Inhalation Drug Delivery: Techniques and Products

207 Pages·2013·7.521 MB·English

Inhalation Drug
Delivery
Inhalation Drug
Delivery
Techniques and Products
Paolo Colombo
DepartmentofPharmacy,TheUniversityofParma,Parma,Italy
Daniela Traini
RespiratoryTechnology,TheWoolcockInstituteof MedicalResearch&TheDiscipline
ofPharmacology,TheUniversityofSydney,Sydney,Australia
Francesca Buttini
DepartmentofPharmacy,TheUniversityofParma,Parma,Italy
http://www.u-l-l-a.org/
Thiseditionfirstpublished2013.#2013byJohnWiley&Sons,Ltd
Wiley-BlackwellisanimprintofJohnWiley&Sons,formedbythemergerofWiley’sglobalScientific,
TechnicalandMedicalbusinesswithBlackwellPublishing.
Registeredoffice:JohnWiley&Sons,Ltd,TheAtrium,SouthernGate,Chichester,WestSussex,
PO198SQ,UK
Editorialoffices:9600GarsingtonRoad,Oxford,OX42DQ,UK
TheAtrium,SouthernGate,Chichester,WestSussex,PO198SQ,UK
111RiverStreet,Hoboken,NJ07030-5774,USA
Fordetailsofourglobaleditorialoffices,forcustomerservicesandforinformationabouthowtoapplyfor
permiss io n t o reu se t he co pyri ght materi al in t hi s bo ok pleas e see o ur webs it e at www.wi l ey.com/ wi l ey-b lack wel l
TherightoftheauthortobeidentifiedastheauthorofthisworkhasbeenassertedinaccordancewiththeUK
Copyright,DesignsandPatentsAct1988.
Allrightsreserved.Nopartofthispublicationmaybereproduced,storedinaretrievalsystem,ortransmitted,in
anyformorbyanymeans,electronic,mechanical,photocopying,recordingorotherwise,exceptaspermitted
bytheUKCopyright,DesignsandPatentsAct1988,withoutthepriorpermissionofthepublisher.Designations
usedbycompaniestodistinguishtheirproductsareoftenclaimedastrademarks.Allbrandnamesandproduct
namesusedinthisbookaretradenames,servicemarks,trademarksorregisteredtrademarksoftheirrespective
owners.Thepublisherisnotassociatedwithanyproductorvendormentionedinthisbook.Thispublicationis
designedtoprovideaccurateandauthoritativeinformationinregardtothesubjectmattercovered.Itissoldon
theunderstandingthatthepublisherisnotengagedinrenderingprofessionalservices.Ifprofessionaladviceor
otherexpertassistanceisrequired,theservicesofacompetentprofessionalshouldbesought.
Thecontentsofthisworkareintendedtofurthergeneralscientificresearch,understanding,anddiscussion
onlyandarenotintendedandshouldnotberelieduponasrecommendingorpromotingaspecificmethod,
diagnosis,ortreatmentbyphysiciansforanyparticularpatient.Thepublisherandtheauthormakeno
representationsorwarrantieswithrespecttotheaccuracyorcompletenessofthecontentsofthisworkand
specificallydisclaimallwarranties,includingwithoutlimitationanyimpliedwarrantiesoffitnessfora
particularpurpose.Inviewofongoingresearch,equipmentmodifications,changesingovernmental
regulations,andtheconstantflowofinformationrelatingtotheuseofmedicines,equipment,anddevices,the
readerisurgedtoreviewandevaluatetheinformationprovidedinthepackageinsertorinstructionsforeach
medicine,equipment,ordevicefor,amongotherthings,anychangesintheinstructionsorindicationof
usageandforaddedwarningsandprecautions.Readersshouldconsultwithaspecialistwhereappropriate.
ThefactthatanorganizationorWebsiteisreferredtointhisworkasacitationand/orapotentialsourceof
furtherinformationdoesnotmeanthattheauthororthepublisherendorsestheinformationtheorganization
orWebsitemayprovideorrecommendationsitmaymake.Further,readersshouldbeawarethatInternet
Websiteslistedinthisworkmayhavechangedordisappearedbetweenwhenthisworkwaswrittenandwhen
itisread.Nowarrantymaybecreatedorextendedbyanypromotionalstatementsforthiswork.Neitherthe
publishernortheauthorshallbeliableforanydamagesarisingherefrom.
LibraryofCongressCataloging-in-PublicationData
Colombo,Paolo,1944-
Inhalationdrugdelivery:techniquesandproducts/PaoloColombo,DanielaTraini,andFrancescaButtini.
p.;cm.
Includesbibliographicalreferencesandindex.
Summary:“Providesstudentsandthoseinindustrywithconciseclearguidetotheessentialfundamentals
ininhalationdrugdelivery”–Providedbypublisher.
