Novel Delivery Systems for Transdermal and Intradermal Drug Delivery E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Advances in Pharmaceutical Technology
• Sprache: Englisch

Seitenzahl: 668

Veröffentlichungsjahr: 2015

Beschreibung

This research book covers the major aspects relating to the use of novel delivery systems in enhancing both transdermal and intradermal drug delivery. It provides a review of transdermal and intradermal drug delivery, including the history of the field and the various methods employed to produce delivery systems from different materials such as device design, construction and evaluation, so as to provide a sound background to the use of novel systems in enhanced delivery applications.

Furthermore, it presents in-depth analyses of recent developments in this exponentially growing field, with a focus on microneedle arrays, needle-free injections, nanoparticulate systems and peptide-carrier-type systems. It also covers conventional physical enhancement strategies, such as tape-stripping, sonophoresis, iontophoresis, electroporation and thermal/suction/laser ablation Discussions about the penetration of the stratum corneum by the various novel strategies highlight the importance of the application method. Comprehensive and critical reviews of transdermal and intradermal delivery research using such systems focus on the outcomes of in vivoanimal and human studies. The book includes laboratory, clinical and commercial case studies featuring safety and patient acceptability studies carried out to date, and depicts a growing area for use of these novel systems is in intradermal vaccine delivery. The final chapters review recent patents in this field and describe the work ongoing in industry.

