Percutaneous Absorption. Drugs, Cosmetics, Mechanisms, Methods

Front cover......Page 1
Preface......Page 14
Contents......Page 16
Contributors......Page 32
Mathematical Models in Percutaneous Absorption......Page 38
A. In Vitro Skin Permeability Studies with a Constant Donor Concentration and Sink Receptor Conditions......Page 40
B. Amount and Flux–Time Profiles on Removing the Donor Phase After Reaching the Steady State for Conditions Described in sec. I.A......Page 45
C. In Vitro Permeability Studies with a Constant Donor Concentration and Finite Receptor Volume......Page 46
D. In Vitro Permeability Studies with a Constant Donor Concentration or Defined Input Flux and Finite Clearance of Solute from the Epidermis......Page 49
E. In Vitro Skin Permeability Studies with Finite Donor Volume and Receptor Sink Conditions......Page 51
F. In Vitro Permeability Studies with a Finite Donor Volume and a Finite Clearance from the Epidermis into the Receptor......Page 53
G. In Vitro Skin Permeability Studies with Diffusion Limited Finite Donor and Sink Receptor Conditions......Page 54
H. In Vitro Permeability Studies with Two-Layer Diffusion Limitations in Transport......Page 55
J. SC Heterogeneity......Page 57
B. Release of a Suspended Drug by Diffusion......Page 58
III. COMPARTMENTAL MODELS AS AN ALTERNATIVE TO DIFFUSION MODELS IN PERCUTANEOUS ABSORPTION......Page 59
B. Bioconversion/Metabolism of Solutes in the Skin......Page 61
C. Solute–Vehicle, Vehicle–Skin, and Solute–Skin Interactions......Page 62
D. Effect of Surface Loss Through Processes Such as Evaporation and Adsorption to Skin Surface......Page 63
V. SIMPLE IN VIVO MODELS IN PERCUTANEOUS ABSORPTION A. Compartmental Pharmacokinetic Models......Page 64
B. Diffusion Pharmacokinetic Models......Page 67
C. Physiologically Based Pharmacokinetic and Pharmacodynamic (PBPK/PD) Models......Page 68
E. Penetration into Tissues Underlying Topical Application Site......Page 70
F. Pharmacodynamic Modeling......Page 71
IV. OTHER PROCESSES AFFECTING IN VITRO PERCUTANEOUS ABSORPTION A. Concentration-Dependent Diffusive Transport Processes......Page 60
VI. MODELING WITH FACILITATED TRANSDERMAL DELIVERY A. Iontophoresis......Page 72
VII. PRACTICAL ISSUES IN APPLYING MATHEMATICAL MODELS TO PERCUTANEOUS ABSORPTION DATA......Page 73
VIII. CONCLUSION......Page 74
REFERENCES......Page 75
II. SKIN VIABILITY......Page 82
III. SKIN METABOLISM......Page 83
REFERENCES......Page 85
II. XENOBIOTIC-METABOLIZING ENZYMES......Page 88
III. PHASE I METABOLISM: CYTOCHROME P-450 MONOOXYGENASES......Page 89
A. Isoenzymes of Cytochrome P-450......Page 90
A. Transferases......Page 91
B. Beta-Adrenoceptor Antagonists......Page 93
VI. METABOLISM OF ENVIRONMENTAL XENOBIOTICS......Page 94
A. Polycyclic Aromatic Hydrocarbons......Page 95
A. Dynamic Factors......Page 96
VIII. CONSEQUENCES OF CUTANEOUS XENOBIOTIC METABOLISM......Page 98
REFERENCES......Page 99
I. INTRODUCTION......Page 102
III. PERCUTANEOUS ABSORPTION OF VOLATILE COMPOUNDS......Page 103
IV. PERCUTANEOUS ABSORPTION OF STEROIDS IN HUMANS......Page 105
V. PERCUTANEOUS ABSORPTION OF PHENOLS IN HUMANS......Page 109
