Percutaneous Penetration Enhancers

Preface
Contents
Contributors

Part I: Factors Influencing Percutaneous Drug Penetration

1: Basic Mathematics in Skin Absorption
1.1 Mathematical Background of Analyzing Skin Absorption Processes
1.2 Analysis of Skin Permeation
1.2.1 Dealing with Infinite Dose Skin Permeation
1.2.2 Dealing with Finite Dose Skin Permeation
1.3 Analysis of Skin Penetration
1.3.1 Skin-Concentration Depth Profiles
1.3.2 Skin Compartmental Approaches
1.4 Advanced Mathematical Approaches for Studying Skin Absorption
1.4.1 Laplace Domain Solutions
1.4.2 Numerical Diffusion Models
1.5 In Vitro–In Vivo Correlation (IVIVC)
1.6 Tips and Tricks
1.6.1 Infinite Sums in Analytical Solutions
1.6.2 Fitting of Experimental Data
References
2: Occlusive Versus Nonocclusive Application in Transdermal Drug Delivery
2.1 Introduction
2.2 Permeability Barrier of Human Skin
2.3 Enhancing Effect of Occlusion on Transdermal Delivery
2.4 Delivery Systems Utilizing the Method of Application
2.4.1 TransfersomesTM
2.4.2 Supersaturable Transdermal Delivery Systems
References
3: Finite and Infinite Dosing
3.1 Introduction
3.2 Skin Absorption Kinetics
3.2.1 Permeation Kinetics
3.2.1.1 Infinite-Dose Permeation
3.2.1.2 Finite-Dose Permeation
3.2.2 Penetration Kinetics
3.2.2.1 Infinite-Dose Penetration
3.2.2.2 Finite-Dose Penetration
References
4: Non-formulation Parameters That Affect Penetrant-Skin-Vehicle Interactions and Percutaneous Abso
4.1 Introduction
4.2 Skin Responsiveness as It Applies to Targets for Drugs and Cosmetics
4.3 Structure-Permeation Relationship in Percutaneous Absorption
4.4 Permeation Through Intact Epidermis
4.5 Physicochemical Properties That Favour Appendageal Permeation
4.6 Physicochemical Properties That Favour Direct Subcutaneous and Deeper Tissue Permeation
4.7 Skin Hydration and Percutaneous Absorption
4.8 Age-Related Skin Barrier Performance
4.9 Site-Related Skin Barrier Performance
4.10 Gender-Related Skin Barrier Performance
4.11 Barrier Performance in Cosmetically Treated Skin
4.11.1 Insect Repellents
4.11.2 Chemical Depilatories
4.11.3 Peeling Agents
4.11.4 Other Cosmetic Products
4.12 Compromised Barrier Performance
4.12.1 Intrinsic Barrier Defects
4.12.2 Thermally Damaged Skin and Its Manipulation
4.13 Prevention of Percutaneous Permeation: A Possibility and a Necessity
References
5: The Influence of Emollients on Dermal and Transdermal Drug Delivery
5.1 Introduction
5.2 Current Emollients, Their Modes of Action, and Their Use in Practice
5.2.1 Sebum
5.2.2 Emollient Classes and Properties
5.2.3 Effect of Emollients on Skin Lubrication
5.2.4 Effect of Emollients on Skin TEWL and Skin Hydration
5.2.5 Emollient Substantivity
5.2.6 An Overall Comparison of Emollient Properties
5.3 Effects of Emollients on Percutaneous Absorption
5.3.1 How Do the Various Emollients Differ in their Ability to Dissolve and Release Different A
5.3.2 How Do the Emollients Differ in their Ability to Affect and Enter the Skin (Size and So
5.3.3 What Do Other Ingredients in a Moisturizing Formulation Do to Enhance or Inhibit the Effe
5.4 Practical Aspects
References
6: The Effects of Vehicle Mixtures on Transdermal Absorption: Thermodynamics, Mechanisms, Assessme
6.1 Introduction
6.2 Thermodynamics of Mixtures
6.2.1 Solubility
6.2.2 Partition Coefficient
6.2.3 Diffusion
6.3 Potential Mechanisms of Interaction
6.3.1 Skin Surface
6.3.2 Stratum Corneum
6.3.3 Epidermis and Dermis
6.4 Experimental Assessment of Interactions
6.4.1 Diffusion Cells
6.4.2 Isolated Perfused Porcine Skin Flap
6.4.3 Model Membrane Systems
6.5 Predicting Absorption from Complex Vehicle Mixtures
References
7: Mechanistic Studies of Permeation Enhancers
7.1 Introduction
7.2 Methods
7.2.1 Animal Model
7.2.2 Transport Experiments
7.2.2.1 Permeability Coefficient Determination
7.2.2.2 Reversibility Study
7.2.2.3 Model Description and Analysis of Experimental Data
7.2.2.4 Permeant Solubility Determination
7.2.2.5 Determination of Partition Coefficient in Bulk Organic Solvent/PBS Systems
7.2.3 Partition Experiments
7.2.3.1 n-Heptane Treatment and SC preparation
7.2.3.2 HMS SC Delipidization
7.2.3.3 Partition Experiments with Heptane-Treated and Delipidized HMS SC
7.2.3.4 Permeant Partitioning into the Transport Rate-­Limiting Domain and Equilibrium Permeant
7.3 Results and Discussion
7.3.1 Isoenhancement Concentrations and Enhancer Effects
7.3.2 Effects of Alkyl Chain Length
7.3.3 Effects of Polar Head Functional Groups
7.3.4 Effects of Hydrocarbon Chain Carbon–Carbon Double Bond
7.3.5 Effects of Branched Alkyl Chain
7.3.6 Equilibrium Partition Enhancement of ES into SC Intercellular Lipids
7.3.7 Transport Rate-Limiting Domain and Equilibrium Partitioning Domain
7.3.8 Effects of Permeation Enhancement on Permeants of Different Molecular Sizes
7.3.9 Permeation Enhancers in a Nonaqueous System in Transdermal Drug Delivery
References
8: High Throughput Screening of Transdermal Penetration Enhancers: Opportunities, Methods, and App
8.1 Introduction
8.2 Overview of INSIGHT Screening
8.2.1 Skin Impedance–Skin Permeability Correlation
8.3 Validation of INSIGHT with FDC
8.4 Applications of INSIGHT Screening
8.4.1 Discovery of Rare Formulations
8.4.2 Generation of Database for Quantitative Understanding
References

