Percutaneous Penetration Enhancers, Second Edition

by Smith; Eric Wane

• ISBN13: 9780849321528
• ISBN10: 0849321522
• Edition: 2nd
• Format: Hardcover
• Copyright: 2005-11-02
• Publisher: CRC Press

Summary

Thoroughly updated, this second edition is the most comprehensive reference on the methods available for the enhancement of percutaneous penetration. The book examines a broad scope of chemical enhancers and various physical methods of enhancement. The range of chemicals discussed is, arguably, unsurpassed anywhere in the literature. This edition contains comprehensive descriptions of the latest techniques and several chapters cover the modern analytical techniques adapted to assess and measure penetration enhancement. New to this volume are chapters addressing penetration retardation, important for substances such as sunscreen agents, for which skin penetration is not desirable.

Table of Contents

I. INTRODUCTION	1	(64)
Penetration Enhancer Classification	3	(14)
Brian W. Barry
Introduction	4	(1)
Drug Transport Routes through Human Skin	4	(1)
Enhancing Transdermal Drug Delivery	5	(9)
Interactions between Drug and Vehicle	5	(1)
Selection of Correct Drug or Prodrug	5	(1)
Chemical Potential Adjustment	6	(1)
Ion Pairs and Complex Coacervates	7	(1)
Eutectic Systems	7	(1)
Vesicles and Particles	7	(1)
Liposomes and Analogs	7	(1)
High-Velocity Particles	8	(1)
Stratum Corneum Modified	8	(1)
Hydration	8	(1)
Chemical Enhancers	9	(2)
Stratum Corneum Bypassed or Removed	11	(1)
Microneedle Array	11	(1)
Stratum Corneum Ablated	11	(2)
Follicular Delivery	13	(1)
Electrically Assisted Techniques	13	(1)
Ultrasound (Phonophoresis, Sonophoresis)	13	(1)
Iontophoresis	13	(1)
Electroporation	13	(1)
Magnetophoresis	14	(1)
Radio Waves	14	(1)
Photomechanical Wave	14	(1)
References	14	(3)
Structure-Activity Relationship of Chemical Penetration Enhancers	17	(18)
Narayanasamy Kanikkannan
R. J. Babu
Mandip Singh
Introduction	17	(1)
Fatty Acids	18	(4)
Effect of Carbon Chain Length	18	(2)
Saturated and Unsaturated Fatty Acids	20	(1)
Branched versus Unbranched Fatty Acids	20	(1)
Position of Double Bond	21	(1)
Geometric Isomers	21	(1)
Number of Double Bonds	21	(1)
Fatty Alcohols	22	(2)
Fatty Acids versus Fatty Alcohols	24	(1)
Terpenes	24	(2)
Pyrrolidones	26	(2)
Surfactants	28	(1)
Conclusions	29	(1)
References	29	(6)
Quantitative Structure-Enhancement Relationship and the Microenvironment of the Enhancer Site of Action	35	(16)
S. Kevin Li
William I. Higuchi
Introduction	35	(1)
Methods	36	(2)
Quantitative Structure-Enhancement Relationships Based on Aqueous Concentrations of the Enhancer	38	(4)
Quantitative Structure-Enhancement Relationship Based on Enhancer Concentrations in the Stratum Corneum Intercellular Lipids	42	(3)
Microenvironment of the Site of Enhancer Action	45	(1)
Transdermal Drug Delivery	46	(1)
Acknowledgment	47	(1)
References	47	(4)
The Role of Prodrugs in Penetration Enhancement	51	(14)
Kenneth B. Sloan
Scott C. Wasdo
Push versus Pull Mechanisms for Penetration Enhancers	52	(1)
Basis for Prodrugs as Penetration Enhancers	52	(2)
Acyl versus Soft Alkyl Promoieties	54	(1)
Mechanisms for Penetration Enhancement	54	(8)
Decrease Crystal Lattice Energy by Masking Hydrogen Bond Donor Functional Groups	54	(5)