VI. DISCUSSION......Page 111
REFERENCES......Page 119
II. REGIONAL VARIATION IN HUMANS......Page 122
III. REGIONAL VARIATION IN ANIMALS......Page 126
IV. APPLICATIONS TO HUMAN RISK ASSESSMENT......Page 128
REFERENCES......Page 129
I. PERCUTANEOUS ABSORPTION MEASUREMENTS......Page 132
II. TRANSEPIDERMAL WATER LOSS MEASUREMENTS......Page 133
REFERENCES......Page 141
A. Water......Page 144
B. Water: Finite and Infinite Doses......Page 148
C. Soil......Page 149
E. Skin Contact Time......Page 152
II. DISCUSSION......Page 153
REFERENCES......Page 157
II. MATERIALS AND METHODS......Page 160
C. Measurement of the Thickness of the Stratum Corneum......Page 161
E. Theory and Data Treatment......Page 163
IV. DISCUSSION......Page 165
ACKNOWLEDGMENTS......Page 172
REFERENCES......Page 173
II. INTRODUCTION......Page 176
A. Protein Contact Dermatitis and Contact Urticaria......Page 177
C. Skin Conditions and Enzymes......Page 179
A. Ovalbumin......Page 180
B. Latex Proteins......Page 182
B. Latex Protein Penetration......Page 183
C. Penetration of Other Macromolecules......Page 184
VI. STRATUM CORNEUM STRUCTURE AND BARRIER DISRUPTION......Page 185
VII. CONCLUSIONS......Page 186
REFERENCES......Page 187
I. INTRODUCTION......Page 192
II. RISK ASSESSMENT......Page 193
III. MECHANISMS OF INTERACTIONS......Page 194
IV. IMPACT OF MULTIPLE INTERACTIONS......Page 197
V. CONCLUSIONS......Page 198
REFERENCES......Page 199
I. INTRODUCTION......Page 202
II. MODELING DERMAL ABSORPTION AND DESQUAMATION......Page 203
III. RESULTS AND DISCUSSION......Page 204
ABBREVIATIONS......Page 211
REFERENCES......Page 212
I. ABSTRACT......Page 214
B. Structure......Page 215
C. Appendages......Page 216
III. TRANSDERMAL AND DERMAL DELIVERY......Page 219
B. Analysis Methods for Follicular Delivery......Page 220
REFERENCES......Page 225
Evaluation of Stratum Corneum Heterogeneity......Page 230
II. THE ROLE OF APPENDAGES AND THE SKIN’S POLAR PATHWAY......Page 231
III. THE ROLE OF CORNEOCYTES IN THE STRATUM CORNEUM BARRIER......Page 232
IV. THE INFLUENCE OF ASYMMETRY ON SC TRANSPORT......Page 234
V. DISCUSSION......Page 244
ABBREVIATIONS......Page 245
REFERENCES......Page 246
I. INTRODUCTION......Page 250
III. HISTORICAL PERSPECTIVE ON THE STRATUM CORNEUM RESERVOIR FOR DRUGS......Page 251
A. Diffusivity......Page 252
B. Stratum Corneum Partitioning or Capacity......Page 254
VI. STRATUM CORNEUM RESERVOIR AND SUBSTANTIVITY......Page 255
VII. MODELING THE VASOCONSTRICTOR EFFECT ASSOCIATED WITH THE CORTICOSTEROID RESERVOIR......Page 257
VIII. CHANGES IN PLASMA STEROID LEVELS ASSOCIATED WITH THE CORTICOSTEROID RESERVOIR......Page 260
IX. ROLE OF DESQUAMATION ON STRATUM CORNEUM RESERVOIR EFFECT......Page 261
X. STRATUM CORNEUM RESERVOIR FOR OTHER SOLUTES......Page 263
XI. VIABLE EPIDERMIS AND DERMAL RESERVOIR......Page 265
XII. IN VITRO–IN VIVO CORRELATIONS......Page 267
XIII. CONCLUSION......Page 268
REFERENCES......Page 269
II. PERCUTANEOUS ABSORPTION IN VITRO......Page 272
III. PERCUTANEOUS ABSORPTION IN VIVO A. Animals......Page 274
B. Man......Page 275
IV. DISCUSSION......Page 277
Table 1......Page 279
