供雾化器用液体制剂的雾化特性质量控制进展
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摘要
供雾化器用的液体制剂因其独特的优势,广泛应用于呼吸道疾病的治疗,中国药典2015版中已收载了此类制剂的质控项目及检测方法,目前国际上对此类制剂的雾化特性已经开展了大量新型检测方法的研究,为此类制剂的质量控制提供科学数据与参考,通过模拟体内药物吸收与分布的体外测定方法研究,与药物制剂的体内行为建立相关性,可更好地为临床应用提供参考。供雾化器用液体制剂的临床使用效果由雾化器和雾化溶液决定。雾化溶液的雾化特性受雾化器影响较大,因此亟需加强对雾化器的质量控制和管理,本文对此提出意见及建议。
The inhalation products for nebulisation are used widely in treatment of respiratory disease due to their unique advantages. The quality control items and methods of atomization characteristics for nebulization have been adopted in Chinese Pharmacopoeia 2015 edition. More and more new in-vitro methods of atomization characteristics were investigated worldwide for the purpose of providing the scientific support for quality control standard. The in-vitro method was carried out by simulating the absorption and distribution of drug invivo to establish the in-vivo and in-vitro correlation. That would provide the references for the clinical practice.The clinical efficacy of preparations for nebulisation is decided by the nebulizer and the nebulisation liquid.The atomization characteristics of the products for nebulisation are significantly influenced by nebulizers.Therefore,the quality control and administration of the nebulizers should be strengthened. The paper puts forward some comments and recommendations.
The inhalation products for nebulisation are used widely in treatment of respiratory disease due to their unique advantages. The quality control items and methods of atomization characteristics for nebulization have been adopted in Chinese Pharmacopoeia 2015 edition. More and more new in-vitro methods of atomization characteristics were investigated worldwide for the purpose of providing the scientific support for quality control standard. The in-vitro method was carried out by simulating the absorption and distribution of drug invivo to establish the in-vivo and in-vitro correlation. That would provide the references for the clinical practice.The clinical efficacy of preparations for nebulisation is decided by the nebulizer and the nebulisation liquid.The atomization characteristics of the products for nebulisation are significantly influenced by nebulizers.Therefore,the quality control and administration of the nebulizers should be strengthened. The paper puts forward some comments and recommendations.
引文
[1]中国药典2015年版.二部[S].2015:15Ch P 2015.VolⅡ[S].2015:15
[2]ANDERSON PJ.History of aerosol therapy liquid nebulization to MDIs and DPIs[J].Respir Care,2005,50(9):1139
[3]DENNIS JH.A Review of issues relating to nebulizer standards[J].J Aerosol Med,1998,11(S1):S73
[4]ISO 27427Anaesthetic and Respiratory Equipment:Nebulizing Systems and Components[S].2013
[5]EMA2006:Guideline on the pharmaceutical quality of inhalation and nasal products[S].2006
[6]HATLEY RH,BYMEIN SM.Variability in delivered dose and respirable delivered dose from nebulizers:are current regulatory testing guidelines suffcient to produce meaningful information[J].Med Devices:Evid Res,2017,(10):17
[7]SUGGETT J,NAGEL M,DOYLE C,et al.The use of patientgenerated breathing waveforms for the clinically appropriate evaluation of a representative nebulizing system[J].J Aerosol Med Pulm Drug Deliv,2015,28(3):A9
[8]ERZINGER S.Facemasks and aerosol delivery in vivo[J].J Aerosol Med Offic J Intl Soc Aerosol Med,2007,20(Suppl1):S78
[9]AMIRAV I,NEWHOUSE MT.Aerosol therapy with valved holding chambers in young children:importance of the facemask seal[J].Pediatrics,2001,108(2):389
[10]MITCHELL JP,FINLAY JB,NUTTALL JM,et al.Validation of a new model infant face with nasopharynx for the testing of valved holding chambers with facemask as a patient interface[J].Respiratory Drug Deliv,2010,3(7):777
