李键;

• 1:上海交通大学生命科学技术学院

摘要(Abstract)：

冻干是疫苗研发及制备过程中的关键技术,在疫苗冻干及储藏过程中疫苗的化学成分、冻结温度和速率、干燥温度及干燥固体中剩余水分、储藏环境的温度和湿度等均会对疫苗的活性产生影响。为防止疫苗在冻干过程中活性组分的变性,需添加合适的冻干保护剂,可尽量减少冻干及储藏过程对疫苗活性造成的损伤。本文就几种常见冻干保护剂的保护机理及应用、筛选方法与面临的挑战及其未来的发展趋势作一综述。

关键词(KeyWords)： 冻干保护剂;活疫苗;病毒滴度

Abstract:

Keywords:

基金项目(Foundation):

作者(Authors): 李键;

DOI: 10.13200/j.cnki.cjb.001671

参考文献(References)：

• [1]HANSEN L J J,DAOUSSI R,VERVAET C,et al.Freezedrying of live virus vaccines:a review[J].Vaccine,2015,33(42):5507-5519.
• [2]CHEN S,GUO D,GUO B,et al.Investigation on formulation and preparation of adenovirus encoding human endostatin lyophilized powders[J].Int J Pharm,2012,427(2):145-152.
• [3]LANG R,WINTER G,VOGT L,et al.Rational design of a stable,freeze-dried virus-like particle-based vaccine formulation[J].Drug Dev Ind Pharm,2009,35(1):83-97.
• [4]ZILLIES J C,ZWIOREK K,HOFFMANN F,et al.Formulation development of freeze-dried oligonucleotide-loaded gelatin nanoparticles[J].Eur J Pharm Biopharm,2008,70(2):514-521.
• [5]CHESKO J,FOX C,DUTILL T,et al.Lyophilization and stabilization of vaccines,//development of vaccines:from discovery to clinical testing[M].Hoboken,NJ,USA:John Wiley&Sons,Inc.,2011:385-397.
• [6]NIREESHA G R,DIVYA L,SOWMYA C,et al.Lyophilization/freeze drying-an review[J].Int J Novel Trends Pharma Sci,2013,3(4):87-93.
• [7]SPADARO D,CIAVORELLA A A,LOPEZ-REYES J G,et al.Effect of culture age,protectants,and initial cell concentration on viability of freeze-dried cells of Metschnikowia pulcherrima[J].Can J Microbiol,2010,56(10):809-815.
• [8]BERGENHOLTZ A S,WESSMAN P,WUTTKE A,et al.Acase study on stress preconditioning of a Lactobacillus strain prior to freeze-drying[J].Cryobiology,2012,64(3):152-159.
• [9]Silva A C,Carrondo M J,Alves P M.Strategies for improved stability of Peste des Petits Ruminants Vaccine[J].Vaccine,2011,29(31):4983-4991.
• [10]CZYZ M,DEMBCZYNSKI R,MARECIK R,et al.Freezedrying of plant tissue containing HBV surface antigen for the oral vaccine against hepatitis B[J].Biomed Res Int,2014,2014:485689.
• [11]SANTIVARANGKNA C,HIGL B,FOERST P.Protection mechanisms of sugars during different stages of preparation process of dried lactic acid starter cultures[J].Food Microbiol,2008,25(3):429-441.
• [12]PEIREN J,HELLEMANS A,DE VOS P.Impact of the freezedrying process on product appearance,residual moisture content,viability,and batch uniformity of freeze-dried bacterial cultures safeguarded at culture collections[J].Appl Microbiol Biotechnol,2016,100(14):6239-6249.
• [13]FRANKS F.Solid aqueous solutions[J].Pure Appl Chem,2009,65(12):2527-2537.
• [14]GARIDEL P,PEVESTORF B,BAHRENBURG S.Stability of buffer-free freeze-dried formulations:a feasibility study of a monoclonal antibody at high protein concentrations[J].Eu J Pharm Biopharm,2015,97(P t A):125-139.
• [15]PRAMANICK S,CHANDEL V,SINGODIA D.Excipient selection in parenteral formulation development[J].Pharma Times,2013,45(3):65-77.
• [16]JAMIL R K,TAQAVIAN M,SADIGH Z A,et al.Evaluation of the thermal stability of a novel strain of live-attenuated mumps vaccine(RS-12 strain)lyophilized in different stabilizers[J].J Virol Methods,2014,199(1):35-38.
• [17]DAVIS J M,ZHANG N,PAYNE R W,et al.Stability of lyophilized sucrose formulations of an Ig G1:subvisible particle formation[J].Pharm Dev Technol,2013,18(4):883-896.
• [18]BHAMBHANI A,KISSMANN J M,JOSHI S B,et al.Formulation design and high-throughput excipient selection based on structural integrity and conformational stability of dilute and highly concentrated Ig G1 monoclonal antibody solutions[J].JPharm Sci,2012,101(3):1120-1135.
• [19]刘松友,付永其,王长太,等.统计学方法在麻疹疫苗生产工艺改进中的应用[J].中国生物制品学杂志,2006,19(2):198-200.
• [20]LI G P,LIU J Y,WANG P F,et al.Preparation of protective additive of freeze-dried live attenuated hepatitis A vaccine[J].Chin J Biologicals,2002,15(6):361-362.(in Chinese)李光谱,刘景晔,王鹏富,等.甲型肝炎减毒活疫苗冻干保护剂的研究[J].中国生物制品学杂志,2002,15(6):361-362.
• [21]兰芸,胡凝珠,姬秋彦,等.脊髓灰质炎病毒冻干保护剂的筛选[J].中国生物制品学杂志,2006,19(4):384-386.