Part II: Methods for Measuring the Percutaneous Drug Penetration

9: Models, Methods, and Measurements in Transdermal Drug Delivery
9.1 Introduction
9.1.1 Transdermal Drug Delivery
9.1.2 Scope of Review
9.2 Structure of Skin
9.2.1 Ultra-structure of Stratum Corneum
9.2.2 Lipids of Stratum Corneum
9.2.2.1 Ceramides
9.2.2.2 Cholesterol
9.2.2.3 Fatty Acids
9.2.3 Proteins of Stratum Corneum
9.3 Routes of Permeation
9.3.1 Skin Appendages
9.3.2 Intracellular Route
9.3.3 Intercellular Route
9.4 In Vitro Skin Models
9.4.1 Excised Human skin
9.4.2 Excised Animal Skin
9.4.3 Living Skin Equivalents
9.4.4 Polymers
9.4.5 Lipids
9.5 Evaluation of Skin Permeability In Vitro
9.5.1 Diffusion Measurements
9.5.1.1 Theory
9.5.1.2 Model Solutes
9.5.1.3 Diffusion Cells
9.5.2 Tape Stripping
9.5.2.1 Theory
9.5.3 Impedance Spectroscopy
9.5.3.1 Theory
9.5.4 Infrared Spectroscopy
9.5.4.1 Theory
9.5.5 Trans Epidermal Water Loss
9.6 Evaluation of Skin Permeability In Vivo
9.6.1 Diffusion Measurements
9.6.1.1 Systemic Bioavailability
9.6.1.2 Surface Loss
9.6.2 Pharmacological Response
9.6.3 Other Approaches
References
10: Human Native and Reconstructed Skin Preparations for In Vitro Penetration and Permeation Stu
10.1 Introduction
10.1.1 Needs for In Vitro Skin Absorption Studies
10.1.2 Rate Determining Processes Involved in Skin Absorption
10.1.2.1 Pathways Through the Healthy Skin
10.1.2.2 Pathways Through the Diseased Skin
10.2 In Vitro Barriers for Skin Absorption Studies
10.2.1 Excised Human Skin
10.2.1.1 Full Thickness Skin
10.2.1.2 Dermatomed or Split Skin
10.2.1.3 Epidermis Sheets
10.2.1.4 Stratum Corneum Sheets
10.2.1.5 Skin with Impaired Barrier Function
10.2.2 Animal Skin
10.2.3 Bioengineered Skin
10.2.4 Artificial Skin Surrogates
10.3 In Vitro Experimental Setups for Skin Absorption Studies
10.3.1 Finite Versus Infinite Dosing
10.3.2 Open Versus Occluded Dosing
10.3.3 Diffusion Cells
10.3.4 Barrier Integrity Check
10.3.5 Temperature
10.3.6 Selection of Receptor Fluid
10.3.7 Duration of Exposure and Sampling Period
10.3.8 Quantification Methods
10.3.9 Influence of Thickness of Skin Preparation
10.3.10 Number of Experiments/Replicates
10.3.11 Segmentation of Skin in Different Skin Layers
10.3.11.1 Removal of the Stratum Corneum by Tape Stripping
10.3.11.2 Segmentation of the Deeper Skin Layers Consisting of Viable Epidermis and Dermis (Cry
10.4 Results Obtained from Permeation Studies
10.4.1 Infinite Dosing Studies
10.4.2 Finite Dosing Studies
10.5 Results Obtained from Penetration Studies
References
11: Stripping Procedures for Penetration Measurements of Topically Applied Substances
11.1 Introduction
11.2 Tape Stripping
11.3 Differential Stripping
11.4 Summary
References
12: Application of EPR-spin Probes to Evaluate Penetration Efficiency, Storage Capacity of Nanotr
12.1 Introduction
12.2 Nanocarriers
12.2.1 Invasomes
12.2.2 Core Multishell Nanotransporters
12.2.3 Nanostructured Lipid Carriers
12.3 Electron Paramagnetic Resonance Spectroscopy
12.4 Stable Nitroxide Spin Probes—Aminoxyl Radicals
12.5 Applications
12.5.1 Partitioning of a Drug Within a Carrier
12.5.2 Skin Penetration Enhancement
12.5.3 Stabilization of Nitroxides—Determination of Sustained Release of TEMPO