[11]CARRIGY NB,C O'REILLY,SCHMITT J,et al.Effect of facial material softness and applied force on face mask dead volume,face mask seal,and inhaled corticosteroid delivery through an i-dealized infant replica[J].J Aerosol Med Pulm Drug Deliv,2014,27(4):290
[12]XU Z,HSU W,VON HD,et al.Methodology for the in vitro evaluation of the delivery efficiency from valved holding chambers with facemasks[J].J Aerosol Med Pulm Drug Deliv,2014,27(Suppl 1):S44
[13]AMIRAV I,HALAMISH A,GORENBERG M,et al.More realistic face model surface improves relevance of pediatric in vitro aerosol studies[J].Plos One,2015,10(6):e0128538
[14]MITCHELL JP,NAGELl M,FINLAY B.More advances in models for laboratory testing of inhalers:there's more to it than meets the nose or mouth[J].Respiratory Drug Deliv Eur,2011,2:457
[15]FINALY WH,STAPLETON KW.Undersizing of dropets from a vented nebulizer caused by aerosol heating during transit through an anderson impactor[J].J Aerosol Sci,1999,30(1):105
[16]NEN EN 13544-1:2007+A1Respiratory therapy equipment.Part1:Nebulizing systems and their components[S].2009:33
[17]MARPLE VA,OLSON BA,SANTHANAKRISHNAN K,et al.Next generation pharmaceutical impactor:A new impactor for pharmaceutical inhaler testing.part iii.extension of archival calibration to 15 L/min[J].J Aerosol Med,2004,17(4):335
[18]DENNIS J,BERG BA,SANDELL D,et al.Cooling the NGI-an approach to size a nebulised aerosol more accurately[J].Pharmeur Sci Notes,2008,2008(1):1
[19]BERLINSKI A,HAYDEN JB.Optimization of a procedure used to measure aerosol characteristics of nebulized solutions using a cooled next generation impactor[J].J Aerosol Med Pulm Deliv,2010,23(6):397
[20]SONG XH,HU JH,ZHAN SY,et al.Effects of temperature and humidity on laser diffraction measurements to jet nebulizer and comparison with NGI[J].Aaps Pharm Sci Technol,2016,17(2):380
[21]CHENG YS.Mechanisms of pharmaceutical aerosol deposition in the respiratory tract[J].Aaps Pharm Sci Technol,2014,15(3):630
[22]CHENGYS,ZHOU Y,SU WC.Deposition of particles in human mouth–throat replicas and a USP induction Por[J].J Aerosol Med Pulm Deliv,2015,28(3):147
[23]STAPLETON KW,GUENTSCH E,HOSKINSON MK,et al.On the suitability of k-turbulence modeling for aerosol deposition in the mouth and throat:a comparison with experiment[J].J Aerosol Sci,2000,31(6):739
[24]GOLSHAHI L,FINLAYWH.An idealized child throat that mimics average pediatric oropharyngeal deposition[J].Aerosol Sci Technol,2012,46(5):i
[25]ZHOU Y,SUN JJ,CHENG YS.Comparison of deposition in the USP and physical mouth–throat models with solid and liquid particles[J].J Aerosol Med Pulm Deliv,2011,24(6):277
[26]王健,王伟,陈芳.噻托溴铵雾化吸入溶液在三种口喉模型中的沉积行为[J].中国医药工业杂志,2013,44(7):677WANG J,WANG J,CHEN F.In vitro behaviors of titropium bromide inhalation solution in three mouth-throat model[J].Chin J Pharm,2013,44(7):677
[27]KESKINEN J,PIETARINEN K,LEHTIMAKI M.Electrical lowpressure impactor[J].J Aerosol Sci,1992,23(4):353
[28]MARJAMAKI M,KESKINEN J,CHEN DR,et al.Performance evaluation of the electrical low-pressure impactor(ELPI)[J].J Aerosol Sci,2000,31(2):249
[29]GLOVER W,CHAN HK.Electrostatic charge characterization of pharmaceutical aerosols using electrical low-pressure impaction(ELPI)[J].J Aerosol Sci,2004,35(6):755
[30]JARVINEN A,AITOMAA M,ROSTEDT A,et al.Calibration of the new electrical low-pressure impactor(ELPI+)[J].J Aerosol Sci,2014,69:150
[31]HOE S,YOUNG PM,CHAN HK,et al.Introduction of the electrical next generation impactor(engi)and investigation of its capabilities for the study of pressurized metered dose inhalers[J].Pharm Res,2009,26(2):431
[32]2180DFTguidance for industry:metered dose inhaler(MDI)and dry powder inhaler(DPI)drug products;chemistry,manufacturing,and controls Documentation[S].1998