Incorporation of Water Solubility Enhancing Functional Groups into the Promoiety	59	(3)
Conclusion	62	(1)
References	63	(2)
II. VEHICLE EFFECTS IN PENETRATION ENHANCEMENT	65	(110)
Penetration Enhancement by Skin Hydration	67	(6)
Jin Zhang
Carryn H. Purdon
Eric W. Smith
Howard I. Maibach
Christian Surber
Introduction	67	(1)
Stratum Corneum Hydration by Occlusion	68	(1)
Stratum Corneum Hydration by Exogenous Chemicals	69	(1)
Conclusions	70	(1)
References	71	(2)
Enhancement of Delivery with Transdermal Sprays	73	(10)
Barrie C. Finnin
Jonathan Hadgraft
Introduction	74	(1)
Enhancement of Delivery of the Dose to the Skin	75	(1)
Metering Valves	75	(1)
Spray Pattern and Droplet Size	75	(1)
Applicator Design	75	(1)
Control of Area	75	(1)
Volume Delivered Per Unit Area	75	(1)
Containment of Spray	76	(1)
Minimizing Nonproductive Loss	76	(1)
Enhancement of Delivery into the Stratum Corneum	76	(3)
Topology of Skin Surface	76	(1)
Sebum	77	(1)
Available Area	78	(1)
Increase in Thermodynamic Activity of Drug	78	(1)
Evaporation of the Volatile Component of the Vehicle	78	(1)
Choice of Nonvolatile Solvent	78	(1)
Increasing the Solubility of Drug in the Stratum Corneum	78	(1)
Enhancement of Permeation through Skin	79	(1)
Solvent Drag	79	(1)
Effect on Lipid Arrangement	79	(1)
Extraction of Lipids	79	(1)
Selective Extraction of Cholesterol	79	(1)
Enhancement of Bioavailability	80	(1)
Characteristics of Solvents and Enhancers Required for Metered Dose Spray Delivery	80	(1)
Volatile Solvent	80	(1)
Nonvolatile Solvent	80	(1)
Penetration Enhancer	81	(1)
References	81	(2)
Hydrogel Vehicles for Hydrophilic Compounds	83	(12)
Teresa Cerchiara
Barbara Luppi
Hydrogels	83	(4)
Introduction	83	(1)
Physical and Chemical Properties of Hydrogels	84	(3)
Applications of Hydrogels and Patches in Transdermal Delivery	87	(4)
Hydrogels	89	(1)
Transdermal Patches	90	(1)
Conclusions	91	(1)
References	91	(4)
Enhanced Skin Permeation Using Ethosomes	95	(14)
Elka Touitou
Biana Godin
Introduction	95	(1)
Definition, Structure, and the Main Properties of Ethosomes	96	(1)
Mechanism of Skin Permeation Enhancement by Means of Ethosomes	97	(2)
Various Aspects of Ethosomal Delivery System	99	(6)
Efficiency to Enhance Drug Permeation into and through the Skin	99	(1)
Skin Permeation Performance of Ethosomes versus Liposomes and Hydroethanolic Solution	99	(1)
Enhanced In Vitro Delivery of Molecules with Diverse Chemical Properties	100	(2)
Proof of Concept in Animals and in Clinical Trials	102	(2)
Safety Evaluation In Vitro, in Animals and in Human Studies	104	(1)
Stability and Manufacture	104	(1)
Summary	105	(1)
Acknowledgment	106	(1)
References	106	(3)
Microemulsions in Topical Drug Delivery	109	(8)
Sari Pappinen
Arto Urtti
Introduction	109	(2)
Microemulsions in Topical Drug Delivery	111	(3)
Introduction	111	(1)
Solubilization of Drugs by Microemulsions	111	(1)
Microemulsions and Drug Permeability	112	(2)
In Vivo Results	114	(1)
Irritation	114	(1)
Conclusions	114	(1)
References	115	(2)
Nanoparticles as Carriers for Enhanced Skin Penetration	117	(8)
Shozo Miyazaki
Introduction	117	(1)
Microparticles for Enhancing Skin Penetration	118	(1)