REFERENCES......Page 280
I. INTRODUCTION......Page 284
II. MATERIALS AND METHODS......Page 285
III. RESULTS......Page 287
IV. DISCUSSION......Page 290
REFERENCES......Page 292
II. METHOD ANALYSES: ATRAZINE......Page 294
III. METHOD ANALYSES: BORATES......Page 295
IV. SOLVENTS......Page 297
V. LIMITATIONS......Page 298
REFERENCES......Page 299
III. DIFFUSION CELL......Page 302
VII. RECEPTOR FLUID......Page 303
IX. DETERMINATION OF ABSORPTION......Page 304
REFERENCES......Page 305
II. MODIFICATION OF RECEPTOR FLUID......Page 308
V. FATE OF ABSORBED MATERIAL IN SKIN......Page 309
REFERENCES......Page 312
I. IN VIVO DECONTAMINATION MODEL......Page 314
II. IN VITRO DECONTAMINATION MODEL......Page 318
III. EFFECTS OF OCCLUSION AND EARLY WASHING......Page 319
IV. TRADITIONAL SOAP AND WATER WASH AND EMERGENCY SHOWER......Page 322
V. CONCLUSION: SUBSTANTIVITY......Page 324
REFERENCES......Page 325
I. INTRODUCTION......Page 328
II. PHSC AND PHYSICAL–CHEMICAL PROPERTIES OF STRATUM CORNEUM......Page 329
III. PHSC AND CHEMICAL PARTITIONING......Page 330
V. PHSC AND THE SKIN BARRIER FUNCTION......Page 332
VII. PHSC AND ENVIRONMENTALLY HAZARDOUS CHEMICALS......Page 333
VIII. PHSC AND CHEMICAL DECONTAMINATION......Page 334
X. PHSC AND QSAR PREDICTIVE MODELING......Page 335
XI. DISCUSSION......Page 337
REFERENCES......Page 338
II. GLYPHOSATE (WATER-SOLUBLE HERBICIDE)......Page 340
III. MALATHION (LIPID-SOLUBLE PESTICIDE)......Page 342
IV. PARATHION (LIPID-SOLUBLE PESTICIDE)......Page 343
V. ETHYLENE OXIDE (COLORLESS GAS AT ORDINARY ROOM TEMPERATURE AND PRESSURE)......Page 344
VI. 2-BUTOXYETHANOL (VAPOR)......Page 345
VII. DISCUSSION......Page 346
REFERENCES......Page 347
I. ABSTRACT......Page 348
IV. RESULTS......Page 349
V. DISCUSSION......Page 352
REFERENCES......Page 353
I. DOSE–RESPONSE IN REAL TIME......Page 354
III. DOSE–RESPONSE INTERRELATIONSHIPS......Page 356
IV. ACCOUNTABILITY (MASS BALANCE)......Page 357
V. EFFECTS OF CONCENTRATION ON PERCUTANEOUS ABSORPTION......Page 358
VII. CONCENTRATION AND WATER TEMPERATURE......Page 361
IX. CONCENTRATION, DURATION OF CONTACT, AND MULTIPLE-DOSE APPLICATION......Page 362
XI. EFFECT OF APPLICATION FREQUENCY......Page 363
XIII. DISCUSSION......Page 364
REFERENCES......Page 365
I. INTRODUCTION......Page 368
B. Advantages......Page 369
III. CONCEPTS AND DESIGN OF EXPERIMENTAL STUDIES USING LDF A. Planning and Performing LDF Blood Flow Measurements......Page 370
A. Skin Physiology, Pharmacology, and Pathology......Page 372
B. General Conditions and Diseases......Page 376
V. CONCLUSION AND FUTURE PROSPECTS......Page 386
REFERENCES......Page 387
I. INTRODUCTION......Page 398
II. SAMPLING TECHNIQUES A. Suction Blister Technique......Page 399
B. Cantharidin Blister Technique......Page 400
D. Surface Recovery......Page 401
F. Sebum Collection......Page 402
G. Hair and Nail Collection......Page 403
H. Skin Biopsy......Page 404
I. Microdialysis......Page 407
III. ANALYTICAL TECHNIQUES A. Autoradiography......Page 408
B. Fluorescence......Page 410
C. Sample Collection and Drug Analysis: Critical Parameters......Page 411