[33]TOUGAS TP,GOODEY AP,HARDWELL G,et al.A comparison of the performance of efficient data analysis versus fine particle dose as metrics for the quality control of aerodynamic particle size distributions of orally inhaled pharmaceuticals[J].Aaps Pharm Sci Technol,2017,18(2):451
[34]TOUGAS TP,CHRISTOPHER D,MITCHEL JP,et al.Improved quality control metrics for cascade impaction measurements of orally inhaled drug products(OIPs)[J].Aaps Pharm Sci Technol,2009,10(4):1276
[35]BONAM M,CHRISTOPHER D,CIPOLLA D,et al.Minimizing variability of cascade impaction measurements in inhalers and nebulizers[J].Aaps Pharm Sci Technol,2008,9(2):404
[36]NICHOLS SC,MITCHILL JP,SANDELL D,et al.A Multi-laboratory in vitro study to compare data from abbreviated and pharmacopeial impactor measurements for orally inhaled products:a report of the european aerosol group(EPAG)[J].Aaps Pharm Sci Technol,2016,17(6):1383
[37]MOHANM,LEE S,GUO C,et al.Evaluation of abbreviated impactor measurements(AIM)and efficient data analysis(EDA)for dry powder inhalers(DPIs)against the full-resolution next generation impactor(NGI)[J].Aaps Pharm Sci Technol,2017,18(5):1585
[38]DENYER J,DYCHE T.The adaptive aerosol delivery(AAD)technology:past,present,and future[J].J Aerosol Med Pulm Deliv,2010,3(S1):S1
[39]HARDAKER LE,HATLEY RH.In Vitro Characterization of the I-neb adaptive aerosol delivery(AAD)system[J].J Aerosol Med Pulm Deliv,2010,23(S1):S11
[40]ARI A.Jet,ultrasonic,and mesh nebulizers:an evaluation of nebulizers for beter clinical outcomes[J].Eurasian J Pulmonol,2014,16:1
[41]PRITCHARD JN.Nebulized drug delivery in respiratory medi-cine:what does the future hold[J].Therapeutic Deliv,2017,8(6):391
[42]SIDLER-MOIX AL,DI PE,DOLCI U.Physicochemical aspects and efficiency of albuterol nebulization:comparison of three aerosol types in an in vitro pediatric model[J].Respir Care,2015,60(1):38
[43]BERG B,PICARD RJ.In vitro delivery of budesonide from 30jet nebulizer/compressor combinations using infant and child breathing patterns[J].Respir Care,2009,54(12):1671
[44]LIN HL,WANGH,CHEN YH,et al.Influence of nebulizer type with different pediatric aerosol masks on drug deposition in a model of a spontaneously breathing small child[J].Respir Care,2012,57(11):1894
[45]MOJARRABI B,BUTLER R,MACKENZIE PI.Nebulization of active pharmaceutical ingredients with the e-Flowrapid:impact of formulation variables on aerodynamic characteristics[J].J Pharm Sci,2014,103(8):2585
[46]ELPHICK M,VON HD,PRICHARD JN.et al.Factors to consider when selecting a nebulizer for a new inhaled drug product development program[J].Exp Opinion Drug Deliv,2015,12(8):1375
[47]YY0109—2013中华人民共和国医药行业标准:医用超声雾化器[S].2013YY0109—2013 Standard of the Medical Industry of the people's Republic of China:Medical Ultrasonic Nebulizer[S].2013
[48]DENNIS JH.Standardization issues:in vitro assessment of nebulizer performance[J].Respir Care,2002,47(12):1445
[49]DOLOVICH MB.Assessing nebulizer performance[J].Respir Care,2002,47(11):1290
[2]ANDERSON PJ.History of aerosol therapy liquid nebulization to MDIs and DPIs[J].Respir Care,2005,50(9):1139
[3]DENNIS JH.A Review of issues relating to nebulizer standards[J].J Aerosol Med,1998,11(S1):S73
[4]ISO 27427Anaesthetic and Respiratory Equipment:Nebulizing Systems and Components[S].2013
[5]EMA2006:Guideline on the pharmaceutical quality of inhalation and nasal products[S].2006
[6]HATLEY RH,BYMEIN SM.Variability in delivered dose and respirable delivered dose from nebulizers:are current regulatory testing guidelines suffcient to produce meaningful information[J].Med Devices:Evid Res,2017,(10):17
