Table Of Content

O D RAL ELIVERY OF T P HERAPEUTIC EPTIDES AND P ROTEINS This pageintentionallyleftblank O D RAL ELIVERY OF T P HERAPEUTIC EPTIDES AND P ROTEINS Edited by PUNEET TYAGI Dosage Form Design and Development, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States J. ANAND SUBRAMONY Biologics Engineering & Targeted Delivery, Oncology R&D, AstraZeneca, Gaithersburg, MD, United States AcademicPressisanimprintofElsevier 125LondonWall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1650,SanDiego,CA92101,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom Copyright©2022ElsevierInc.Allrightsreserved. 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Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgein evaluatingandusinganyinformation,methods,compounds,orexperimentsdescribed herein.Inusingsuchinformationormethodstheyshouldbemindfuloftheirownsafety andthesafetyofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility. Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,or editors,assumeanyliabilityforanyinjuryand/ordamagetopersonsorpropertyasamatter ofproductsliability,negligenceorotherwise,orfromanyuseoroperationofanymethods, products,instructions,orideascontainedinthematerialherein. ISBN:978-0-12-821061-1 ForInformationonallAcademicPresspublications visitourwebsiteathttps://www.elsevier.com/books-and-journals Publisher:StacyMasucci AcquisitionsEditor:AndreG.Wolff EditorialProjectManager:SaraPianavilla ProductionProjectManager:KiruthikaGovindaraju CoverDesigner:ChristianJ.Bilbow TypesetbyMPSLimited,Chennai,India Contents Listofcontributors xi Abouttheeditors xiii ForewordbySamirMitragotri xv PrefacebyPuneetTyagiandJ.AnandSubramony xvii Acknowledgments xix 1. Landscapefor oral delivery ofpeptides 1 MarkJ.Jackman,NigelM.Davies,AnnetteBakandSanyogittaPuri 1.1 Introduction 1 1.2 Barrierstooraldeliveryofpeptides 1 1.3 Strategiestoimprovetheoralbioavailabilityofpeptides 3 1.3.1 Transientpermeationenhancers 3 1.3.2 Oralnanoparticlesforpeptidedelivery 12 1.3.3 Transporter-mediatedoralpeptidedrugdelivery 23 1.3.4 Ingestibleinjectiondevices 30 1.4 Progressversusanoralpeptidetargetproductprofile 37 Acknowledgments 41 References 41 2. Design andsynthesis of chemically modified peptides and proteins —critical considerations for oraldelivery 51 JeffersonD.Revell 2.1 Introduction 51 2.2 Enzymaticbarrierstoabsorptionofintactpeptidesandproteins 54 2.3 Overcomingrenalclearanceofunmodifiedpeptides 58 2.4 Peptidedesignconsiderationstoimproveoralbioavailability 59 2.4.1 ImprovingstabilityofpeptidedrugsintheGItract 60 2.4.2 Optimizingmembranepermeability 67 2.4.3 Disulfidebondsurrogates 69 2.4.4 Reducingeliminationofpeptidedrugsinthecirculation 72 2.5 Rybelsus,anoralsemaglutideformulation,ashortcasestudy 74 2.6 Conclusions 77 References 78 v vi Contents 3. Abiopharmaceutics perspective on oral peptide developabilityand drug delivery 87 AhilN.Ganesh,SudhakarGaradandManuelV.Sanchez-Felix 3.1 Introduction 87 3.2 Lessonslearnedfromsmallmoleculedevelopability 88 3.2.1 Solubility 89 3.2.2 Permeability 90 3.2.3 Stability 91 3.2.4 Ionization 92 3.2.5 Inter-andintramolecularinteractions 93 3.3 Barrierstooralpeptidedelivery 94 3.3.1 Biochemicalbarriers 94 3.3.2 Cellularbarrier 96 3.3.3 Physicochemicalpropertiesoftherapeuticpeptides 97 3.4 Chemistryapproachestooralpeptidedevelopability 98 3.4.1 Aminoacidsequence 99 3.4.2 Peptidecyclization 100 3.4.3 Hydrophobicmodifications 101 3.4.4 Nonnaturalaminoacids 103 3.4.5 Examplesofchemicallymodifiedpeptideanalogs 103 3.5 Formulationapproachesforpeptidedevelopability 105 3.5.1 Modulationofflux 105 3.5.2 Entericcoatings 107 3.5.3 Proteaseinhibitors 110 3.5.4 Permeationenhancers 111 3.5.5 