Leseprobe

Table of Contents

Cover

Title Page

About the Editors

Ryan F. Donnelly

Thakur Raghu Raj Singh

Contributors

Advances in Pharmaceutical Technology: Series Preface

Preface

1 Introduction

1.1 The Subcutis (Subcutaneous Fat Layer)

1.2 The Dermis

1.3 Skin Appendages

1.4 The Subcutaneous Sensory Mechanism

1.5 The Epidermis

1.6 The

stratum germinativum

1.7 The

stratum spinosum

1.8 The

stratum granulosum

1.9 The

stratum lucidum

1.10 The

stratum corneum

1.11 Theoretical Considerations

1.12 Physicochemical Properties of the Penetrant

1.13 Physiological Properties of the Skin

1.14 Vehicle Effects

1.15 Modulation and Enhancement of Topical and Transdermal Drug Delivery

References

2 Application of Spectroscopic Techniques to Interrogate Skin

2.1 Introduction

2.2 Vibrational Spectroscopic Methods

2.3 Electronic Spectroscopic Methods

2.4 Miscellaneous Spectroscopic Methods

2.5 Conclusions and Future

References

3 Analysis of the Native Structure of the Skin Barrier by Cryo-TEM Combined with EM-Simulation

3.1 Introduction

3.2 Our Approach:

In Situ

Biomolecular Structure Determination in Near-Native Skin

3.3 Molecular Organisation of the Horny Layer’s Fat Matrix

3.4 Molecular Organisation of the Horny Layer’s Keratin Filament Matrix

3.5 Final Remark

References

4 Intradermal Vaccination

4.1 Vaccination

4.2 Dendritic Cells Immunobiology

4.3 Skin Anatomy and Physiology

4.4 The Skin Dendritic Cell Network

4.5 The DTR-DT Depletion System

4.6 Dendritic Cells and the Differentiation of T Lymphocytes

4.7 Summary

References

5 Film-Forming and Heated Systems

5.1 Film-Forming Systems

5.2 Heated Systems

5.3 Conclusions

References

6 Nanotechnology-Based Applications for Transdermal Delivery of Therapeutics

6.1 Introduction

6.2 Nanocarriers for Topical and Transdermal Delivery

6.3 Interactions of Nanoparticles with the Skin

6.4 Limitations of Nanotechnology for Skin Delivery

6.5 Conclusions

References

7 Magnetophoresis and Electret-Mediated Transdermal Delivery of Drugs

7.1 Introduction

7.2 Physical Permeation Enhancement Techniques

7.3 Magnetophoresis

7.4 Electret-Mediated Drug Delivery

References

8 Microporation for Enhanced Transdermal Drug Delivery

8.1 Introduction

8.2 High-Pressure Gas or Liquid Microporation

8.3 Ultrasound (Phonophoresis and Sonophoresis) Microporation

8.4 Iontophoresis

8.5 Electroporation

8.6 Laser Microporation

8.7 Thermal Microporation

8.8 RF Microporation

8.9 Microneedles

8.10 Conclusion

References

9 Microneedle Technology

9.1 Introduction

9.2 MN Materials and Fabrication

9.3 MN-Mediated Drug Delivery

9.4 MN Vaccination

9.5 Further MN Applications

9.6 Patient Factors Relating to MN Use

9.7 The Next Steps in MN Development

9.8 Conclusion

References

10 Intradermal Delivery of Active Cosmeceutical Ingredients

10.1 Introduction

10.2 Emulsions

10.3 Vesicular Systems

10.4 Solid Particulate Systems

10.5 Cosmetic Foams

10.6 Cosmetic Patches

10.7 Cosmeceuticals: The Future

References

11 Commercial and Regulatory Considerations in Transdermal and Dermal Medicines Development

11.1 Introduction

11.2 Dermal and Transdermal Product/Device Development

11.3 Product Scale-Up and Process Optimisation, Validation and Stability Testing

11.4 The Commercial Future of Transdermal Devices

References

Index

End User License Agreement

List of Tables

Chapter 01

Table 1.1 Effect of molecular structure and functional group on in vitro permeability

Chapter 04

Table 4.1 Phenotype of the murine cutaneous dendritic cell subsets

Table 4.2 Phenotype of the human cutaneous dendritic cell subsets

Chapter 06

Table 6.1 List of dendrimers used in transdermal delivery of therapeutics

Table 6.2 Lipid-based nanocarriers for transdermal delivery of therapeutics

Chapter 07

Table 7.1 Classification of physical methods of transdermal enhancement

Table 7.2 Permeation flux and flux enhancement factor of LH across porcine epidermis

Table 7.3 Transport flux of [

3

H] Water and [1-

14

C] Mannitol across porcine epidermis

Table 7.4 Permeation of naltrexone from human epidermis and PDMS membrane under passive and PEMF treatment

Table 7.5 Pharmacokinetic parameters of salicylic acid after topical application of 1% salicylic acid ointment for electrets-treated group (−3000 V) vs. control group (untreated)

Table 7.6 Cumulative permeation of meloxicam from different enhancer incorporated patches across excised rat full thickness skin

Chapter 08

Table 8.1 High-pressure jet injector devices on the market or that have already received FDA clearance

List of Illustrations

Chapter 01

Figure 1.1 Schematic diagram of the skin.

Figure 1.2 Detailed schematic structure of the stratum corneum.

Figure 1.3 Pathways of drug penetration through skin.

Figure 1.4 Chemical structures of some penetration enhancers employed for transdermal drug delivery.

Figure 1.5 A typical anodic iontophoretic setup, where D

+

represents the positively charged drug, and A

−

its counter ion. H

+

and A

−

are charged species, usually Na

+

and Cl

−

, associated with the extracellular fluid beneath the skin.

Chapter 02

Figure 2.1 IR spectrum of skin.

Figure 2.2 IR spectra from psoriatic skin pre- and post-treatment with UV radiation.

Figure 2.3 Raman spectrum of human skin (untreated).

Chapter 03

Figure 3.1 Schematic drawing of skin. Left part: schematic cellular-scale drawing of epidermis. Midpart: molecular-scale drawing of the lamellar lipid matrix occupying the space between the cells of the stratum corneum. Right part: atomic model of the lipid matrix repeating unit, composed of two mirrored subunits, each composed of one fully extended ceramide molecule (CER), one cholesterol molecule (CHOL) and one free fatty acid (FFA) molecule. With kind permission from Springer Science and Business Media.

Figure 3.2 Step 1: Cryo-electron microscopy of vitreous sections (CEMOVIS). (a) Medium magnification CEMOVIS micrograph of the interface between two cells in the midpart of stratum corneum. Note that in CEMOVIS the tissue is unstained, and that the pixel intensity is directly related to the local electron density of the sample. The stacked lamellar pattern represents the extracellular lipid matrix. Dark approximately 10 nm dots represent keratin intermediate filaments filling out the intracellular space. (b) High magnification CEMOVIS micrograph of the extracellular space in the midpart of stratum corneum. The averaged intensity profile of the lipid matrix was obtained by fuzzy distance-based image analysis. The stars in (b) represent the manually chosen start and end points for fuzzy distance based path growing. (c) The vertical line in the centre represents the traced out path. Stacked lines mark extracted intensity profiles. (d) Enlarged area of the central part of (b). (e) Reversed averaged pixel intensity profile obtained from the extracted area in (c). Peaks in (e) correspond to dark bands and valleys to lucent bands in (d). Black arrows in (b) denote electron lucent narrow bands at the centre of the 6.5 nm bands. Section thickness approximately 50 nm (a–d). Scale bar (a): 100 nm. Pixel size in (a–d): 6.02 Å.

