Novel Delivery Systems for Transdermal and Intradermal Drug Delivery

Dr Ryan Donnelly is Reader in Pharmaceutics at Queen's University Belfast. Dr Donnelly's research is centred on design and physicochemical characterisation of advanced polymeric drug delivery systems for transdermal and topical drug delivery, with a strong emphasis on improving therapeutic outcomes for patients. He is also a technical director at Swedish Pharma AB. Still at a relatively early stage of his career, he has authored over 300 peer-reviewed publications, including 3 patent applications, 3 textbooks, 16 book chapters and approximately 100 full papers. He’s the holder of many awards including the current GSK Emerging Scientist Award. Dr Raj Thakur is Lecturer in Pharmaceutics at Queen's University Belfast. He obtained his PhD in polymer science in 2009 from Queens University Belfast and his MSc in drug delivery in 2006 from University Science Malaysia. He has a BSc in Pharmacy from Jawaharlal Nehru Technological University, India. Dr Thakur's research interests are in development and evaluation of novel in situ forming controlled release implants and ocular and transdermal drug delivery using novel minimally-invasive devices. He has published a textbook and over 30 scientific papers.

• About the Editors xiiiContributors xvAdvances in Pharmaceutical Technology: Series Preface xviiPreface xix1 Introduction 1Gary P.J. Moss1.1 The Subcutis (Subcutaneous Fat Layer) 11.2 The Dermis 21.3 Skin Appendages 21.4 The Subcutaneous Sensory Mechanism 31.5 The Epidermis 51.6 The stratum germinativum 51.7 The stratum spinosum 51.8 The stratum granulosum 61.9 The stratum lucidum 61.10 The stratum corneum 61.10.1 Routes of Absorption 91.10.2 Transdermal Permeation – Mechanisms of Absorption 91.11 Theoretical Considerations 111.12 Physicochemical Properties of the Penetrant 131.12.1 Partition Coefficient 131.12.2 Molecular Size and Shape 141.12.3 Applied Concentration/Dose 151.12.4 Solubility and Melting Point 151.12.5 Ionisation 151.12.6 Physiological Factors Affecting Percutaneous Absorption 161.13 Physiological Properties of the Skin 161.13.1 Skin Condition 161.13.2 Skin Hydration and Occlusion 171.13.3 Skin Age 171.13.4 Regional Variation (Body Site) 181.13.5 Race 191.13.6 Skin Temperature 191.14 Vehicle Effects 191.15 Modulation and Enhancement of Topical and Transdermal Drug Delivery 201.15.1 Chemical Modulation of Permeation 211.15.2 Physical Methods of Enhancement 262 Application of Spectroscopic Techniques to Interrogate Skin 41Jonathan Hadgraft, Rita Mateus and Majella E. Lane2.1 Introduction 412.2 Vibrational Spectroscopic Methods 422.3 Electronic Spectroscopic Methods 462.3.1 UV and Fluorescence 462.3.2 Nuclear Magnetic Resonance 472.4 Miscellaneous Spectroscopic Methods 482.4.1 Opto‐Thermal Transient Emission Radiometry 482.4.2 Electron Spin Resonance 482.4.3 Impedance Spectroscopy 492.4.4 Laser‐Induced Breakdown Spectroscopy 492.4.5 Photoacoustic Spectroscopy 502.4.6 Mass Spectrometry Imaging 502.5 Conclusions and Future 503 Analysis of the Native Structure of the Skin Barrier by Cryo‐TEM Combined with EM‐Simulation 57Lars Norlén3.1 Introduction 573.2 Our Approach: In Situ Biomolecular Structure Determination in Near‐Native Skin 583.2.1 Step 1: Cryo‐Electron Microscopy of Vitreous Sections 603.2.2 Steps 2–3: Molecular Model Building and Electron Microscopy Simulation 663.2.3 Step 4: Confrontation of Observed Data with Simulated Data 663.3 Molecular Organisation of the Horny Layer’s Fat Matrix 673.4 Molecular Organisation of the Horny Layer’s Keratin Filament Matrix 673.5 Final Remark 684 Intradermal Vaccination 71Marija Zaric and Adrien Kissenpfennig4.1 Vaccination 714.1.1 Disadvantages Associated with Conventional Vaccination 724.2 Dendritic Cells Immunobiology 734.3 Skin Anatomy and Physiology 744.3.1 The Role of Skin in Vaccine Delivery 754.4 The Skin Dendritic Cell Network 764.4.1 Langerhans Cells and the ‘Langerhans Cell Paradigm’ 764.4.2 Dermal Dendritic Cell Network 774.4.3 Dendritic Cell Subsets in the Skin‐Draining Lymph Node 794.4.4 Human Dendritic Cells in the Skin 804.4.5 The Role of Skin Dendritic Cells Subsets in Transdermal Immunisation 814.5 The DTR‐DT Depletion System 824.5.1 Langerin‐DTR Mouse Models 834.6 Dendritic Cells and the Differentiation of T Lymphocytes 844.6.1 CD8 + T Cell Activation 854.6.2 CD4 + T Cell Polarisation 854.7 Summary 885 Film‐Forming and Heated Systems 97William J. McAuley and Francesco Caserta5.1 Film‐Forming