Nanoparticles for Enhancing Skin Penetration	118	(1)
PNBCA Nanocapsules as a Carrier for Enhanced Skin Penetration of Indomethacin	119	(3)
Conclusions	122	(1)
References	123	(2)
Solid Lipid Nanoparticles for Topical Delivery	125	(12)
Zhinan Mei
Introduction	125	(1)
Preparation of Solid Lipid Nanoparticles	126	(1)
High Shear Homogenization and Ultrasonic Dispersion	126	(1)
High Pressure Homogenization	126	(1)
Hot Homogenization	127	(1)
Cold Homogenization	127	(1)
Emulsification or Vaporization Method	127	(1)
Microemulsion	127	(1)
Characterization of SLN	127	(1)
SLN Incorporation and Release of Drug	128	(1)
SLN for Topical Delivery	128	(3)
SLN as a Novel Carrier System for Sunscreens	131	(3)
Occlusive Effect of SLN	132	(1)
In Vitro Occlusion of SLN	132	(1)
SLN In Vivo Occlusion	133	(1)
Conclusions	134	(1)
References	134	(3)
Fatty Alcohols and Fatty Acids	137	(22)
R. J. Babu
Mandip Singh
Narayanasamy Kanikkannan
Introduction	137	(1)
General Overview of Fatty Alcohols and Fatty Acids on the Skin Permeation	138	(1)
Fatty Alcohols	139	(5)
Fatty Acids	144	(4)
Effect of Carbon Chain Length of Fatty Acids	145	(1)
Saturated versus Unsaturated Fatty Acids	145	(1)
The Number and Position of Double Bonds in Unsaturated Fatty Acids	146	(1)
Fatty Acid Esters	146	(1)
Chemical Modification of Drugs with Fatty Acids	147	(1)
Mechanism of Penetration Enhancement	148	(2)
Lipid Disruption at the Intercellular Level: The Enhancer Disrupts Stratum Corneum Lipid Organization, Making It Permeable to Drugs	148	(1)
Fatty Acids Form Solvated Complexes or Molar Addition Compounds and Permeate through Skin Simultaneously with Drugs	149	(1)
Fatty Acids Increase the Diffusivity and Partitioning of Drugs and Vehicles through Stratum Corneum	150	(1)
Formulation Considerations	150	(2)
Enhancer Configuration in TDS	150	(1)
Fatty Alcohols and Acids in Transdermal Patches	151	(1)
Skin Irritation Potential	152	(1)
Summary	153	(1)
References	154	(5)
Essential Oils and Terpenes	159	(16)
Rashmi A. Thakur
Yiping Wang
Bozena B. Michniak
Introduction	159	(1)
Structural Classification	160	(2)
Structure-Activity Relationships	162	(1)
Improving Permeation Enhancement Ability of Terpenes	163	(2)
Mechanism of Action of Terpenes	165	(3)
Terpene Derivatives as Enhancers	168	(3)
Conclusions	171	(1)
References	171	(4)
III. PHYSICAL METHODS OF PENETRATION ENHANCEMENT	175	(94)
Iontophoresis: Clinical Applications and Future Challenges	177	(44)
Nada Abla
Aarti Naik
Richard H. Guy
Yogeshvar N. Kalia
Introduction	178	(1)
Principles of Iontophoresis	179	(5)
Mechanisms	179	(1)
Electromigration	180	(1)
Electroosmosis	181	(1)
Practical Considerations	181	(1)
Electrode Choice	181	(1)
Current	182	(1)
Drug Concentration in the Donor	182	(1)
pH	183	(1)
Exisiting Therapeutic Applications of Iontophoresis	184	(9)
FDA Approved Applications	184	(1)
Pilocarpine Delivery for the Diagnosis of Cystic Fibrosis	184	(1)
Tap Water Delivery for the Treatment of Hyperhidrosis	184	(1)
Lidocaine Delivery	185	(2)
The GlucoWatch® Biographer for Noninvasive Glucose Monitoring	187	(2)
E-TRANS® Fentanyl HCI (Ionsys™)---Pending Approval from the FDA	189	(1)
Other Applications of Iontophoresis In Vivo	190	(1)
Physical Medicine	191	(1)
Dentistry and Other Oral Pathologies	191	(1)