Figure 3.3 Steps 2–3: Molecular model building and electron microscopy (EM) simulation. (a) High-magnification CEMOVIS micrograph of the extracellular space in the midpart of stratum corneum. (b) Corresponding averaged intensity profile obtained by fuzzy distance based path growing (cf. Figure 2b and c). (c) Schematic 2D illustration of ceramides (tetracosanylphytosphingosine (C24:0)) in fully extended conformation with cholesterol associated with the ceramide sphingoid part and free fatty acids (lignoceric acid (C24:0)) associated with the ceramide fatty acid part. (d) Atomic 3D model of the repeating unit composed of two mirrored subunits, each composed of one fully extended ceramide molecule, one cholesterol molecule and one free fatty acid molecule. (e) Calculated electron scattering potential of one model subunit. (f) Calculated electron scattering potential 3D maps of the topmost layer out of 20 superimposed layers used to generate the simulated electron micrograph (g). Defocus (a, g): −2.5 µm. Pixel size in (a and g): 3.31 Å.

Figure 3.4 Step 4: Confrontation of observed data with simulated data. Electron microscopy simulation of alternating fully extended ceramides with selective localisation of cholesterol to the ceramide sphingoid part. (a–c) High-magnification CEMOVIS micrographs (first exposition images) of the extracellular space in the midpart of stratum corneum obtained at −0.5 µm (a), −2 µm (b) and −5 µm (c) defocus. (d–f) represents corresponding atomic 3D model (cf. Figure 3.1, right part) electron microscopy simulation images recorded at −0.5 µm (d), −2 µm (e) and −5 µm (f) defocus. (g–i) Sequential CEMOVIS micrograph defocus-series obtained at very high magnification (1.88 Å pixel-size). Note the fine changes in interference patterns caused by gradually increasing the microscope’s defocus during repeated image acquisition at a fixed position. (j–l) represents corresponding atomic 3D model (see Figure 3.1, right part) electron microscopy simulation images recorded at −1 µm (j), −2 µm (k) and −3 µm (l) defocus. It is shown that the atomic 3D model in Figure 3.1 accurately accounts not only for the major features of the CEMOVIS micrographs (a–f) but also for the interference intensity pattern changes observed upon varying the microscope’s defocus during image acquisition at very high magnification (g–l). Pixel size in (c and f): 3.31 Å, in (b and e): 6.02 Å, and in (a and d and g–l): 1.88 Å.

