Percutaneous Absorption: Drugs, Cosmetics, Mechanisms, Methods, Fourth Edition (Drugs and the Pharmaceutical Sciences)

Focusing on recent advances as well as updating and expanding the scope of topics covered in the previous edition, the fourth edition of Percutaneous Absorption: Drugs, Cosmetics, Mechanisms, Methodology includes new chapters on topics currently impacting the field including chemical mixtures, in-vivo and in-vitro absorption correlations, transcutaneous immunization, and hair follicle penetration. It emphasizes drug delivery techniques such as the use of microneedles, nanosomes, liposomes, microemulsions, phonophoresis, and the enhancement of oligonucleotide drug penetration. The Journal of Applied Cosmetology said the first edition was "indispensable." 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