Ophthalmology	192	(1)
Otorhinolaryngology	192	(1)
Potential Candidates for Iontophoretic Delivery	193	(15)
Animal Models	193	(1)
Cardiovascular Agents	193	(1)
Dermal Applications	193	(7)
Opioids	200	(1)
Antiinflammatory Agents	201	(1)
Miscellaneous Nonpeptidic Drugs	201	(1)
Protein and Peptide Drugs	201	(3)
Human Studies	204	(1)
Dermal Applications	204	(2)
Opioids	206	(1)
Antiinflammatory Agents	207	(1)
Miscellaneous Nonpeptidic Drugs	207	(1)
Protein and Peptide Drugs	208	(1)
Conclusions	208	(1)
Successes and Opportunities for the Future	208	(1)
Limitations	208	(1)
Remaining Challenges	209	(1)
References	209	(12)
Electroporation	221	(18)
Babu M. Medi
Jagdish Singh
Introduction	221	(1)
Mechanisms of Percutaneous Penetration Enhancement	222	(2)
Expansion of Preexisting Pathways	223	(1)
Creation of New Pathways	223	(1)
Thermal Effects Due to Electroporation	224	(1)
Factors Influencing Percutaneous Penetration Enhancement by Electroporation	224	(4)
Electrical Parameters	224	(2)
Physicochemical Factors	226	(2)
Effects of Electroporation on Skin	228	(4)
Potential Applications	232	(2)
Conclusions and Future Prospects	234	(1)
Acknowledgment	234	(1)
References	235	(4)
Microneedles	239	(18)
Mark R. Prausnitz
John A. Mikszta
Jennifer Raeder-Devens
Introduction	239	(1)
Microneedle Fabrication	240	(4)
Solid Silicon Microneedles	240	(1)
Solid Metal Microneedles	241	(1)
Solid Polymer Microneedles	242	(2)
Hollow Metal Microneedles	244	(1)
Hollow Silicon Microneedles	244	(1)
Microneedle Properties	244	(3)
Insertion into Skin	244	(2)
Avoidance of Pain	246	(1)
Transdermal Delivery Using Microneedles	247	(5)
In Vitro Delivery of Model Compounds	247	(2)
In Vivo Delivery of Peptides and Proteins	249	(2)
In Vivo Delivery of Genetic Material	251	(1)
Discussion and Conclusions	252	(2)
Manufacturing	252	(1)
Optimization of Microneedle Design	252	(1)
Strengths and Limitations of Microneedles	253	(1)
References	254	(3)
Vesicles under Voltage	257	(12)
Michael C. Bonner
Brian W. Barry
Introduction	257	(1)
Iontophoresis	258	(1)
Iontophoresis in Drug Delivery	258	(1)
Pathways of Iontophoretic Transport	258	(1)
Electroporation	259	(1)
Liposomes for Dermal and Transdermal Delivery	259	(1)
Transfersomes® and Analogs --- Ultradeformable Vesicles	260	(1)
Combined Liposomal and Iontophoretic Delivery	261	(2)
Liposomes and Electroporation	263	(2)
Concluding Remarks	265	(1)
References	265	(4)
IV. ASSESSMENT OF PENETRATION ENHANCEMENT	269	(90)
Mechanistic Studies of Permeation Enhancers	271	(22)
S. Kevin Li
William I. Higuchi
Introduction	272	(1)
Methods	273	(5)
Animal Model	273	(1)
Transport Experiments	273	(1)
Permeability Coefficient Determination	273	(1)
Reversibility Study	274	(1)
Model Description and Analysis of Experimental Data	275	(1)
Permeant Solubility Determination	276	(1)
Determinations of Partition Coefficients in Bulk Organic Solvent/PBS Systems	276	(1)
Partition Experiments	276	(1)
n-Heptane Treatment and SC Preparation	276	(1)
HMS SC Delipidization	276	(1)
Partition Experiments with Heptane-Treated and Delipidized HMS SC	277	(1)
Permeant Partitioning into the Transport Rate-Limiting Domain and Equilibrium Permeant Partitioning into the Stratum Corneum Intercellular Lipids	278	(1)