ISBN978-1-118-35412-4(hardback)
I. Traini,Daniela. II. Buttini,Francesca. III. Title.
[DNLM: 1. Administration,Inhalation. 2. DrugDeliverySystems–methods. WB342]
6150.6–dc23
2012028075
AcataloguerecordforthisbookisavailablefromtheBritishLibrary.
Wileyalsopublishesitsbooksinavarietyofelectronicformats.Somecontentthatappearsinprintmaynot
beavailableinelectronicbooks.
Setin10.5/13ptTimes-RomanbyThomsonDigital,Noida,India.
FirstImpression2013
Contents
Listofcontributors xi
Seriesforeword xiii
Preface xv
1 Inhalationdrugdelivery 1
DanielaTraini
1.1 Introduction 1
1.2 Briefreviewoftherespiratorysystemanditsphysiology 1
1.3 Depositionandthefateofparticlesintherespiratorytract 3
1.4 Depositionmechanisms 4
1.5 Parametersinfluencingparticledeposition 6
1.6 Theclearanceofdepositedparticles 7
1.7 Airwaysgeometryandhumidity 7
1.8 Lungclearancemechanisms 8
1.9 Localandsystemicdrugdelivery 10
1.10 Conclusion 11
References 11
2 Inhalationandnasalproducts 15
DanielaTrainiandPaulM.Young
2.1 Introduction 15
2.2 Drypowderinhalers(DPIs) 15
2.3 Liquidandpropellant-basedinhalers 18
2.3.1 Pressurizedmetered-doseinhalers(pMDIs) 18
2.3.2 Nebulizers 22
2.4 Nasalformulations 23
2.4.1 Nasalphysiology 24
2.4.2 Deliveryissuesandconcerns 25
2.4.3 Strategyforenhancednasaldelivery 26
2.4.4 Marketednasalproducts 26
2.4.5 Pharmaceuticaldevelopmentstudiesfornasalproducts 26
2.5 Conclusion 27
References 29
vi CONTENTS
3 Formulationofinhalationmedicines 31
DanielaTrainiandPaulM.Young
3.1 Introduction 31
3.2 Pressurizedmetered-doseinhaler(pMDI)formulation 31
3.2.1 Suspensiontechnology 33
3.2.2 Solutiontechnology 35
3.3 Drypowderinhaler(DPI)formulation 36
3.3.1 Carriertechnology 37
3.3.2 Agglomeratetechnology 42
3.4 Conclusion 43
References 43
4 Novelparticleproductiontechnologiesforinhalationproducts 47
Hak-KimChanandPhilipChiLipKwok
4.1 Introduction 47
4.2 Conventionalcrystallizationandmilling 47
4.3 Specializedmilling 48
4.3.1 Fluid-energymillingatelevatedhumidity 48
4.3.2 Wet-millingnanotechnology 49
4.4 Solventprecipitation 49
4.4.1 Sono-crystallization 50
4.4.2 Microprecipitationbyopposingliquidjetsandtangential
liquidjets 52
4.4.3 High-gravitycontrolledprecipitation 52
4.5 Spray-dryingandrelateddropletevaporationmethods 54
4.5.1 Spray-drying 54
4.5.2 Controlledevaporationofdroplets 57
4.5.3 Evaporationoflow-boiling-pointsolutions 57
4.5.4 Sprayfreeze-drying 57
4.6 Supercriticalfluid(SCF)technology 58
4.7 Conclusion 59
Acknowledgements 59
References 59
5 Methodsforunderstanding,controlling,predicting,andimproving
drugproductperformance 63
DavidA.V.Morton
5.1 Introduction 63
5.1.1 Thecomplexitiesandchallengesofaerosolperformance 63
5.1.2 Understandingpowder/particlecharacteristics:
implicationsforaerosolproductperformance 65
5.1.3 Liquidsystems 66
5.1.4 Summary 67
CONTENTS vii
5.2 Particlesizing 68
5.2.1 Sieveanalysis 68
5.2.2 Imageanalysis 68
5.2.3 Lightscatter 69
5.2.4 Time-of-flight 70
5.2.5 Othermethods 70
5.3 Powderandparticulatecharacterizationsystems 71
5.3.1 Introduction 71
5.3.2 Powdercohesionandadhesion 72
5.3.3 Microscopicmaterialcharacterization 73
5.3.4 Methodsforstudyingbulkpowders 78
5.4 Practicalissuesinprocesscontrol 80
5.4.1 Commonprimaryandsecondaryprocessingmethodsandissues
arisingforcontrol 80
5.5 Biopharmaceuticalpowderstability 81
5.6 Liquids:solutionsandsuspensions 82
5.6.1 Liquidformulationstability 83
5.7 Conclusion 84
References 85
6 Aerodynamicassessmentforinhalationproducts:
fundamentalsandcurrentpharmacopoeialmethods 91
FrancescaButtini,GaiaColombo,PhilipChiLipKwok,
andWongTinWui
6.1 Introduction 91
6.2 Impactor/impingerdesign 92
6.3 Aerodynamicassessment 94
6.4 Inertialimpactionandcut-offdiameter 97
6.5 Pharmacopoeialprocedure 98
6.5.1 Thedurationofinvivoinspirationneededfor4L 99
6.5.2 Settingflowrate,Q,togiveapressuredropof4kPa 99
6.5.3 Flow-ratestability 100