Figure 3.5 (a) Electron microscopy simulation results from seven fully extended ceramide bilayer models with varying cholesterol distribution. (A–C) CEMOVIS micrographs of the stratum corneum extracellular lipid matrix acquired at −5 µm (a), −2 µm (B) and −0.5 µm (C) defocus. (D3–J5) Corresponding simulated electron micrographs obtained from seven fully extended ceramide models. (D1–J1) Repeating units for each simulated model. (D2–J2) Calculated electron scattering potential 3D maps of the topmost layer out of 20 superimposed layers used to generate each individual simulated micrograph (D3–J5). In model (D), cholesterol is selectively localised to the ceramide sphingoid part. In model (E), cholesterol has been removed to evaluate whether the simulation method could discriminate the presence (D) or absence (E) of cholesterol. In model (F), cholesterol is selectively localised to the ceramide fatty acid part. In models (G–J), cholesterol is homogenously distributed between the ceramide sphingoid and fatty acid parts. Contrary to models (G and J), models (H and I) express axial headgroup displacement of cholesterol and free fatty acids. Models (H and I) differ in that model (H) expresses a pair-wise lateral distribution of ceramides, while model (I) expresses a homogeneous lateral distribution of ceramides. Note that except for the position of the lipid headgroups, the localisation of cholesterol within the fully extended ceramide structure largely determines the electron scattering properties of the models. (b) Electron microscopy simulation results from seven fully extended ceramide stacked monolayer models with varying cholesterol distribution. (A–C) CEMOVIS micrographs of the stratum corneum extracellular lipid matrix acquired at −5 µm (A), −2 µm (B) and −0.5 µm (C) defocus. (D3–J5) Corresponding simulated electron micrographs obtained from seven stacked fully extended ceramide models. (D1–J1) Two repeating units for each simulated model. (D2–J2) Calculated electron scattering potential 3D maps of the topmost layer out of 20 superimposed layers used to generate each individual simulated micrograph (D3–J5). In model (D) cholesterol is selectively localised to the ceramide sphingoid part. In model (E) cholesterol has been removed to evaluate whether the simulation method could discriminate the presence (D) or absence (E) of cholesterol. In model (F), cholesterol is selectively localised to the ceramide fatty acid part. In models (G–J), cholesterol is distributed homogenously between the ceramide sphingoid and fatty acid parts. Contrary to models (G and J), models (H and I) express axial headgroup displacement of cholesterol and free fatty acids. Models (H and I) differs in that model (H) expresses a pair-wise lateral distribution of ceramides while model (I) expresses a homogeneous lateral distribution of ceramides. Note that except for the position of the lipid headgroups, the localisation of cholesterol within the fully extended ceramide structure largely determines the electron scattering properties of the models. (c) Electron microscopy simulation results from two-folded ceramide bilayer models with and without the presence of cholesterol. (A–C) CEMOVIS micrographs of the stratum corneum extracellular lipid matrix acquired at −5 µm (A), −2 µm (B) and −0.5 µm (C) defocus. (D3–E5) Corresponding simulated electron micrographs obtained from two-folded ceramide models. (D1–E1) Repeating units for each simulated model. (D2–E2) Calculated electron scattering potential 3D maps of the topmost layer out of 20 superimposed layers used to generate each individual simulated micrograph (D3–E5). In model (D), cholesterol is present. In model (E), cholesterol has been removed to ascertain if the simulation method could distinguish the presence (D) or absence (E) of cholesterol. Note that the presence of cholesterol within the folded ceramide structure largely determines the electron scattering properties of the models.

Chapter 04

Figure 4.1 Schematic illustration demonstrating skin structure. The skin contains three main layers – the epidermis, dermis and hypodermis. Different structures present throughout the skin including various cell populations allow for efficient barrier protection against water loss and microbial invasions. The blood and lymph vessels permit the migration of immune cells through the skin during the steady-state and under inflammatory conditions.

Figure 4.2 Phenotype of dendritic cell subsets in the skin and cutaneous draining lymph node (cLNs). Based on the expression of langerin, CD11b and CD103, five separate DC subsets can be distinguished in a mouse steady-state skin. In the dermis, two langerin subsets (Langerin

–

CD11b

+

dDCs and Langerin

–

CD11b

–

dDCs) coexist with two langerin

+

DC subsets (Langerin

+

CD103

–

dDCs and Langerin

+

CD103

+

dDCs). The residual MHCII

high

dermal cells correspond to migratory epidermal LCs on their route to the skin draining LNs. In addition to skin-derived migratory DCs, blood-derived Langerin

−

CD8

+

and Langerin

+

CD8

+

DCs, as well as CD8

–

DC can be identified in the cLNs.

Figure 4.3 Langerin knock-in mice (a) Schematic representation of different final recombinant langerin genes. (b) Efficient and specific ablation of LCs. Fixed epidermal sheets from Lang-eGFP mouse (i) showing Langerin expressing cells (white) that are not eliminated after DT administration (iii). Epidermal sheets form hDTR-eGFP mouse (ii) showing eGFP

+

cells corresponding to LCs that are efficiently eliminated 24 h post DT administration (iv). All panels (confocal images) correspond to 206.8 × 206.8 × 10.4 µm.

Figure 4.4 Dendritic cell – T cell activation and polarisation. Naïve CD8

+

T cells differentiate into effector CTLs, while naïve CD4

+

T cells, once activated, can differentiate into various CD4

+

T helper subsets. This differentiation depends on the presence of cytokines implicated in induction of important transcription factors leading to formation of distinct subsets. The different CD4

+

T cell subsets produce various cytokines and perform effector functions accordingly. Main populations of CD4

+

T cells, the factors inducing them and their effector profiles are shown.

Chapter 05

Figure 5.1 Schematic representation of the bricks and mortar structure of the SC, showing the lamellar and possible lateral organisation of the intercellular lipids.