IV. C CONCEPT: RELATIONSHIP OF SKIN TARGET SITE FREE DRUG CONCENTRATION (C) TO THE IN VIVO EFFICACY......Page 412
REFERENCES......Page 413
Stripping Method for Measuring Percutaneous Absorption In Vivo......Page 420
I. IN VIVO RELATIONSHIP BETWEEN STRATUM CORNEUM CONCENTRATION AND PERCUTANEOUS ABSORPTION......Page 421
II. INFLUENCE OF APPLICATION CONDITIONS ON THE RELATIONSHIP BETWEEN STRATUM CORNEUM CONCENTRATION AND PERCUTANEOUS ABSORPTION A. Influence of Application Time......Page 424
B. Influence of Dose Applied......Page 426
C. Influence of Vehicle......Page 427
D. Influence of Anatomical Site......Page 429
REFERENCES......Page 433
II. APPLICATION OF THE TAPE-STRIPPING TECHNIQUE IN DERMATOPHARMACOLOGY......Page 436
IV. PROTOCOL OUTLINE FOR A TAPE-STRIPPING EXPERIMENT......Page 440
V. UNANSWERED QUESTIONS AND CONCERNS......Page 441
VI. RELATED TECHNIQUES......Page 443
REFERENCES......Page 444
I. INTRODUCTION......Page 448
III. HAIR FOLLICLE AND SEBACEOUS GLAND ANATOMY......Page 449
IV. ANIMAL MODELS A. Hairless Animals......Page 450
C. Syrian Hamster Ear......Page 454
A. Radiolabel Deposition......Page 455
D. Confocal Laser Scanning Microscopy......Page 456
G. Pharmacological Effect......Page 457
I. Gene Expression......Page 458
A. Liposomes......Page 459
B. Polymeric Microspheres......Page 462
REFERENCES......Page 463
II. MATERIALS AND METHODS A. Chemicals......Page 466
C. Human Exposure Conditions......Page 467
E. PBPK Model......Page 468
III. RESULTS......Page 470
IV. DISCUSSION......Page 472
REFERENCES......Page 473
II. MATERIALS AND METHODS A. Radioisotopes and Chemicals......Page 476
D. Skin Membrane/Water Partition Coefficient Determination......Page 477
III. RESULTS A. Partitioning Studies......Page 478
B. Data Relations......Page 481
REFERENCES......Page 483
A. Single Daily Dose Application Over Many Days: Human......Page 486
C. Hydrocortisone Dosing Sequence......Page 489
D. Triple Daily Dose Application: Diclofenac......Page 491
E. Animal Models......Page 492
REFERENCES......Page 493
A. Ultradeformable Liposomes......Page 496
B. Electrical Methods for Enhancing Skin Delivery......Page 497
A. Iontophoresis and Ultradeformable Liposomes......Page 498
B. Electroporation and Ultradeformable Liposomes......Page 502
III. CONCLUDING REMARKS......Page 504
REFERENCES......Page 506
I. INTRODUCTION......Page 510
II. IN VITRO RELEASE TESTING......Page 511
III. DISCUSSION......Page 512
IV. IN VITRO RELEASE-CORTICOSTEROIDS......Page 513
B. Waivers for Lower Strength......Page 515
REFERENCES......Page 516
I. INTRODUCTION......Page 518
A. Surrogate Model......Page 519
IV. DISCUSSION A. Percutaneous Absorption......Page 520
REFERENCES......Page 524
I. INTRODUCTION......Page 526
II. METHODS......Page 527
III. RESULTS AND DISCUSSION......Page 528
REFERENCES......Page 531
A. Creating Nanometer Pathways to Increase Skin Permeability......Page 534
A. Microneedle Delivery Scenarios......Page 535
C. Drug Delivery Using Solid Microneedles......Page 536
D. Drug Delivery Using Hollow Microneedles......Page 537
III. PAIN, SAFETY, AND CONVENIENCE OF MICRONEEDLES......Page 538
A. Avoidance of Pain by Microneedles......Page 540