• [22]OHTAKE S,KITA Y,ARAKAWA T.Interactions of formulation excipients with proteins in solution and in the dried state[J].Adv Drug Deliv Rev,2011,63(13):1053-1073.
• [23]HELLER M C,CARPENTER J F,RANDOLPH T W.Manipulation of lyophilization-induced phase separation:implications for pharmaceutical proteins[J].Biotechnol Prog,1997,13(5):590-596.
• [24]SKRABANJA A T,DE MEERE A L,DE RUITER R A,et al.Lyophilization of biotechnology products[J].PDA J Pharm Sci Technol,1994,48(6):311-317.
• [25]MIYAMOTO-SHINOHARA Y,SUKENOBE J,IMAIZUMI T,et al.Survival curves for microbial species stored by freezedrying[J].Cryobiology,2006,52(1):27-32.
• [26]COSTANTINO H R,PIKAL M J.Lyophilization of biopharmaceuticals[M].Arlington,VA,USA:AAPS Press,2004:195.
• [27]ABDUL-FATTAH A M,DELLERMAN K M,BOGNER R H,et al.The effect of annealing on the stability of amorphous solids:chemical stability of freeze-dried moxalactam[J].J Pharm Sci,2007,96(5):1237-1250.
• [28]JIN T H,NGUYEN L,QU T,et al.Improved formulation and lyophilization cycle for r BCG vaccine[J].Vaccine,2011,29(29-30):4848-4852.
• [29]LI C S,ZOU L,LI T J,et al.Effect of formula of stabilizer on inactivation of porcine parvovirus in human coagulation factorⅧby terminal dry heat treatment[J].Chin J Biologicals,2013,26(12):1772-1775.(in Chinese)李策生,邹莉,李陶敬,等.不同配方的冻干保护剂对人凝血因子Ⅷ制品干热法灭活猪细小病毒效果的影响[J].中国生物制品学杂志,2013,26(12):1772-1775.
• [30]CHATTERJEE K,SHALAEV E Y,SURYANAYANAN R.Partially crystalline systems in lyophilization:II.Withstanding collapse at high primary drying temperatures and impact on protein activity recovery[J].J Pharm Sci,2005,94(4):809-820.
• [31]SCHERSCH K,BETZ O,GARIDEL P,et al.Systematic investigation of the effect of lyophilizate collapse on pharmaceutically relevant proteins I:Stability after freeze-drying[J].JPharm Sci,2010,99(5):2256-2278.
• [32]LUECKEL B,BODMER D,HELK B,et al.Formulations of sugars with amino acids or mannitol-influence of concentration ratio on the properties of the freeze-concentrate and the lyophilizate[J].Pharm Dev Technol,1998,3(3):325-336.
• [33]KIM A I,AKERS M J,NAIL S L.The physical state of mannitol after freeze-drying:effects of mannitol concentration,freezing rate,and a noncrystallizing cosolute[J].J Pharm Sci,1998,87(8):931-935.
• [34]BUSH L,WEBB C,BARTLETT L,et al.The formulation of recombinant factor IX:stability,robustness,and convenience[J].Semin Hematol,1998,35(2 Suppl 2):18-21.
• [35]KUMRU O S,JOSHI S B,SMITH D E,et al.Vaccine instability in the cold chain:mechanisms,analysis and formulation strategies[J].Biologicals,2014,42(5):237-259.
• [36]JI Z J,GUO D J.Optimization of formula of protective additive of bifidobacterium by response surface method[J].Chin JBiologicals,2008,21(9):813-816.(in Chinese)纪振杰,郭德军.利用响应面法优化双歧杆菌冻干保护剂的配比[J].中国生物制品学杂志,2008,21(9):813-816.
• [37]STEWART M,WARD S J,DREW J.Use of adenovirus as a model system to illustrate a simple method using standard equipment and inexpensive excipients to remove live virus dependence on the cold-chain[J].Vaccine,2014,32(24):2931-2938.
• [38]PEHKONEN K S,ROOS Y H,MIAO S,et al.State transitions and physicochemical aspects of cryoprotection and stabilization in freeze-drying of Lactobacillus rhamnosus GG(LGG)[J].J Appl Microbiol,2008,104(6):1732-1743.
• [39]SANTOS M I,GERBINO E,ARAUJO-ANDRADE C,et al.Stability of freeze-dried Lactobacillus delbrueckii subsp.bulgaricus in the presence of galacto-oligosaccharides and lactulose as determined by near infrared spectroscopy[J].Food Res Int,2014,59(4):53-60.
• [40]SCHNEID S C,STRTZEL P M,LETTNER P,et al.Robustness testing in pharmaceutical freeze-drying:inter-relation of process conditions and product quality attributes studied for a vaccine formulation[J].Pharm Dev Technol,2011,16(6):583-590.
• [41]DURU C,SWANN C,DUNLEAVY U,et al.The importance of formulation in the successful lyophilization of influenza reference materials[J].Biologicals,2015,43(2):110-116.