Chapter 06

Figure 6.1 Three pathways for nanoparticle penetration through skin. The three major sites involved in nanoparticle delivery through skin are stratum corneum (SC) surface (a), furrows (dermatoglyphs) (b) and openings of hair follicles (infundibulum) (c). D and E are dermis and epidermis.

Figure 6.2 Schematic representation of various nanocarriers used for transdermal delivery of therapeutics.

Figure 6.3 Schematic representation of internalisation pattern of PAMAM dendrimers with various surface groups.

Chapter 07

Figure 7.1 High-gradient magnetic field–induced curvature in plant root by the virtue of displacement of amyloplasts (diamagnetic) in the direction of magnetic field.

Figure 7.2 In vitro experimental set-up for magnetophoretically assisted transdermal drug delivery.

Figure 7.3 Graphical representation of a magnetophoretic transdermal patch.

Figure 7.4 Diagrammatic representation of charges in an electret.

Figure 7.5 Effect of different corona-charged electret () on in vitro transdermal enhancement of methyl salicylate as compared with control group ().

Chapter 08

Figure 8.1 Schematic representation of drug delivery using liquid jet injector: (a) formation of liquid jet, (b) initiation of hole formation due to impact of jet on skin surface, (c) development of hole inside skin with progress of injection and (d) deposition of drug at the end of hole in a near spherical or hemispherical pattern (spherical pattern shown).

Figure 8.2 Schematic representation of iontophoresis-mediated transdermal drug delivery.

Figure 8.3 Histological analysis of laser-microporated (using P.L.E.A.S.E. device) mouse skin. Upper left: top view of an array of micropores (500 pores/cm

2

). Paraffin section and SEM picture of a single micropore generated with four laser pulses delivered at 1.9 J/cm

2

/pulse (upper right) or eight laser pulses delivered at 0.76 J/cm

2

/pulse (bottom).

Figure 8.4 Schematic presentation of RF-microchannels.

Chapter 09

Figure 9.1 Commercialised MN devices for intradermal delivery: (a) BD Soluvia prefillable MN device and (b) NanoPass Technologies Ltd. MicronJet single-use, MN-based device.

Figure 9.2 (a1) Schematic representation of solid MNs for skin pre-treatment and application of drug-loaded reservoir. (a2) Digital image of solid metallic MNs. (a3) Scanning electron micrograph (SEM) image of stainless steel solid MNs. (b1) Schematic representation of coated MNs for deposition of drug-containing layer in the skin. (b2) Digital image of dip-coated MNs containing Vitamin-B

2

. (b3) SEM image of stainless steel coated MNs. (c1) Schematic representation of dissolving MNs for delivery of incorporated drug into the skin. (c2) Digital image of dissolving MNs composed of chondroitin sulphate. (c3) SEM image of trehalose dissolving MNs. (d1) Schematic representation of hollow MNs for insertion into the skin and infusion of drug via the MN pore. (d2) Digital image of 3M hollow Microneedle Transdermal System (hMTS) polymeric MN array. (d3) SEM image of hollow silicon MN array. (e1) Schematic representation of swelling MNs for drug delivery through hydrogel matrix in ‘dry’ and ‘swollen’ form. (e2) Digital image of swollen MNs composed of cross-linked PMVE/MA and PEG 10 000. (e3) SEM image of MNs composed of cross-linked PMVE/MA and PEG 10 000.

Figure 9.3 Schematic representation of the key steps in the photolithographic method of MN fabrication: (i) silicon wafer, (ii) silicon wafer coated with silicon oxide, (iii) photo-resistive material applied by spin coating, (iv) high-intensity UV light applied in conjunction with a protective veneering agent, (v) positive resist and (vi) negative resist.

Figure 9.4 Schematic representation of the micromoulding technique, often used for the production of polymeric MNs.

Figure 9.5 Schematic illustration of immunisation using dissolving MN arrays loaded with vaccine particles. The vaccine particles, when delivered into the dermis, activate T cells, which are then transported to the cutaneous draining lymph nodes, resulting in clearance of virus.

Figure 9.6 Optical coherence tomographic image showing PMVE/MA MNs (height, 600 µm; width at base, 300 µm; spacing, 50 µm) inserted into human skin in vivo.

Chapter 11

Figure 11.1 Marketed products organised by molecular weight obtained from Citeline’s Pipeline Database.

Figure 11.2 Schematic representation of a Franz cell.