B. Safety of Microneedles......Page 541
ACKNOWLEDGMENTS......Page 542
REFERENCES......Page 543
A. Percutaneous Absorption......Page 546
B. Regional Variation in Humans......Page 547
C. Individual Variation......Page 549
II. TRANSEPIDERMAL WATER LOSS......Page 551
A. Correlation of Percutaneous Absorption and TEWL......Page 552
REFERENCES......Page 556
I. INTRODUCTION......Page 558
II. PRINCIPLE OF OPERATION......Page 559
A. Dermal Irritation......Page 561
VI. INDUCTION OF LOCAL ANESTHESIA......Page 562
REFERENCES......Page 563
I. ABSTRACT......Page 566
A. Regional Variation Human Percutaneous Absorption......Page 567
C. Chemical Warfare Agents......Page 568
E. Structure and Percutaneous Absorption......Page 569
Table 2......Page 571
Table 3......Page 573
Table 5......Page 581
F. Theoretical Constructs of Percutaneous Absorption and Toxicity......Page 584
III. DISCUSSION......Page 589
REFERENCES......Page 593
I. INTRODUCTION......Page 598
II. STUDIES COMPARING IN VITRO ABSORPTION IN EXCISED SKIN WITH HUMAN VOLUNTEERS OR PRIMATES IN VIVO A. The Influence of the Physicochemical Properties of the Test Compound......Page 599
B. Variability—Relationship Between In Vitro and In Vivo......Page 604
C. The Skin Reservoir In Vitro and In Vivo......Page 605
IV. CONCLUSIONS A. The Design of In Vitro and In Vivo Studies......Page 607
B. Does the Closeness of Predictions Vary with Lipophilicity of Chemicals?......Page 608
REFERENCES......Page 609
I. ABSTRACT......Page 612
IV. PERMETHRIN PHARMACOKINETICS......Page 613
V. SOURCE FOR BIOAVAILABILITY AND BODY BURDEN CALCULATIONS......Page 614
A. Risk Assessment......Page 615
VI. DISCUSSION......Page 616
REFERENCES......Page 617
II. INTRODUCTION A. TEWL......Page 620
D. Main Review Correlation Studies......Page 621
A. Using In Vitro Methods to Model In Vivo Experiments......Page 624
B. Using Animal Skin to Model Human Skin......Page 625
C. Percutaneous Absorption Measurement Methods......Page 626
E. Exploring the Qualitative Reasoning for the Correlation Between Percutaneous Absorption and TEWL......Page 627
REFERENCES......Page 628
I. INTRODUCTION......Page 632
A. Dermal Exposure......Page 633
IV. SAFETY ASSESSMENTS A. Non-carcinogenic Cosmetic Ingredient Safety Evaluation: Assume a Threshold for Toxicity......Page 634
V. CASE STUDY—EXPOSURE ESTIMATE FOR THE DERMALLY APPLIED FRAGRANCE MUSK XYLOL......Page 636
A. RIFM Dermal Exposure Estimate......Page 637
B. Dermal Exposure Estimates Using Monte Carlo Simulation......Page 639
VI. CONCLUSION......Page 640
REFERENCES......Page 641
I. INTRODUCTION......Page 642
B. 2NPPD Materials and Methods......Page 643
C. Results—Skin Penetration......Page 645
D. Results—Rat Skin Metabolism......Page 646
III. DISCUSSION......Page 647
IV. SKIN ABSORPTION OF DISPERSE BLUE 1 A. Introduction......Page 652
B. Disperse Blue 1—Materials and Methods......Page 653
C. Dermal Penetration and Absorption of Disperse Blue 1......Page 654
D. Discussion......Page 655
V. HAIR DYE ABSORPTION: CORRELATION WITH PARTITION COEFFICIENTS......Page 656
VI. CONCLUSION......Page 657
REFERENCES......Page 658