Lipid-basedformulations 111 3.5.6 Noveltransport-mediateduptake 113 3.6 Insilicoandinvitromodels 114 3.6.1 Insilicomethods 114 3.6.2 Characterizationofpeptideconformationandaggregation 115 3.6.3 Invitrostabilityassessment 116 3.6.4 Invitropermeabilityandfluxmeasurements 117 3.7 Outlook 119 3.7.1 Reevaluatingpatientpreferences 119 3.7.2 Inter-andintraspeciesvariability 120 3.7.3 Rationaledesignofasuccessfuloralpeptideproduct 121 Acknowledgments 122 References 122 Contents vii 4. Nanoparticle-assisted oral delivery ofsmall and large peptides 131 MeenakshiArora,DianxiongZouandM.N.V.RaviKumar 4.1 Introduction 131 4.2 Insulin 138 4.3 Cyclosporine 144 4.4 Calcitonin 147 4.5 Exenatide 149 4.6 Futureperspectives 153 Acknowledgments 154 References 155 5. Novel formulation approaches for gastrointestinaltargeting: characterization and animal model considerations 167 SwapnilKhadke,FionaMacDougallandTariqIslam 5.1 Introduction 167 5.2 Oralrouteandhumangastrointestinalanatomy(generalphysiological considerationsforcolonicdrugdelivery) 168 5.2.1 IntraluminalpHofthehumangastrointestinaltract 171 5.2.2 Gastrointestinalmotility 172 5.2.3 Gastricemptyingtime,smallintestine,andcolonictransittime 173 5.3 Formulationstrategiesforcolon-targeteddrugdelivery 175 5.3.1 Time-delayedsystems 175 5.3.2 pH-dependentdrugdeliverysystems 183 5.3.3 Enzyme-sensitivedrugdeliverysystems 184 5.4 Animalmodelsfortargetedoralformulations 185 5.4.1 Generalconsiderations 185 5.4.2 Gastrointestinalconsiderations 187 5.5 Conclusion 190 References 191 6. CMC considerations for conventionalformulations. Scale up andvalidation 199 RuchitTrivedi 6.1 Introduction 199 6.2 Chemistry,manufacturing,andcontrols 200 6.2.1 Drugproductconsiderations 200 6.2.2 Manufacturingprocessconsiderations 203 6.2.3 Qualitycontrolreleasetesting,stability,andspecifications 215 viii Contents 6.2.4 Manufacturingfacilityconsiderations 216 6.3 Typicalchallengesinchemistry,manufacturing,andcontrols 221 References 222 7. Clinicaltranslation of oral peptidedelivery technologies 225 PuneetTyagiandJ.AnandSubramony 7.1 Introduction 225 7.2 Clinicallytranslatedoralpeptides 227 7.2.1 Salmoncalcitonin 227 7.2.2 Octreotide 229 7.2.3 Parathyroidhormone 231 7.2.4 Insulin 233 7.2.5 Semaglutide 235 7.3 Potentialreasonsforvariablebioavailabilityintranslationalstudies 240 7.3.1 VariabilityinGIparametersbetweenhumansubjects 241 7.3.2 VariabilityinintestinalandgastricpH 243 7.3.3 Effectsofgastricemptying 244 7.3.4 Effectoffood(mealandwaterintake) 244 7.3.5 Effectofpeptidases 245 7.4 Futuredirections 245 References 246 8. Regulatoryaspects of oral peptidedelivery 251 EricGruff 8.1 Basisofregulationandregulatoryframework 251 8.2 InvestigationalstudiesunderanIND 252 8.3 Pre-INDmeeting 252 8.4 Investigationalnewdrugapplication 254 8.5 Chemistry,manufacturing,andcontrolsregulatoryrequirements 254 8.5.1 Drugsubstance 254 8.5.2 Drugproduct 261 8.6 Nonclinicalrequirements 267 8.7 Pharmacology 267 8.8 Pharmacokinetics 268 8.9 Toxicology 270 8.9.1 Safetypharmacologystudies 270 8.9.2 Toxicokineticstudies 270 Contents ix 8.9.3 Acutetoxicitystudies 271 8.9.4 Repeat-dosetoxicitystudies 271 8.9.5 Immunogenicitystudies 271 8.10 Clinicalrequirements 272 8.11 Drug(cid:1)druginteractions 272 8.12 Immunogenicity 273 8.13 Regulatoryaffairs 273 8.14 Regulatorymeetings 274 8.15 Marketingauthorization 275 8.16 Pre-NDAmeeting 275 8.17 NDA/MAAsubmission 276 8.17.1 Module1:administrativeinformation 277 8.17.2 Module2:summaries 277 8.17.3 Module3:quality 278 8.17.4 Drugsubstance 278 8.17.5 Drugproduct 280 8.17.6 Module4:nonclinical 287 8.17.7 Module5:clinical 288 8.18 Drug(cid:1)druginteractions 289 8.19 Immunogenicity 289 References 290 Index 291