adenovirus in the preparation, studied the influence of propylene glycol concentration to recombinant adenovirus preparation stability in the preparation, composition and the result of study of preparation see Table 6.
By table 6 as seen, propylene glycol concentration and recombinant adenovirus stability are linear dependence substantially, and namely propylene glycol concentration is more high, and the stability of recombinant adenovirus is more good in the preparation.And, when the concentration of propylene glycol is not less than 10w/v%, get final product the stability of recombinant adenovirus in the fine preservation preparation.
Table 6 propylene glycol concentration is to the influence of recombinant adenovirus stability in the preparation
Annotate: Tris concentration is 50mM in the Tris-HCl damping fluid, regulates pH7.8 with HCl; Citric acid-Na
2HPO
4Citric acid concentration is 50mM in the damping fluid, uses Na
2HPO
4Regulate pH7.8; Arginine concentration is 50mM in arginine-HCl damping fluid, regulates pH7.8 with HCl; The percentage of propylene glycol is w/v%.
Embodiment 7 buffer salinities are to the influence of recombinant adenovirus stability in the preparation
Under 25 ℃ of conditions, the present invention has studied in the buffer system buffer salinity (10mM, 50mM, 100mM) to the influence of recombinant adenovirus stability in the preparation.
By detecting virus titer (TCID50/mL) and the specific activity of recombinant adenovirus in the preparation, studied the influence of buffer salinity to recombinant adenovirus preparation stability in the preparation, composition and the result of study of preparation see Table 7.
Table 7 buffer salinity is to the influence of recombinant adenovirus stability in the preparation
Annotate: pH7.8, the percentage of propylene glycol is w/v%.
By table 7 as seen, in the buffer system in citric acid concentration and the preparation stability of recombinant adenovirus be tangible linear relationship, the concentration of citric acid is more high, the stability of recombinant adenovirus is more good in the preparation, when the concentration of citric acid in the buffer system is not less than 50mM, get final product the stability of recombinant adenovirus in the fine preservation preparation; In the buffer system in arginine concentration and the preparation stability of recombinant adenovirus be tangible linear relationship, arginic concentration is more high, the stability of recombinant adenovirus is more good in the preparation, when arginic concentration is not less than 50mM in the buffer system, get final product the stability of recombinant adenovirus in the fine preservation preparation; In the buffer system in the concentration of Tris and the preparation the stable dependency of recombinant adenovirus not strong, when the concentration of Tris in the buffer system was not less than 10mM, preparation of the present invention was under different Tris concentration, the stability difference of recombinant adenovirus is little in the preparation.
Embodiment 8 preparations of the present invention are preserved the influence 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 the specimen 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 influence of high density recombinant adenovirus stability
Annotate: pH7.8, the percentage of propylene glycol is w/v%.
By table 8 as seen, in three kinds of preparation damping fluids of the present invention, the stability of adenovirus and its concentration is the significant linear relation all, 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 1～2 month stability 25 ℃ of conditions.
Claims (6)
1. preparation that contains recombinant adenovirus, described preparation is made up of recombinant adenovirus, damping fluid and propylene glycol, 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, the concentration of propylene glycol is 5-20w/v% in the described preparation.
4. preparation according to claim 3, the concentration of propylene glycol is 10-20w/v% in the described preparation.
5. according to each described preparation of claim 1-4, the concentration of described damping fluid is 10-100mM.
6. preparation according to claim 5, described preparation is made up of recombinant adenovirus, 50mM damping fluid and 10% propylene glycol, 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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| CN201310053160.8A Division CN103173494B (en) | 2009-09-29 | 2009-09-29 | Preparation containing recombinant adenovirus |
| CN201310053079.XA Division CN103173493B (en) | 2009-09-29 | 2009-09-29 | Preparation containing recombinant adenovirus |
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| CN102205132B (en) * | 2011-05-12 | 2014-04-02 | 华侨大学 | Preparation formula of gene therapy medicament taking recombinant adeno-associated virus (rAAV) as vector |
| CN107312799B (en) * | 2017-06-30 | 2020-05-01 | 深圳宾德生物技术有限公司 | Lentiviral vector cryopreservation protective solution and preparation method and application thereof |
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| 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 |
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| 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 |
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