I. EXPERIMENTAL A. Hair Dyes......Page 660
B. Dyeing Procedure......Page 661
D. Radioactivity Determination in Urine......Page 662
A. Application Only......Page 663
B. Application and Wear......Page 669
REFERENCES......Page 670
II. MATERIALS AND METHODS A. Materials......Page 672
B. Oil-in-Water Emulsion Formulations......Page 673
C. Percutaneous Absorption Experiments......Page 674
V. RESULTS......Page 675
VI. DISCUSSION......Page 678
REFERENCES......Page 679
I. INTRODUCTION......Page 680
II. REVIEW OF NAIL PHYSICAL AND CHEMICAL PROPERTIES THAT AFFECT TOPICAL PENETRATION......Page 681
B. Compounds......Page 682
F. Nail Sampling Procedure......Page 683
IV. RESULTS......Page 685
V. DISCUSSION......Page 687
REFERENCES......Page 689
I. INTRODUCTION......Page 692
II. CLASSIFICATION OF TOPICAL VEHICLES......Page 693
III. THE IDEAL VEHICLE......Page 694
IV. THE CHOICE OF VEHICLE......Page 696
REFERENCES......Page 697
I. INTRODUCTION......Page 700
II. INSTRUMENTATION A. Fourier Transform Technique......Page 701
B. Attenuated Total Reflection......Page 702
C. Photoacoustic Spectroscopy: FT-IR–PAS......Page 703
D. IR Microspectroscopy......Page 705
III. PENETRATION OF DRUGS INTO MEMBRANES STUDIED BY FT-IR–ATR......Page 706
IV. PENETRATION OF DRUGS INTO MEMBRANES STUDIED BY FT-IR–PAS......Page 710
V. LATERAL DRUG DIFFUSION STUDIED BY IR MICROSPECTROSCOPY......Page 713
REFERENCES......Page 715
I. INTRODUCTION......Page 718
II. SKIN PERMEATION OF SUNSCREENS A. Data from In Vivo Human Studies......Page 719
B. Data from In Vitro Human Studies......Page 722
C. Animal Models......Page 726
Table 3......Page 729
III. PREDICTION OF THE SKIN PENETRATION OF SUNSCREENS......Page 731
IV. RISKS AND BENEFITS ASSOCIATED WITH TOPICAL SUNSCREEN USE......Page 732
V. CONCLUSIONS......Page 733
REFERENCES......Page 734
I. INTRODUCTION......Page 738
A. Microscopy......Page 739
B. Viscosimetry......Page 740
C. Light and Neutron Scattering......Page 741
III. DERMAL AND TRANSDERMAL DRUG DELIVERY USING MICROEMULSIONS......Page 745
IV. CONCLUSION......Page 751
REFERENCES......Page 752
I. INTRODUCTION......Page 756
II. DEFINITIONS......Page 757
III. PRODUCTION OF LIPID NANOPARTICLES......Page 758
IV. PRODUCTION OF FINAL TOPICAL FORMULATIONS A. Incorporation into Creams and Gels......Page 760
B. Preparation of Lipid Nanoparticle Gels......Page 761
C. Preparation of Lipid Nanoparticle Creams......Page 762
V. PROPERTIES OF LIPID PARTICLES AND EFFECTS ON SKIN A. Stabilization of Chemically Labile Actives......Page 763
D. Skin Hydration and Elasticity......Page 764
E. Modulation of Release and Creation of Supersaturation......Page 766
F. Penetration of Actives......Page 767
G. Prolonged Release of Actives—Sunscreens......Page 769
H. Prolonged Release of Actives—Scents/Perfumes......Page 770
REFERENCES......Page 771
II. INTRODUCTION......Page 776
C. Intensity......Page 777
IV. ULTRASOUND-ENHANCED PERCUTANEOUS ABSORPTION: PHARMACOKINETIC DATA A. Medium (0.8–2 MHz) and High Frequency (3–20 MHz) Phonophoresis......Page 778
B. Low Frequency Sonophoresis (20–150 kHz)......Page 780