Guide

Cover

Table of Contents

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ADVANCES IN PHARMACEUTICAL TECHNOLOGY

A Wiley Book Series

Series Editors:

Dennis Douroumis, University of Greenwich, UK

Alfred Fahr, Friedrich–Schiller University of Jena, Germany

Jűrgen Siepmann, University of Lille, France

Martin Snowden, University of Greenwich, UK

Vladimir Torchilin, Northeastern University, USA

Titles in the Series

Hot-Melt Extrusion: Pharmaceutical Applications

Edited by Dionysios Douroumis

Drug Delivery Strategies for Poorly Water-Soluble Drugs

Edited by Dionysios Douroumis and Alfred Fahr

Forthcoming titles:

In Vitro Drug Release Testing of Special Dosage Forms

Edited by Nikoletta Fotaki and Sandra Klein

Novel Delivery Systems for Transdermal and Intradermal Drug Delivery

RYAN F. DONNELLY and THAKUR RAGHU RAJ SINGH

School of Pharmacy, Queen’s University Belfast, UK

This edition first published 2015© 2015 John Wiley & Sons, Ltd.

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Library of Congress Cataloging-in-Publication Data

Novel delivery systems for transdermal and intradermal drug delivery / Ryan F. Donnelly, Thakur Raghu Raj Singh.  pages cm Includes bibliographical references and index.

 ISBN 978-1-118-73451-3 (cloth)1. Drug delivery systems. 2. Transdermal medication. 3. Injections, Intradermal. I. Donnelly, Ryan F., editor. II. Singh, Thakur Raghu Raj, editor. RS199.5.N68 2015 615′.6–dc23      2015015480

A catalogue record for this book is available from the British Library.

Unfortunately during the preparation of this book, one of the authors, Dr Sian Lim died in a tragic cycling accident and left behind a wife Evelyn, a daughter Caelyn and a son Elijah. Sian was a brilliant scientist and an expert formulator who was involved in the development of over 20 topical and transdermal medicines that are now on the market. We would like to dedicate this book to his memory.

About the Editors

Ryan F. Donnelly

Ryan Donnelly graduated with a BSc (First Class) in Pharmacy from Queen’s University Belfast in 1999 and was awarded the Pharmaceutical Society of Northern Ireland’s Gold Medal. Following a year of pre-registration training spent in Community Pharmacy, he returned to the School of Pharmacy to undertake a PhD in Pharmaceutics. He graduated in 2003 and, after a short period of post-doctoral research, was appointed to a Lectureship in Pharmaceutics in January 2004. He was promoted to Senior Lecturer in 2009, Reader in 2011 and, in 2013, to a Chair in Pharmaceutical Technology.

Professor Donnelly’s research is centered 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. His bioadhesive patch design was used in successful photodynamic therapy of over 100 patients and this technology has now been licensed to Swedish Pharma AB, for whom Professor Donnelly acts as a Technical Director. Currently, Professor Donnelly’s group is focused on novel polymeric microneedle arrays for transdermal administration of ‘difficult-to-deliver’ drugs and intradermal delivery of vaccines and photosensitisers. His work has attracted funding of approximately £4.5 million, from a wide range of sources, including BBSRC, EPSRC, MRC, the Wellcome Trust, Action Medical Research, the Royal Society and the pharmaceutical and medical devices industries.

Still at a relatively early stage of his career, he has authored over 350 peer-reviewed publications, including 4 patent applications, 3 textbooks and approximately 120 full papers. He has been an invited speaker at numerous national and international conferences. Professor Donnelly is the Associate Editor of Recent Patents on Drug Delivery & Formulation and a member of the Editorial Advisory Boards of The American Journal of Pharmacology and Toxicology, Pharmaceutical Technology Europe, Expert Review of Medical Devices and Journal of Pharmacy & Bioallied Sciences and is Visiting Scientist at the Norwegian Institute for Cancer Research, where he is Associate Member of the Radiation Biology Group.