[7]SUGGETT J,NAGEL M,DOYLE C,et al.The use of patientgenerated breathing waveforms for the clinically appropriate evaluation of a representative nebulizing system[J].J Aerosol Med Pulm Drug Deliv,2015,28(3):A9
[8]ERZINGER S.Facemasks and aerosol delivery in vivo[J].J Aerosol Med Offic J Intl Soc Aerosol Med,2007,20(Suppl1):S78
[9]AMIRAV I,NEWHOUSE MT.Aerosol therapy with valved holding chambers in young children:importance of the facemask seal[J].Pediatrics,2001,108(2):389
[10]MITCHELL JP,FINLAY JB,NUTTALL JM,et al.Validation of a new model infant face with nasopharynx for the testing of valved holding chambers with facemask as a patient interface[J].Respiratory Drug Deliv,2010,3(7):777
[11]CARRIGY NB,C O'REILLY,SCHMITT J,et al.Effect of facial material softness and applied force on face mask dead volume,face mask seal,and inhaled corticosteroid delivery through an i-dealized infant replica[J].J Aerosol Med Pulm Drug Deliv,2014,27(4):290
[12]XU Z,HSU W,VON HD,et al.Methodology for the in vitro evaluation of the delivery efficiency from valved holding chambers with facemasks[J].J Aerosol Med Pulm Drug Deliv,2014,27(Suppl 1):S44
[13]AMIRAV I,HALAMISH A,GORENBERG M,et al.More realistic face model surface improves relevance of pediatric in vitro aerosol studies[J].Plos One,2015,10(6):e0128538
[14]MITCHELL JP,NAGELl M,FINLAY B.More advances in models for laboratory testing of inhalers:there's more to it than meets the nose or mouth[J].Respiratory Drug Deliv Eur,2011,2:457
[15]FINALY WH,STAPLETON KW.Undersizing of dropets from a vented nebulizer caused by aerosol heating during transit through an anderson impactor[J].J Aerosol Sci,1999,30(1):105
[16]NEN EN 13544-1:2007+A1Respiratory therapy equipment.Part1:Nebulizing systems and their components[S].2009:33
[17]MARPLE VA,OLSON BA,SANTHANAKRISHNAN K,et al.Next generation pharmaceutical impactor:A new impactor for pharmaceutical inhaler testing.part iii.extension of archival calibration to 15 L/min[J].J Aerosol Med,2004,17(4):335
[18]DENNIS J,BERG BA,SANDELL D,et al.Cooling the NGI-an approach to size a nebulised aerosol more accurately[J].Pharmeur Sci Notes,2008,2008(1):1
[19]BERLINSKI A,HAYDEN JB.Optimization of a procedure used to measure aerosol characteristics of nebulized solutions using a cooled next generation impactor[J].J Aerosol Med Pulm Deliv,2010,23(6):397
[20]SONG XH,HU JH,ZHAN SY,et al.Effects of temperature and humidity on laser diffraction measurements to jet nebulizer and comparison with NGI[J].Aaps Pharm Sci Technol,2016,17(2):380
[21]CHENG YS.Mechanisms of pharmaceutical aerosol deposition in the respiratory tract[J].Aaps Pharm Sci Technol,2014,15(3):630
[22]CHENGYS,ZHOU Y,SU WC.Deposition of particles in human mouth–throat replicas and a USP induction Por[J].J Aerosol Med Pulm Deliv,2015,28(3):147
[23]STAPLETON KW,GUENTSCH E,HOSKINSON MK,et al.On the suitability of k-turbulence modeling for aerosol deposition in the mouth and throat:a comparison with experiment[J].J Aerosol Sci,2000,31(6):739
[24]GOLSHAHI L,FINLAYWH.An idealized child throat that mimics average pediatric oropharyngeal deposition[J].Aerosol Sci Technol,2012,46(5):i
[25]ZHOU Y,SUN JJ,CHENG YS.Comparison of deposition in the USP and physical mouth–throat models with solid and liquid particles[J].J Aerosol Med Pulm Deliv,2011,24(6):277
[26]王健,王伟,陈芳.噻托溴铵雾化吸入溶液在三种口喉模型中的沉积行为[J].中国医药工业杂志,2013,44(7):677WANG J,WANG J,CHEN F.In vitro behaviors of titropium bromide inhalation solution in three mouth-throat model[J].Chin J Pharm,2013,44(7):677
[27]KESKINEN J,PIETARINEN K,LEHTIMAKI M.Electrical lowpressure impactor[J].J Aerosol Sci,1992,23(4):353
[28]MARJAMAKI M,KESKINEN J,CHEN DR,et al.Performance evaluation of the electrical low-pressure impactor(ELPI)[J].J Aerosol Sci,2000,31(2):249
