Ryan F. Donnelly, Senior Lecturer in Pharmaceutics, School of Pharmacy, Queen's University Belfast, UK Thakur Raghu Raj Singh, Lecturer in Pharmaceutics, School of Pharmacy, Queen's University Belfast, UKDesmond I.J. Morrow, Honorary Research Fellow, School of Pharmacy, Queen's University Belfast, UKA. David Woolfson, Chair in Pharmaceutics and Head of the School  of Pharmacy, Queen’s University Belfast, UK

• Preface, ix About the Authors, xiii1 Transdermal Drug Delivery, 11.1 Genesis of transdermal drug delivery, 11.2 Skin anatomy, 21.2.1 The epidermis, 21.2.2 The stratum corneum, 41.2.3 The dermis, 61.2.4 Skin appendages, 61.3 Routes to percutaneous drug absorption, 71.4 Facilitated transdermal drug delivery, 111.4.1 Cryopneumatic and photopneumatic technologies, 121.4.2 Sonophoresis (low-frequency ultrasound), 121.4.3 Iontophoresis, 131.4.4 Electroporation, 141.4.5 Jet injection, 141.4.6 Microneedles, 15References, 152 Microneedles: Design, Microfabrication and Optimization, 202.1 Introduction, 202.2 Methods of fabricating microneedles, 212.2.1 Microfabrication of silicon microneedles, 222.2.2 Microfabrication of metal and other types of MNs, 312.2.3 Microfabrication of polymeric microneedles, 342.3 Optimization to MN design for transdermal drug delivery, 462.4 Conclusion, 49References, 513 Microneedle Applicator Designs for Transdermal Drug Delivery Applications, 573.1 Introduction, 573.2 Considerations of microneedle applicators designs, 723.3 Conclusion, 76References, 764 Transdermal Delivery Applications, 794.1 Introduction, 794.2 Transdermal drug delivery, 794.2.1 Partition co-efficient between 1 and 3, 804.2.2 A relatively low melting point, 804.2.3 A molecular weight less than 500 Da, 814.2.4 Unionized, 814.3 Modulation of transdermal penetration using microneedles, 824.4 Transdermal delivery using solid microneedles, 834.4.1 Transdermal delivery of low molecular weight compounds (RMM < 600 Da) in vitro using solid microneedles, 844.4.2 Transdermal delivery of low molecular weight compounds (RMM < 600 Da) in vivo using solid microneedles, 864.4.3 Transdermal delivery of high molecular weight compounds (RMM > 600 Da) in vitro using solid microneedles, 884.4.4 Transdermal delivery of high molecular weight compounds (RMM > 600 Da) in vivo using solid microneedles, 894.5 Transdermal delivery using hollow microneedles, 914.5.1 Transdermal delivery of low molecular weight compounds (RMM < 600 Da) in vitro using hollow microneedles, 914.5.2 Transdermal delivery of low molecular weight compounds (RMM < 600 Da) in vivo using hollow microneedles, 924.5.3 Transdermal delivery of high molecular weight compounds (RMM > 600 Da) in vitro using hollow microneedles, 934.5.4 Transdermal delivery of high molecular weight compounds (RMM > 600 Da) in vivo using hollow microneedles, 934.6 Transdermal delivery using biodegradable microneedles, 964.6.1 Transdermal delivery of low molecular weight compounds in vitro using biodegradable MN, 964.6.2 Transdermal delivery of low molecular weight compounds in vivo using biodegradable MN, 984.6.3 Transdermal delivery of high molecular weightcompounds in vitro using biodegradable MN, 984.6.4 Transdermal delivery of high molecular weight compounds in vivo using biodegradable MN, 1004.7 Microneedles in combination with other enhancement strategies, 1024.8 Conclusion, 105References, 1075 Microneedle-mediated Intradermal Delivery, 1135.1 Introduction, 1135.2 Vaccine delivery, 1135.2.1 Vaccination, 1135.3 Intradermal vaccination, 1165.3.1 Skin structure, 1175.3.2 Skin immune response, 1175.3.3 Conventional strategies for intradermal vaccine delivery, 1185.3.4 