12.5.4 Further Applications
References
13: Confocal Raman Spectroscopy as a Tool to Investigate the Action of Penetration Enhancers In
13.1 Introduction
13.2 Confocal Raman Microscopy for Cutaneous Absorption Experiments
13.3 Confocal Raman Microscopy for Studying the Mechanism of Action of Penetration Enhancers
13.3.1 Water as Penetration Enhancer
13.3.2 DMSO as a Penetration Enhancer
13.3.3 Iminosulfuranes as Penetration Enhancers
13.4 Penetration Enhancement of Drugs Followed by Confocal Raman Microscopy
13.4.1 Penetration Enhancement of Trans-retinol Followed by Confocal Raman Microscopy
13.4.2 Penetration Enhancement of Various Drugs Followed by Confocal Raman Microscopy
References
14: ATR-FTIR Spectroscopy and the Skin Barrier: Evaluation of Penetration-Enhancement Effects
14.1 Introduction and Theoretical Background
14.2 ATR-FTIR Spectroscopy and Dermal Drug Delivery
14.2.1 Characterisation of the Stratum Corneum by ATR-FTIR Spectroscopy
14.2.2 Influence of Selected Penetration Enhancers and Vehicles on the Skin Barrier
References
15: Confocal Microscopy for Visualization of Skin Penetration
15.1 Introduction
15.2 Confocal Laser Scanning Microscope
15.2.1 Principle of CLSM
15.2.2 Major Advantages of CLSM
15.2.3 Major Disadvantages of CLSM
15.2.4 CLSM Used for Tracking Liposomal Formulations in the Skin
15.2.4.1 Tracking Skin Penetration of Liposomally Entrapped or Un-entrapped Hydrophilic Fluorescen
15.2.4.2 Effect of Vesicle Diameter on Skin Penetration of Liposomally Entrapped Drugs
15.2.4.3 Synergistic Penetration Enhancement Effect of Ethanol and Phospholipids on Topical Drug
15.2.4.4 Terpenes as Penetration Enhancers in Liposomes
15.2.5 Tracking the Penetration of Fluorescence Labels into Hair Follicles
15.2.5.1 Tracking of Fluorescently Labeled Cyclosporin A into Rat Hair Follicles
15.2.5.2 Accumulation of CF and N-Rho-PE Loaded Liposomes in the Human Hair Follicles
15.2.6 The Efficacy of Dermaroller® to Enhance Penetration into the Skin
15.3 Two-Photon Fluorescence Microscopy
15.3.1 Principle of Two-Photon Fluorescence Microscopy
15.3.2 Application of Two-Photon Microscopy in Skin Penetration Experiments
15.4 Confocal Raman Microscopy
15.4.1 Principles of Raman Microscopy
15.4.2 Confocal Raman Microscopy for Skin Penetration Experiments
15.5 Coherent Raman Microscopy
References
16: Clinical Cutaneous Drug Delivery Assessment Using Single and Multiphoton Microscopy
16.1 Introduction
16.2 Cutaneous Applications of Single Photon Microscopy
16.2.1 Characterization of Percutaneous Drug Delivery
16.2.2 Reflectance Microscopy for the Assessment of Therapeutic Changes in the Skin
16.3 Applications of Multiphoton Microscopy
16.3.1 Assessment of the Cutaneous Delivery of Nanoparticle Compounds Using Multiphoton Microsco
16.3.2 Analysing the Skin’s Metabolic Response to Drugs Using Multiphoton Microscopy Fluorescen
16.4 Advancements in Non-­invasive Analysis of Drug Delivery to the Skin Using Multimodal Imag
References
17: Corneoxenometry: A Bioassay Exploring Skin Barrier Breaching
17.1 Introduction
17.2 SPBF Modulation and Corneoxenometry
17.3 Dose-Response Corneoxenometry with Chemical Penetration Enhancers
17.4 Corneoxenometry and Organic Solvents
References