His work has attracted numerous awards, including the BBSRC Innovator of the Year Award and the American Association of Pharmaceutical Scientists Pharmaceutical Research Meritorious Manuscript Award in 2013, the GSK Emerging Scientist Award in 2012; he is a previous winner of the Royal Pharmaceutical Society’s Science Award (2011), the Queen’s Improvement to Society Award (2011), an Innovation Leader Award from the NHS Research & Development Office (2009) and a Research Scholarship from the Research Council of Norway (2004). In 2013, he was listed in the 40 most influential business leaders in Northern Ireland under the age of 40 by Belfast Media Group. Professor Donnelly’s microneedles work has featured on the front cover of Journal of Controlled Release and BBSRC Business and he has represented BBSRC and the Royal Society of Chemistry at Parliamentary Receptions at Westminster and Stormont, respectively. He has been extensively involved in activities promoting public engagement with science through regular interviews on television and radio and online platforms, such as You Tube, Twitter and Tumblr. His Pharmacists in Schools Programme has made over 100 school visits and his work featured at the 2014 Great British Bioscience Festival.

Thakur Raghu Raj Singh

Thakur Raghu Raj Singh is Lecturer in Pharmaceutics at the School of Pharmacy, Queen’s University Belfast. Dr Singh’s research interests lie in the design and physicochemical characterisation of advanced polymeric drug delivery systems for ocular, transdermal and topical applications. In particular, his current research involves fabrication and design of novel long-acting injectable and implantable drug delivery systems for treating chronic ocular diseases. Dr Singh has authored over 90 scientific publications, including 40 full papers and a textbook on microneedles. He has been an invited speaker at a number of national/international meetings.

Dr Singh is currently an Editorial Board Member of the International Journal of Pharmacy and Chronicles of Pharmacy and Scientific Advisor to the editors of the Journal of Pharmaceutical Sciences. He is a reviewer for at least 18 other international scientific journals. Following his appointment as Lecturer in August 2010, he has secured funding of approximately £560 000 from Invest NI, WHO and industry. Dr Singh’s group is currently working on design and development of injectable in situ implant-forming systems for ocular drug delivery, funded by Invest Northern Ireland, and on industrial development of novel non-aqueous-based protein eye drops for the treatment of age-related macular degeneration and diabetic retinopathy.

Contributors

Marc. B. Brown, MedPharm Ltd, Guildford, UK, and School of Pharmacy, University of Hertfordshire, UK

Andrzej M. Bugaj, College of Health, Beauty Care and Education, Poznań, Poland

Francesco Caserta, Department of Pharmacy, University of Hertfordshire, UK

Aaron J. Courtenay, School of Pharmacy, Queen’s University Belfast, UK

Ryan F. Donnelly, School of Pharmacy, Queen’s University Belfast, UK

Charles Evans, MedPharm Ltd, Guildford, UK, and School of Pharmacy, University of Hertfordshire, UK

Chirag Gujral, School of Pharmacy, Queen’s University Belfast, UK

Jonathan Hadgraft, Department of Pharmaceutics, UCL School of Pharmacy, UK

Mary-Carmel Kearney, School of Pharmacy, Queen’s University Belfast, UK

Adrien Kissenpfennig, The Centre for Infection & Immunity, Queen’s University Belfast, UK

Majella E. Lane, Department of Pharmaceutics, UCL School of Pharmacy, UK

Jon Lenn, Stiefel, A GSK Company, USA

Cui Lili, Department of Inorganic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, China

Sian Lim, MedPharm Ltd, Guildford, UK

Rita Mateus, Department of Pharmaceutics, UCL School of Pharmacy, UK

Abhijeet Maurya, School of Pharmacy, The University of Mississippi, USA

William J. McAuley, Department of Pharmacy, University of Hertfordshire, UK

Gary P.J. Moss, School of Pharmacy, Keele University, UK

S. Narasimha Murthy, School of Pharmacy, The University of Mississippi, USA

Lars Norlén, Department of Cell and Molecular Biology (CMB), Karolinska Institute, Stockholm, Sweden and Dermatology Clinic, Karolinska University Hospital, Sweden

Helen L. Quinn, School of Pharmacy, Queen’s University Belfast, UK

Thakur Raghu Raj Singh, School of Pharmacy, Queen’s University Belfast, UK

Venkata K. Yellepeddi, College of Pharmacy, Roseman University of Health Sciences, South Jordan, UT, USA and College of Pharmacy, University of Utah, USA

Marija Zaric, The Centre for Infection & Immunity, Queen’s University Belfast, UK

Advances in Pharmaceutical Technology: Series Preface

The series Advances in Pharmaceutical Technology covers the principles, methods and technologies that the pharmaceutical industry uses to turn a candidate molecule or new chemical entity into a final drug form and hence a new medicine. The series will explore means of optimizing the therapeutic performance of a drug molecule by designing and manufacturing the best and most innovative of new formulations. The processes associated with the testing of new drugs, the key steps involved in the clinical trials process and the most recent approaches utilized in the manufacture of new medicinal products will all be reported. The focus of the series will very much be on new and emerging technologies and the latest methods used in the drug development process.