Results and Discussion	278	(12)
Isoenhancement Concentrations and Enhancer Effects	278	(1)
Effects of Alkyl Chain Length	279	(2)
Effects of Polar Head Functional Groups	281	(1)
Effects of Hydrocarbon Chain Carbon--Carbon Double Bond	281	(2)
Effects of Branched Alkyl Chain	283	(3)
Equilibrium Partition Enhancement of ES into SC Intercellular Lipids	286	(1)
Transport Rate-Limiting Domain and Equilibrium Partitioning Domain	286	(1)
Effects of Permeation Enhancement on Permeants of Different Molecular Sizes	287	(2)
Permeation Enhancers in a Nonaqueous System in Transdermal Drug Delivery	289	(1)
Conclusions	290	(1)
Acknowledgment	290	(1)
References	290	(3)
Penetration Enhancer Assessment by Corneoxenometry	293	(6)
Claudine Pierard-Franchimont
Frederique Henry
Emmanuelle Uhoda
Caroline Flagothier
Gerald E. Pierard
Introduction	293	(1)
Corneoxenometry	294	(1)
Corneoxenometry and Dose-Response Effect of Chemical Penetration Enhancers	295	(1)
Corneoxenometry and Organic Solvents	296	(1)
Conclusion	297	(1)
References	297	(2)
Assessment of Vehicle Effects by Skin Stripping	299	(12)
Carryn H. Purdon
Carolina Pellanda
Christian Surber
Eric W. Smith
Introduction	299	(1)
Investigation of the Delivery Vehicle and Skin Reservoir Effect	300	(1)
Investigation of Stratum Corneum Lipid Biochemistry	300	(2)
Bioequivalence Assessments	302	(1)
Lateral Drug Distribution	303	(1)
Corneocyte Quantification	303	(1)
Follicular Penetration	304	(1)
Limitations of Tape Stripping	304	(1)
Conclusions	305	(1)
References	306	(5)
The Use of Skin Alternatives for Testing Percutaneous Penetration	311	(8)
Charles Scott Ashill
Gary W. Bumgarner
Bozena B. Michniak
Introduction	311	(2)
Types of Cultured Skin Models	313	(3)
Epidermal Models	313	(1)
Epiderm™	313	(1)
SkinEthic	314	(1)
Full-Thickness Models	315	(1)
EpidermFT™	315	(1)
Apligraf	315	(1)
Orcel®	315	(1)
Episkin™	315	(1)
Bioengineered-Human Skin Equivalent	316	(1)
Conclusions	316	(1)
References	317	(2)
High Throughput Screening of Transdermal Penetration Enhancers: Opportunities, Methods, and Applications	319	(16)
Amit Jain
Pankaj Karande
Samir Mitragotri
Introduction	319	(3)
Ability to Screen a Large Number of Formulations	321	(1)
Use of a Surrogate End Point That Is Quick, Easy, and Independent of the Physicochemical Properties of the Model Permeant	321	(1)
Low Incubation Times to Further Increase the Throughput and Hence Time Efficiency	321	(1)
Minimal Use of Test Chemicals and Efficient Utilization of Model Membrane such as Animal Skin	322	(1)
Adaptability to Automation to Reduce Human Interference	322	(1)
Use of a Common Model Membrane to Represent Human Skin	322	(1)
Use of Consistent Thermodynamic Conditions for Enhancer Formulations	322	(1)
Overview of Insight Screening	322	(2)
Skin Impedance-Skin Permeability Correlation	324	(3)
Validation of Insight with FDC	327	(1)
Applications of Insight Screening	327	(3)
References	330	(5)
Confocal Laser Scanning Microscopy: An Excellent Tool for Tracking Compounds in the Skin	335	(24)
Daya D. Verma
Alfred Fahr
Abstract	336	(1)
Introduction	336	(3)
Confocal Laser Scanning Microscopy (CLSM)	339	(2)
Principles of CLSM	339	(1)
Major Advantages of CLSM	340	(1)