Part III: The Retardation of Percutaneous Drug Penetration

18: Retardation Strategies for Sunscreen Agents
18.1 Introduction
18.2 Cyclodextrins and Photostability
18.3 Transcutol®
18.4 Encapsulation Structures
18.5 Physical Properties of Organic Particulate UV Absorbers
18.6 Inorganic Materials
18.7 Penetration Retarders
18.8 Vehicle Effects
References
19: Retardation of Dermal Release by Film Forming Emulsions
19.1 Introduction
19.2 Manufacture and Characterization of Film Forming Emulsions
19.3 Main Characteristics of Emulsion Films
19.4 In Vitro Performance of Film Forming Emulsions
19.4.1 In Vitro Skin Permeation
19.4.2 In Vitro Skin Penetration
References

Part IV: Current Status of Dermal and Transdermal Drug Delivery

20: Penetration-Enhancement Strategies for Dermal and Transdermal Drug Delivery: An Overview of
20.1 Introduction
20.2 Skin Penetration Enhancement Techniques
20.2.1 Microneedles
20.2.2 Sonophoresis
20.2.3 Electroporation
20.2.4 Magnetophoresis
20.2.5 Thermal Ablation
20.2.6 Photomechanical Waves
20.2.7 Inclusion Complex
20.2.8 Solid Lipid Nanoparticles (SLN)
20.2.9 Microemulsion
20.2.10 Dendrimers
20.2.11 Vesicles
20.2.11.1 Liposomes
20.2.11.2 Niosomes
20.2.11.3 Transfersomes
20.2.11.4 Ethosomes
20.2.11.5 Invasomes
20.3 Synergistic Use of Enhancement Techniques
References
21: Perspectives on Dermal Delivery of Macromolecular Drugs
21.1 Introduction
References
22: Active Enhancement Methods in Transdermal Drug Delivery: Current Status and Future Perspective
22.1 Introduction
22.2 Active Enhancement Strategies
22.3 Moving Forwards
References

Part V: Safety Issues and Ethics in Studies on Dermal and Transdermal Delivery

23: Efficacy, Safety and Targets in Topical and Transdermal Active and Excipient Delivery
23.1 Role of Efficacy/Active Potency in Topical and Transdermal Delivery
23.1.1 Safety and Efficacy-Based Selection of Medication
23.1.2 Systemic Concentration of Solutes and Their Effect on Active Performance
23.1.3 Enhancing Efficacy by Increasing Fractional Solubility of an Active in the Formulation
23.2 Role of Intended Targets on Topical and Transdermal Delivery
23.2.1 Topical Delivery
23.2.2 Targeting of Keratinocytes
23.2.3 Targeting of Melanocytes
23.2.4 Targeting of Langerhans Cells
23.2.5 Targeting of Fibroblasts
23.2.6 Intradermal and Systemic Targeting
23.3 Role of Safety and Active Toxicity in Transdermal Formulation
23.3.1 Mechanisms of Contact and Photo Allergies and Irritations
23.3.2 Testing of Dermatologics, Cosmetics and Their Safety Evaluation
23.3.3 In Vitro Skin Irritancy Tests: A Need for Triangulation
Conclusions
References
24: Ethical Considerations in Research Involving Dermal and Transdermal Drug Delivery
24.1 Introduction
24.2 General Ethical Considerations in Research
24.2.1 General Ethical Principles in Research Involving Human Beings
24.2.2 Ethical Issues in Animal Skin Testing
24.3 Ethical Issues on Skin Absorption Studies
24.3.1 Ethical Issues Related to In Vivo Techniques
24.3.2 Ethical Issues of In Vitro Techniques Involving Human Skins
24.3.3 Ethical Issues in Animal In Vitro Tests
Conclusion
References
Index