V. MECHANISM OF ACTION OF ULTRASOUND ON TRANSDERMAL TRANSPORT......Page 784
A. Heating......Page 785
B. Cavitation......Page 786
VI. BIOLOGICAL CONSEQUENCES OF ULTRASOUND APPLICATION ON SKIN......Page 788
B. Imaging Pathway of Sonophoretic Transport......Page 789
VII. STABILITY OF DRUGS EXPOSED TO ULTRASOUND......Page 790
VIII. PROSPECTS: IS PAINLESS NEEDLE-FREE INJECTION A REALISTIC GOAL?......Page 791
REFERENCES......Page 792
I. INTRODUCTION......Page 796
III. SKIN INTERACTION OF OLIGONUCLEOTIDES......Page 797
V. TAPE STRIPPING......Page 798
VI. ELECTROPORATION AND IONTOPHORESIS......Page 799
VII. ANTISENSE OLIGONUCLEOTIDES SEMISOLID FORMULATIONS......Page 800
VIII. LIPOSOMAL FORMULATIONS......Page 801
IX. FIRST OLIGONUCLEOTIDE DRUG: ISIS 2922......Page 802
REFERENCES......Page 803
I. INTRODUCTION......Page 806
II. BACKGROUND......Page 807
IV. OPTIMIZATION OF DELIVERY......Page 808
V. IMMUNE RESPONSES TO TCI—ADJUVANT AND ANTIGEN IN A PATCH......Page 812
VI. HUMAN STUDIES......Page 814
VII. SUMMARY......Page 821
REFERENCES......Page 822
I. INTRODUCTION......Page 826
III. STRIPPING VS. IMMUNE RESPONSE......Page 827
IV. ELECTROPORATION......Page 828
V. MICROMECHANICAL DISRUPTION METHOD......Page 829
VI. LIPOSOME AND LIPOSOMAL CREAM FORMULATION......Page 830
VII. MICROEMULSION DELIVERY SYSTEM......Page 831
VIII. Th1 AND Th2 RESPONSE OF TOPICAL DNA VACCINE......Page 832
IX. MECHANISM OF TOPICAL DNA VACCINES......Page 833
XI. CONCLUSIONS......Page 834
REFERENCES......Page 835
I. INTRODUCTION......Page 838
A. Vehicle–Drug Interactions......Page 840
B. Vehicle–Skin Interactions......Page 841
D. Vehicle–Drug–Skin Interactions......Page 842
B. Phospholipid Vesicular Carriers......Page 843
C. Polymeric Microspheres......Page 844
IV. CONCLUSIONS......Page 845
REFERENCES......Page 846
I. INTRODUCTION......Page 848
III. STRIPPING FACTORS......Page 849
IV. TAPE STRIPPING VS. PERCUTANEOUS ABSORPTION AND PENETRATION......Page 851
V. TAPE STRIPPING AND TOPICAL VACCINATION......Page 852
VI. UNANSWERED QUESTIONS......Page 854
REFERENCES......Page 855
I. INTRODUCTION......Page 860
II. TOXICITY OF ARSENIC FROM PERCUTANEOUS ABSORPTION......Page 861
C. Geochemical Controls on the Percutaneous Absorption of Arsenic......Page 862
D. Research on Environmentally Relevant Substrates......Page 864
E. Key Considerations in Study Design......Page 865
F. Statistical Evaluation......Page 866
III. STUDY DESIGN......Page 867
A. Test Animals......Page 868
B. Results from Testing of Environmental Samples......Page 869
Table 2......Page 871
Table 3......Page 873
Table 4......Page 875
IV. CONCLUSIONS......Page 876
REFERENCES......Page 878
I. INTRODUCTION......Page 880
II. CLINICAL STUDIES......Page 882
REFERENCES......Page 885
I. INTRODUCTION......Page 888
II. OVERVIEW OF INSIGHT SCREENING......Page 890
III. SKIN IMPEDANCE–SKIN PERMEABILITY CORRELATION......Page 892
IV. VALIDATION OF INSIGHT WITH FDCs......Page 894
V. APPLICATIONS OF INSIGHT SCREENING A. Discovery of Rare Formulations......Page 895
B. Generation of Database for Quantitative Understanding......Page 896
REFERENCES......Page 897
Index......Page 902
Back cover......Page 916