Systems 975.1.1 The Design of Film‐Forming Systems 985.1.2 Advantages of Using Film‐Forming Systems for Drug Delivery 995.1.3 Production of a Supersaturated State 1015.1.4 Use with Chemical Penetration Enhancers 1035.1.5 Advantages of Film‐Forming Systems for Patient Use 1055.1.6 Therapeutic Applications 1055.2 Heated Systems 1075.2.1 Mechanisms of Drug Penetration Enhancement 1075.2.2 Partitioning 1085.2.3 Effects of Heat on Skin 1105.2.4 Dermal Clearance 1115.2.5 The Effects of Heat on the Permeation of Drugs Across Skin 1125.2.6 Strategies for Generating Heat 1135.2.7 Therapeutic Applications 1155.3 Conclusions 1166 Nanotechnology‐Based Applications for Transdermal Delivery of Therapeutics 125Venkata K. Yellepeddi6.1 Introduction 1256.1.1 Skin Structure 1266.1.2 Skin Sites for Nanoparticle Delivery 1276.1.3 Skin as a Barrier for Nanoparticle Penetration 1286.1.4 Physicochemical Characteristics of NPs for Penetration through Skin 1296.2 Nanocarriers for Topical and Transdermal Delivery 1296.2.1 Polymeric Nanoparticles 1306.2.2 Lipid Based Nanocarriers 1346.2.3 Metallic and Mineral Nanoparticles 1356.2.4 Carbon‐Based Nanomaterials 1376.3 Interactions of Nanoparticles with the Skin 1376.4 Limitations of Nanotechnology for Skin Delivery 1386.5 Conclusions 1397 Magnetophoresis and Electret‐Mediated Transdermal Delivery of Drugs 147Abhijeet Maurya, Cui Lili and S. Narasimha Murthy7.1 Introduction 1477.2 Physical Permeation Enhancement Techniques 1497.3 Magnetophoresis 1507.3.1 Drug Delivery Applications 1517.3.2 Mechanism of Permeability Enhancement 1527.3.3 Magnetophoretic Transdermal Patch 1547.3.4 Conclusion 1547.4 Electret‐Mediated Drug Delivery 1557.4.1 Electrets for Cutaneous Drug Delivery 1567.4.2 Electret Layer in a Patch 1587.4.3 Mechanism of Permeability Enhancement 1587.4.4 Conclusion 1598 Microporation for Enhanced Transdermal Drug Delivery 163Thakur Raghu Raj Singh and Chirag Gujral8.1 Introduction 1638.2 High‐Pressure Gas or Liquid Microporation 1648.3 Ultrasound (Phonophoresis and Sonophoresis) Microporation 1668.4 Iontophoresis 1688.5 Electroporation 1698.6 Laser Microporation 1708.7 Thermal Microporation 1718.8 RF Microporation 1738.9 Microneedles 1738.10 Conclusion 1749 Microneedle Technology 179Helen L. Quinn, Aaron J. Courtenay, Mary‐Carmel Kearney and Ryan F. Donnelly9.1 Introduction 1799.2 MN Materials and Fabrication 1829.3 MN‐Mediated Drug Delivery 1859.3.1 Combinational Approaches 1879.4 MN Vaccination 1889.4.1 Polymeric MNs and Vaccination 1889.4.2 Solid MNs and Vaccination 1899.4.3 Hollow MNs and Vaccination 1909.4.4 MN Vaccination Moving Forwards 1909.5 Further MN Applications 1919.5.1 Therapeutic Drug Monitoring 1929.5.2 Cosmetic Applications 1939.5.3 Other Potential Applications 1949.6 Patient Factors Relating to MN Use 1949.6.1 Effects of MN Insertion on the Skin 1949.6.2 Patient Safety 1969.6.3 Acceptability to Patients and Healthcare Providers 1979.6.4 Patient Application 1979.7 The Next Steps in MN Development 1989.7.1 Manufacturing Considerations 1999.7.2 Regulatory Considerations 1999.7.3 Commercialisation of MN Technologies 2009.8 Conclusion 20110 Intradermal Delivery of Active Cosmeceutical Ingredients 209Andrzej M. Bugaj10.1 Introduction 20910.2 Emulsions 21010.2.1 Microemulsions 21110.2.2 Nanoemulsions 21210.2.3 Quick‐Breaking Emulsions 21310.2.4 Pickering Emulsions 21410.2.5 Gel Emulsions 21410.2.6 Liquid Crystal Emulsions 21410.2.7 Multiple Emulsions 21510.3 Vesicular Systems 21610.3.1 Liposomes 21610.3.2 Niosomes 22110.3.3 Sphingosomes 22110.3.4 Multiwalled Delivery Systems 22110.4 Solid Particulate Systems 22210.4.1 Microparticles 22210.4.2 Solid Nanoparticles 22510.4.3 Fullerenes 22810.4.4 Cyclodextrins 22810.4.5 Fibrous Matrices 22910.5 Cosmetic Foams 22910.6 Cosmetic Patches 23010.7 Cosmeceuticals: The Future 23011 Commercial and Regulatory Considerations in Transdermal and Dermal Medicines Development 243Marc. B. Brown, Jon Lenn, Charles Evans and Sian Lim11.1 Introduction 24311.2 Dermal and Transdermal Product/Device Development 24511.2.1 Drug Candidate Selection 24611.2.2 Dosage/Device Form 24611.2.3 Pre‐formulation and Formulation/Device Development 24811.2.4 Performance Testing 25011.3 Product Scale‐Up and Process Optimisation, Validation and Stability Testing 25311.3.1 Product Scale‐Up, Process Optimisation and Specification Development 25311.3.2 Analytical Method Validation 25311.3.3 ICH Stability Testing 25411.4 The Commercial Future of Transdermal Devices 254Index 259