Coated microneedles, 1205.3.5 ‘Poke and Patch’ approaches, 1295.3.6 Hollow microneedles, 1315.3.7 Dissolving/biodegrading polymeric microneedles, 1335.3.8 Epidermal gene delivery, 1355.4 Intradermal delivery of photosensitizers for photodynamic therapy, 1395.4.1 Microneedle-mediated intradermal delivery of 5-aminolevulinic acid and derivatives, 1415.4.2 Microneedle-mediated intradermal delivery of preformed photosensitizers, 1435.5 Intradermal delivery of nanoparticles, 1445.6 Conclusion, 146References, 1476 Clinical Application and Safety Studies of Microneedles, 1526.1 Introduction, 1526.2 Clinical and safety consideration for MN application, 1536.2.1 Sensation of pain, 1536.2.2 Recovery of micropores and possibility of infection following microneedle application, 1556.2.3 Erythema, 1566.2.4 Biocompatability and biodegradation of MN material, 1576.3 Conclusion, 159References, 1607 Microneedles: Current Status and Future Perspectives, 1647.1 Introduction, 1647.2 Biological fluid sampling devices, 1677.3 Ocular drug delivery, 1727.4 Cosmetic applications, 1757.5 Industrial perspectives, 1777.6 Hydrogel-forming microneedle arrays, 1797.7 Moving forwards, 1817.8 Conclusion, 184References, 185Index, 188

Ryan F. Donnelly, Senior Lecturer in Pharmaceutics, School of Pharmacy, Queen's University Belfast, UK Thakur Raghu Raj Singh, Lecturer in Pharmaceutics, School of Pharmacy, Queen's University Belfast, UKDesmond I.J. Morrow, Honorary Research Fellow, School of Pharmacy, Queen's University Belfast, UKA. David Woolfson, Chair in Pharmaceutics and Head of the School  of Pharmacy, Queen’s University Belfast, UK

• Preface, ix About the Authors, xiii1 Transdermal Drug Delivery, 11.1 Genesis of transdermal drug delivery, 11.2 Skin anatomy, 21.2.1 The epidermis, 21.2.2 The stratum corneum, 41.2.3 The dermis, 61.2.4 Skin appendages, 61.3 Routes to percutaneous drug absorption, 71.4 Facilitated transdermal drug delivery, 111.4.1 Cryopneumatic and photopneumatic technologies, 121.4.2 Sonophoresis (low-frequency ultrasound), 121.4.3 Iontophoresis, 131.4.4 Electroporation, 141.4.5 Jet injection, 141.4.6 Microneedles, 15References, 152 Microneedles: Design, Microfabrication and Optimization, 202.1 Introduction, 202.2 Methods of fabricating microneedles, 212.2.1 Microfabrication of silicon microneedles, 222.2.2 Microfabrication of metal and other types of MNs, 312.2.3 Microfabrication of polymeric microneedles, 342.3 Optimization to MN design for transdermal drug delivery, 462.4 Conclusion, 49References, 513 Microneedle Applicator Designs for Transdermal Drug Delivery Applications, 573.1 Introduction, 573.2 Considerations of microneedle applicators designs, 723.3 Conclusion, 76References, 764 Transdermal Delivery Applications, 794.1 Introduction, 794.2 Transdermal drug delivery, 794.2.1 Partition co-efficient between 1 and 3, 804.2.2 A relatively low melting point, 804.2.3 A molecular weight less than 500 Da, 814.2.4 Unionized, 814.3 Modulation of transdermal penetration using microneedles, 824.4 Transdermal delivery using solid microneedles, 834.4.1 Transdermal delivery of low molecular weight compounds (RMM < 600 Da) in vitro using solid microneedles, 844.4.2 Transdermal delivery of low molecular weight compounds (RMM < 600 Da) in vivo using solid microneedles, 864.4.3 Transdermal delivery of high molecular weight compounds (RMM > 600 Da) in vitro using solid microneedles, 884.4.4 Transdermal delivery of high molecular weight compounds (RMM > 600 Da) in vivo using solid microneedles, 894.5 Transdermal delivery using hollow microneedles, 914.5.1 Transdermal delivery of low molecular weight compounds (RMM < 600 Da) in vitro using hollow microneedles, 914.5.2 Transdermal delivery of low molecular weight compounds (RMM < 600 Da) in vivo using hollow microneedles, 924.5.3 Transdermal delivery of high molecular weight compounds (RMM > 600 Da) in vitro using hollow microneedles, 934.5.4 Transdermal delivery of high molecular weight compounds (RMM > 600 Da) in vivo using hollow microneedles, 934.6 Transdermal delivery using biodegradable microneedles, 964.6.1 Transdermal delivery of low molecular weight compounds in vitro using biodegradable MN, 964.6.2 Transdermal delivery of low molecular weight compounds in vivo using biodegradable MN, 984.6.3 Transdermal delivery of high molecular weightcompounds in vitro using biodegradable MN, 984.6.4 Transdermal delivery of high molecular weight compounds in vivo using biodegradable MN, 1004.7 Microneedles in combination with other enhancement strategies, 1024.8 Conclusion, 105References, 1075 Microneedle-mediated Intradermal Delivery, 1135.1 Introduction, 1135.2 Vaccine delivery, 1135.2.1 Vaccination, 1135.3 Intradermal vaccination, 1165.3.1 Skin structure, 1175.3.2 Skin immune response, 1175.3.3 Conventional strategies for intradermal vaccine delivery, 1185.3.4 Coated microneedles, 1205.3.5 ‘Poke and Patch’ approaches, 1295.3.6 Hollow microneedles, 1315.3.7 Dissolving/biodegrading polymeric microneedles, 1335.3.8 Epidermal gene delivery, 1355.4 Intradermal delivery of photosensitizers for photodynamic therapy, 1395.4.1 Microneedle-mediated intradermal delivery of 5-aminolevulinic acid and derivatives, 1415.4.2 Microneedle-mediated intradermal delivery of preformed photosensitizers, 1435.5 Intradermal delivery of nanoparticles, 1445.6 Conclusion, 146References, 1476 Clinical Application and Safety Studies of Microneedles, 1526.1 Introduction, 1526.2 Clinical and safety consideration for MN application, 1536.2.1 Sensation of pain, 1536.2.2 Recovery of micropores and possibility of infection following microneedle application, 1556.2.3 Erythema, 1566.2.4 Biocompatability and biodegradation of MN material, 1576.3 Conclusion, 159References, 1607 Microneedles: Current Status and Future Perspectives, 1647.1 Introduction, 1647.2 Biological fluid sampling devices, 1677.3 Ocular drug delivery, 1727.4 Cosmetic applications, 1757.5 Industrial perspectives, 1777.6 Hydrogel-forming microneedle arrays, 1797.7 Moving forwards, 1817.8 Conclusion, 184References, 185Index, 188

Ryan F. Donnelly, Senior Lecturer in Pharmaceutics, School of Pharmacy, Queen's University Belfast, UK Thakur Raghu Raj Singh, Lecturer in Pharmaceutics, School of Pharmacy, Queen's University Belfast, UKDesmond I.J. Morrow, Honorary Research Fellow, School of Pharmacy, Queen's University Belfast, UKA. David Woolfson, Chair in Pharmaceutics and Head of the School  of Pharmacy, Queen’s University Belfast, UK

• Preface, ix About the Authors, xiii1 Transdermal Drug Delivery, 11.1 Genesis of transdermal drug delivery, 11.2 Skin anatomy, 21.2.1 The epidermis, 21.2.2 The stratum corneum, 41.2.3 The dermis, 61.2.4 Skin appendages, 61.3 Routes to percutaneous drug absorption, 71.4 Facilitated transdermal drug delivery, 111.4.1 Cryopneumatic and photopneumatic technologies, 121.4.2 Sonophoresis (low-frequency ultrasound), 121.4.3 Iontophoresis, 131.4.4 Electroporation, 141.4.5 Jet injection, 141.4.6 Microneedles, 15References, 152 Microneedles: Design, Microfabrication and Optimization, 202.1 Introduction, 202.2 Methods of fabricating microneedles, 212.2.1 Microfabrication of silicon microneedles, 222.2.2 Microfabrication of metal and other types of MNs, 312.2.3 Microfabrication of polymeric microneedles, 