[29]GLOVER W,CHAN HK.Electrostatic charge characterization of pharmaceutical aerosols using electrical low-pressure impaction(ELPI)[J].J Aerosol Sci,2004,35(6):755
[30]JARVINEN A,AITOMAA M,ROSTEDT A,et al.Calibration of the new electrical low-pressure impactor(ELPI+)[J].J Aerosol Sci,2014,69:150
[31]HOE S,YOUNG PM,CHAN HK,et al.Introduction of the electrical next generation impactor(engi)and investigation of its capabilities for the study of pressurized metered dose inhalers[J].Pharm Res,2009,26(2):431
[32]2180DFTguidance for industry:metered dose inhaler(MDI)and dry powder inhaler(DPI)drug products;chemistry,manufacturing,and controls Documentation[S].1998
[33]TOUGAS TP,GOODEY AP,HARDWELL G,et al.A comparison of the performance of efficient data analysis versus fine particle dose as metrics for the quality control of aerodynamic particle size distributions of orally inhaled pharmaceuticals[J].Aaps Pharm Sci Technol,2017,18(2):451
[34]TOUGAS TP,CHRISTOPHER D,MITCHEL JP,et al.Improved quality control metrics for cascade impaction measurements of orally inhaled drug products(OIPs)[J].Aaps Pharm Sci Technol,2009,10(4):1276
[35]BONAM M,CHRISTOPHER D,CIPOLLA D,et al.Minimizing variability of cascade impaction measurements in inhalers and nebulizers[J].Aaps Pharm Sci Technol,2008,9(2):404
[36]NICHOLS SC,MITCHILL JP,SANDELL D,et al.A Multi-laboratory in vitro study to compare data from abbreviated and pharmacopeial impactor measurements for orally inhaled products:a report of the european aerosol group(EPAG)[J].Aaps Pharm Sci Technol,2016,17(6):1383
[37]MOHANM,LEE S,GUO C,et al.Evaluation of abbreviated impactor measurements(AIM)and efficient data analysis(EDA)for dry powder inhalers(DPIs)against the full-resolution next generation impactor(NGI)[J].Aaps Pharm Sci Technol,2017,18(5):1585
[38]DENYER J,DYCHE T.The adaptive aerosol delivery(AAD)technology:past,present,and future[J].J Aerosol Med Pulm Deliv,2010,3(S1):S1
[39]HARDAKER LE,HATLEY RH.In Vitro Characterization of the I-neb adaptive aerosol delivery(AAD)system[J].J Aerosol Med Pulm Deliv,2010,23(S1):S11
[40]ARI A.Jet,ultrasonic,and mesh nebulizers:an evaluation of nebulizers for beter clinical outcomes[J].Eurasian J Pulmonol,2014,16:1
[41]PRITCHARD JN.Nebulized drug delivery in respiratory medi-cine:what does the future hold[J].Therapeutic Deliv,2017,8(6):391
[42]SIDLER-MOIX AL,DI PE,DOLCI U.Physicochemical aspects and efficiency of albuterol nebulization:comparison of three aerosol types in an in vitro pediatric model[J].Respir Care,2015,60(1):38
[43]BERG B,PICARD RJ.In vitro delivery of budesonide from 30jet nebulizer/compressor combinations using infant and child breathing patterns[J].Respir Care,2009,54(12):1671
[44]LIN HL,WANGH,CHEN YH,et al.Influence of nebulizer type with different pediatric aerosol masks on drug deposition in a model of a spontaneously breathing small child[J].Respir Care,2012,57(11):1894
[45]MOJARRABI B,BUTLER R,MACKENZIE PI.Nebulization of active pharmaceutical ingredients with the e-Flowrapid:impact of formulation variables on aerodynamic characteristics[J].J Pharm Sci,2014,103(8):2585
[46]ELPHICK M,VON HD,PRICHARD JN.et al.Factors to consider when selecting a nebulizer for a new inhaled drug product development program[J].Exp Opinion Drug Deliv,2015,12(8):1375
[47]YY0109—2013中华人民共和国医药行业标准:医用超声雾化器[S].2013YY0109—2013 Standard of the Medical Industry of the people's Republic of China:Medical Ultrasonic Nebulizer[S].2013
[48]DENNIS JH.Standardization issues:in vitro assessment of nebulizer performance[J].Respir Care,2002,47(12):1445
[49]DOLOVICH MB.Assessing nebulizer performance[J].Respir Care,2002,47(11):1290