Major Limitations of CLSM	340	(1)
Further Perspectives for CLSM Devices Used for Dermatological Applications	341	(1)
CLSM Used for Tracking Liposomal Formulations into the Skin	341	(9)
Tracking of Entrapped and Un-Entrapped Hydrophilic Fluorescent Compounds in Liposomes into the Skin	341	(1)
Visualization of Marker Substances Encapsulated in Vesicles of Different Diameters on the Skin Penetration	342	(2)
Synergistic Penetration Enhancement Effect of Ethanol and Phospholipids on the Topical Drug Delivery	344	(3)
Visualization of Enhanced Penetration from Nanocarriers Containing Penetration Enhancers into the Skin	347	(1)
Penetration Studies Using Rat Abdominal Skin	348	(1)
Penetration Studies Using Double-Labeled Vesicles	349	(1)
Tracking of Fluorescence Labels into Hair Follicles	350	(1)
Tracking of Fluorescently Labeled Cyclosporin A into the Rat Hair Follicles	350	(1)
Accumulation of Liposomally Entrapped Rho-PE and CF into the Human Hair Follicles	350	(1)
The Efficacy of Top-Rol® Dermaroller for Substance Penetration into the Skin	351	(2)
Concluding Remarks	353	(1)
References	354	(5)
V. THE RETARDATION OF PERCUTANEOUS PENETRATION	359	(40)
Fundamentals of Retarding Penetration	361	(12)
Jonathan Hadgraft
Barrie C. Finnin
Introduction	361	(1)
Nature and Structure of Skin	362	(1)
Physicochemical Determinants	363	(1)
Reducing Skin Absorption---Possibilities	364	(1)
Effects of Chemical Structure	364	(3)
Formulation Effects	367	(1)
Conclusions	368	(1)
References	369	(4)
Retardation Strategies for Sunscreen Agents	373	(12)
Carryn H. Purdon
Eric W. Smith
Christian Surber
Introduction	373	(1)
Cyclodextrins and Photostability	374	(1)
Transcutol®	375	(1)
Encapsulation Structures	375	(2)
Physical Properties of Organic Particulate UV-Absorbers	377	(1)
Inorganic Materials	377	(1)
Penetration Retarders	378	(1)
Vehicle Effects	379	(1)
Conclusions	379	(1)
References	380	(5)
Military Perspectives in Chemical Penetration Retardation	385	(14)
Ernest H. Braue, Jr.
Bryce F. Doxzon
Horace L. Lumpkin
Kelly A. Hanssen
Robert S. Stevenson
Robin R. Deckert
John S. Graham
Introduction	385	(2)
Passive Barrier Creams	387	(1)
Active Barrier Creams	388	(5)
Efficacy Evaluation Methods	389	(2)
Results and Conclusions	391	(2)
Transdermal Chemical Inhibitors	393	(1)
Conclusions	394	(1)
References	395	(4)
VI. COMMERCIAL APPLICATIONS OF PENETRATION ENHANCERS	399	(18)
Preclinical and Clinical Development of a Penetration Enhancer SEPA 0009	401	(16)
Thomas C. K. Chan
Introduction	402	(1)
SEPA	402	(1)
Scientific Rationale for Designing SEPA-Type Compounds	402	(4)
Experimental Data	403	(1)
Physical--Chemical Characteristics of SEPA	404	(1)
How Formulation Affects Skin Permeation Performance	405	(1)
Early Successes with SEPA	406	(3)
Proof of Concept	406	(1)
In Vitro Absorption of Indomethacin	406	(1)
In Vivo Percutaneous Absorption	406	(1)
Scalp Hair Growth in Balding Stumptail Macaque	407	(1)
First Clinical Use of SEPA	407	(2)
Nonclinical Evaluations of SEPA	409	(3)
Clinical Safety	412	(1)
Description of Selected Key Clinical Safety and Efficacy Studies	412	(1)
Clinical Programs	412	(2)
Opterone®	412	(2)
EcoNail	414	(1)
Topiglan®	414	(1)
Conclusions	414	(1)
References	415	(2)
Index	417