342.3 Optimization to MN design for transdermal drug delivery, 462.4 Conclusion, 49References, 513 Microneedle Applicator Designs for Transdermal Drug Delivery Applications, 573.1 Introduction, 573.2 Considerations of microneedle applicators designs, 723.3 Conclusion, 76References, 764 Transdermal Delivery Applications, 794.1 Introduction, 794.2 Transdermal drug delivery, 794.2.1 Partition co-efficient between 1 and 3, 804.2.2 A relatively low melting point, 804.2.3 A molecular weight less than 500 Da, 814.2.4 Unionized, 814.3 Modulation of transdermal penetration using microneedles, 824.4 Transdermal delivery using solid microneedles, 834.4.1 Transdermal delivery of low molecular weight compounds (RMM < 600 Da) in vitro using solid microneedles, 844.4.2 Transdermal delivery of low molecular weight compounds (RMM < 600 Da) in vivo using solid microneedles, 864.4.3 Transdermal delivery of high molecular weight compounds (RMM > 600 Da) in vitro using solid microneedles, 884.4.4 Transdermal delivery of high molecular weight compounds (RMM > 600 Da) in vivo using solid microneedles, 894.5 Transdermal delivery using hollow microneedles, 914.5.1 Transdermal delivery of low molecular weight compounds (RMM < 600 Da) in vitro using hollow microneedles, 914.5.2 Transdermal delivery of low molecular weight compounds (RMM < 600 Da) in vivo using hollow microneedles, 924.5.3 Transdermal delivery of high molecular weight compounds (RMM > 600 Da) in vitro using hollow microneedles, 934.5.4 Transdermal delivery of high molecular weight compounds (RMM > 600 Da) in vivo using hollow microneedles, 934.6 Transdermal delivery using biodegradable microneedles, 964.6.1 Transdermal delivery of low molecular weight compounds in vitro using biodegradable MN, 964.6.2 Transdermal delivery of low molecular weight compounds in vivo using biodegradable MN, 984.6.3 Transdermal delivery of high molecular weightcompounds in vitro using biodegradable MN, 984.6.4 Transdermal delivery of high molecular weight compounds in vivo using biodegradable MN, 1004.7 Microneedles in combination with other enhancement strategies, 1024.8 Conclusion, 105References, 1075 Microneedle-mediated Intradermal Delivery, 1135.1 Introduction, 1135.2 Vaccine delivery, 1135.2.1 Vaccination, 1135.3 Intradermal vaccination, 1165.3.1 Skin structure, 1175.3.2 Skin immune response, 1175.3.3 Conventional strategies for intradermal vaccine delivery, 1185.3.4 Coated microneedles, 1205.3.5 ‘Poke and Patch’ approaches, 1295.3.6 Hollow microneedles, 1315.3.7 Dissolving/biodegrading polymeric microneedles, 1335.3.8 Epidermal gene delivery, 1355.4 Intradermal delivery of photosensitizers for photodynamic therapy, 1395.4.1 Microneedle-mediated intradermal delivery of 5-aminolevulinic acid and derivatives, 1415.4.2 Microneedle-mediated intradermal delivery of preformed photosensitizers, 1435.5 Intradermal delivery of nanoparticles, 1445.6 Conclusion, 146References, 1476 Clinical Application and Safety Studies of Microneedles, 1526.1 Introduction, 1526.2 Clinical and safety consideration for MN application, 1536.2.1 Sensation of pain, 1536.2.2 Recovery of micropores and possibility of infection following microneedle application, 1556.2.3 Erythema, 1566.2.4 Biocompatability and biodegradation of MN material, 1576.3 Conclusion, 159References, 1607 Microneedles: Current Status and Future Perspectives, 1647.1 Introduction, 1647.2 Biological fluid sampling devices, 1677.3 Ocular drug delivery, 1727.4 Cosmetic applications, 1757.5 Industrial perspectives, 1777.6 Hydrogel-forming microneedle arrays, 1797.7 Moving forwards, 1817.8 Conclusion, 184References, 185Index, 188