The topics covered by the series include the following:

Formulation:

The manufacture of tablets in all forms (caplets, dispersible, fast-melting) will be described, as will capsules, suppositories, solutions, suspensions and emulsions, aerosols and sprays, injections, powders, ointments and creams, sustained release and the latest transdermal products. The developments in engineering associated with fluid, powder and solids handling, solubility enhancement, colloidal systems including the stability of emulsions and suspensions will also be reported within the series. The influence of formulation design on the bioavailability of a drug will be discussed and the importance of formulation with respect to the development of an optimal final new medicinal product will be clearly illustrated.

Drug Delivery:

The use of various excipients and their role in drug delivery will be reviewed. Amongst the topics to be reported and discussed will be a critical appraisal of the current range of modified-release dosage forms currently in use and also those under development. The design and mechanism(s) of controlled release systems including macromolecular drug delivery, microparticulate controlled drug delivery, the delivery of biopharmaceuticals, delivery vehicles created for gastrointestinal tract targeted delivery, transdermal delivery and systems designed specifically for drug delivery to the lung will all be reviewed and critically appraised. Further site-specific systems used for the delivery of drugs across the blood–brain barrier including dendrimers, hydrogels and new innovative biomaterials will be reported.

Manufacturing:

The key elements of the manufacturing steps involved in the production of new medicines will be explored in this series. The importance of crystallisation; batch and continuous processing, seeding; and mixing including a description of the key engineering principles relevant to the manufacture of new medicines will all be reviewed and reported. The fundamental processes of quality control including good laboratory practice, good manufacturing practice, Quality by Design, the Deming Cycle, Regulatory requirements and the design of appropriate robust statistical sampling procedures for the control of raw materials will all be an integral part of this book series.

An evaluation of the current analytical methods used to determine drug stability, the quantitative identification of impurities, contaminants and adulterants in pharmaceutical materials will be described as will the production of therapeutic bio-macromolecules, bacteria, viruses, yeasts, moulds, prions and toxins through chemical synthesis and emerging synthetic/molecular biology techniques. The importance of packaging including the compatibility of materials in contact with drug products and their barrier properties will also be explored.

Advances in Pharmaceutical Technology is intended as a comprehensive one-stop shop for those interested in the development and manufacture of new medicines. The series will appeal to those working in the pharmaceutical and related industries, both large and small, and will also be valuable to those who are studying and learning about the drug development process and the translation of those drugs into new life saving and life enriching medicines.

Dennis Douroumis

Alfred Fahr

Jűrgen Siepmann

Martin Snowden

Vladimir Torchilin

Preface

Medicines have been delivered across the skin since ancient times. However, the first rigorous scientific studies involving transdermal delivery seeking to determine what caused skin to have barrier properties that prevent molecular permeation were not carried out until the 1920s. Rein proposed that a layer of cells joining the skin’s stratum corneum (SC) to the epidermis posed the major resistance to transdermal transport. Blank modified this hypothesis after removing sequential layers of from the surface of skin and showing that the rate of water loss from skin increased dramatically once the was removed. Finally, Scheuplein and colleagues showed that transdermal permeation was limited by the by a passive process. Despite the significant barrier properties of skin, Michaels and coworkers measured apparent diffusion coefficients of model drugs in the and showed that some drugs had significant permeability. This led to the active development of transdermal patches in the 1970s, which yielded the first patch approved by the United States Food and Drug Administration in 1979. It was a 3-day patch that delivered scopolamine to treat motion sickness. In 1981, patches for nitroglycerin were approved. Understanding of the barrier properties of skin and how they can be chemically manipulated was greatly enhanced in the 1980s and early 1990s through the work of Maibach, Barry, Guy, Potts and Hadgraft. Today there are a number of transdermal patches marketed for delivery of drugs such as clonidine, fentanyl, lidocaine, nicotine, nitroglycerin, oestradiol, oxybutynin, scopolamine and testosterone. There are also combination patches for contraception, as well as hormone replacement.