6.6 Cascadeimpactor:generalset-upandoperation 100
6.7 Impactor/impingercharacteristics 102
6.7.1 Twin-stageimpinger(orglassimpinger,apparatusA) 102
6.7.2 Multistageliquidimpinger(MSLI) 103
6.7.3 Andersencascadeimpactor(ACI) 105
6.7.4 Next-generationimpactor(NGI) 107
6.8 Dataanalysis 109
6.9 Cleaninginstructionsforimpactors 111
6.10 Testlimitations 112
6.11 Futureconsiderations 112
6.11.1 Electricallow-pressureimpactor(ELPI) 113
References 116
viii CONTENTS
7 Proteins,peptides,andcontrolled-releaseformulations
forinhalation 121
PhilipChiLipKwok,RaniaOsamaSalama,andHak-KimChan
7.1 Proteinsandpeptidesforinhalation 121
7.1.1 Stabilityofproteins 123
7.1.2 NebulizersandtheAERxpulmonarydeliverysystem 124
7.1.3 Metered-doseinhalers(MDIs) 124
7.1.4 Drypowderinhalers(DPIs) 125
7.2 Controlled-releaseformulationsforinhalation 127
7.2.1 Challengesfacingcontrolled-releaseinhalationtherapy 128
7.2.2 Productionofinhalablecontrolled-releaseformulations 129
References 134
8 Pharmaceuticaldevelopmentstudiesforinhalationproducts 145
GaiaColombo,ChiaraParlati,andPaolaRusso
8.1 Introduction 145
8.2 Pharmaceuticaldevelopmentstudiesforinhalationproducts 148
8.2.1 Studiesdemonstratingproductperformancewithrespect
toformulation,deliverydevice,andtheircombination 150
8.2.2 Studiesdemonstratingproductperformanceinthehands
ofthepatient(handling,use,storage) 160
8.2.3 Additionalstudiesdemonstratingspecificdevelopment
requirements 163
8.3 Conclusion 165
Acknowledgements 165
References 166
9 Qualityofinhalationproducts:specifications 169
PaoloColombo,FrancescaButtini,andWongTinWui
9.1 Introduction 169
9.2 Inhalation-productspecifications 171
9.2.1 Description 171
9.2.2 Identification 171
9.2.3 Drugcontent 172
9.2.4 Impuritiesanddegradationproducts 173
9.2.5 Preservativecontent 173
9.2.6 Microbiallimits 173
9.2.7 Sterility 174
9.2.8 Delivered-doseuniformity 174
9.2.9 Contentuniformity/uniformityofdosageunits 176
9.2.10 Meandelivereddose 176
9.2.11 Numberofactuationspercontainer 176
9.2.12 Fine-particlemass 177
CONTENTS ix
9.2.13 Spraypatternandplumegeometry 178
9.2.14 Leakrate 179
9.2.15 Moisturecontent 179
9.2.16 Leachables 180
9.2.17 pH 180
9.2.18 Osmolality 180
9.2.19 Extraneousparticles 181
9.3 Additionalqualityaspects 181
9.3.1 Drugsubstances 181
9.3.2 Excipients 182
9.3.3 Containerclosuresystems 183
9.3.4 Inhalation-productstability 184
9.3.5 Packageinsertsandlabels 185
9.3.6 Clinical/bioequivalencerequirements 185
References 189
Index 191
List of contributors
Francesca Buttini
Department of Pharmacy, The University of Parma, Parma, Italy
Hak-Kim Chan
Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney,
Sydney, Australia
Gaia Colombo
Department of Pharmaceutical Sciences, The University of Ferrara, Ferrara, Italy
Paolo Colombo
Department of Pharmacy, The University of Parma, Parma, Italy
Philip Chi Lip Kwok
Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The
University of Hong Kong, Hong Kong, China
David A.V. Morton
Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne,
Australia
Chiara Parlati
Department of Pharmacy, The University of Parma, Parma, Italy; Novartis V&D,
Technology Development, Siena, Italy
Paola Russo
DepartmentofPharmaceuticalandBiomedicalSciences,TheUniversityofSalerno,
Fisciano, Italy
Rania Osama Salama
Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney,
Sydney, Australia; Faculty of Pharmacy, Alexandria University, Egypt
xii LISTOFCONTRIBUTORS
Daniela Traini
Respiratory Technology, The Woolcock Institute of Medical Research & The
Discipline of Pharmacology, The University of Sydney, Sydney, Australia
Wong Tin Wui
Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor,
Malaysia
Paul M. Young
Respiratory Technology, The Woolcock Institute of Medical Research & The
Discipline of Pharmacology, The University of Sydney, Sydney, Australia