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Index
Abbreviated New Drug Applicat ion, 108, 394395,397,422-423,426
Absorption equation, edge loss and , 318Absorption promoters: see Penetration
enhancersAbsorption rate constant, 313-314, 315
formulation-dependence of, 329-330Accelerants: see Penetration enhancersAccountability, 277, 279-280, 288; seealso
Mass-balance proceduresAcetaminophen, stratum corneum reservoir of,
191,192Acetylsalicyclic acid, percutaneous absorption
application site effects, 176-177application time effects, 174-175
Acne medicationsclinical trials, 411, 428screening test, 133
Acoustic streaming, 100, 101Adhesives, for transdermal delivery systems,
421Adverse effects, toxic level and , 21Age factors, in drug permeability, 246-247Alachlor
animal model testing of, 197-207percutaneous absorption, 198-199, 200
201,204-205scintillation counting, 199-200skin decontamination, 198, 199,201-206
powdered human stratum corneumpartit ioning of, 5
Alkane solubility , as thermodynamic activityindicator, 82-84
n-Alkanols , as permeation test compounds,235-236
n-Alkanols (ConI.)permeability coefficients, versus alkyl chain
length, 239-240, 241, 242, 243, 244,248-249
American Association of PharmacologicalScientists, 421
American Society of Clinical Pharmacology,421
Arninocarb, percutaneous absorption, inanimal models, 343-344
Anatomical application sitesfor New Drug Application studies , 419percutaneous absorption effects of, 175-177,
179,282as permeability factor, 246
Androgens , lipoprotein interactions , 433-434Anesthetics , phonophoresis-mediated delivery,
95Angina pectoris , transdermal drug therapy: see
Nitroglycerin, transdermal deliverysystems
Animal modelsofbioavailability and bioequivalence, 132,
401-402blood sampling from, 134, 138of diseased human skin, 137, 138for drug permeability studies , 251for efficacy and safety assessment, 133-136of human skin, 138, 232-234of percutaneous absorption, 333-349
cat, 345-346cow, 346dog, 345-346dog, hairless, 282, 283dose reponses of, 340-342
437
438
Animal models (COni.)
of percutaneous absorption (COni.)
goat, 345-346guinea pig, 338, 339-340, 344horse, 345-346in vitro species comparison of, 344-345marmoset, 345mouse, 335-336, 339-340, 344nonhuman primates, 334, 335, 337, 338,
339,341-342, 343-344, 345-346pig, 334-336, 346. See also Isolated
perfused porcine skin flaprabbit, 337, 344, 346rat, 336-337, 341-342, 346rat, hairless, 339-340, 344regional variation of, 342-344skin physical and dermatological
parameters of, 345-346Antifungal agents, bioequivalence, 428Antihistamines, transdermal delivery systems,
60-61Anti-inflammatory agents, phonophoresis
mediated delivery, 94-95, 96Antimicrobial agents, over-the-counter, 428
429Antiviral agents, stripping method for, 167Application frequency , effect on percutaneous
absorption, 285-287Application site: see Anatomical application
siteApplication thickness, of dermatological
products, 374, 376, 378Application time , effect on percutaneous
absorption, 174-175ApprovedDrugProducts with Therapeutic
Equivalence Ratings (FDA), 397,423Aroclor , percutaneous absorption, in animal
models, 339Artificial membranes: see Synthetic membranesAutoradiography, whole-body, 135-136Azone, as vehicle, 244
Belladonna, 35Benzene, skin distribution, 277-279Benzo[a)pyrene, percutaneous absorption, 8,
11Benzoic acid
diffusion cell for, 123dose response, 280-281penetration level, 164, 166
INDEX
Benzoic acid (COni .)
percutaneous absorptionanatomical applicat ion site effects, 176-
177in animal models, 341application time effects, 174-175vehicle effects, 167, 168, 169, 170, 171,
172Benzyloxycarbonylmitomycin C, flux rate, 81,
82Beta blockers, transdermal delivery systems,
60-61Bethamethasone dipropionate, bioavailability
assessment, 351-366in vitro release across synthetic membranes,
359-362, 364-365in vitrouptake into stratum corneum, 358
359, 364in vivo/in vitrocomparison, 362-363in vivouptake into stratum corneum, 353
358, 364tape stripping technique for, 352-353, 364
Bethamethasone valerate cream , release rateprofile, 113-114
Bilayersdiffusion in, 73-74, 76, 78, 79drug concentration within, 73-74
Bioavailabilityanimal models of, 132,401-402bioequivalnce's relationship to, 129, 130,
131,132,146blood assay of, 197definitions of, 129-130
problems of, 130-131of regulatory agencies, 130-132
factors affecting, 137, 144-145maximum chemical potential and, 267-268measurement methodology, 132-141 , 184
of cutaneous bioavailability, 136-141in vivo in animal models , 133-136in vivo in humans, 138-141
regulatory guidelines for studies of, 130-131,146
systemic, 12-13absolute, 129-130relative, 129
Bioequivalenceanimal models of, 132, 401-402of antifungal agents, 428bioavailability's relationship to, 129, 130,
131, 132, 146
INDEX
Bioequivalence (Cont.)of generic dermatological products, 131,
393-413criteria for generic substitution, 396-397in vitrodissolution test, 397-400in vivo documentation of, 401-411
government regulation of, 395-396, 426in vitro standard for, 130in vivo documentation of, 138-141 , 401-411
animal models for, 401-402clinical trials for, 411dermatopharmacokinetic studies for, 402-
403pharmacodynamic detector for, 407pharmacodynamic studies for, 405-407pharmacokinetic methodology for, 402,
403-405sensitivity of, 407-408specificity of, 408validation procedure for, 409vasoconstrictor assay for, 409-41 1
Bioequivalent drug products, definition , 130Biological response, as percutaneous absorption
determinant, 13-14Biopsy, for dermatological samples, 403Blood, drug pharmacokinetics in, 22-23
radioactivity assay of, 12-13, 139, 140Blood circulation
dermatological products accumulation in,3" I, 403-405
drug disposition in, 318transdermal drugs accumulation in, 371
Blood clotting, estrogen-related, 434Blood flow, cutaneous, 317
laser Doppler imaging of, 140Blood-level profile, transdermal , 21-23, 59-60Blood sampl ing, from animal models, 134, 138Butanol, permeability coefficient, 249
Cadmiumin vitroshort-term skin exposure to, 9-10percutaneous absorption, time of exposure
effect on, 287Cadmium chloride, powdered human stratum
corneum partitioning of, 4, 5Caffeine, percutaneous absorption, 176-177Capillary bed, drug diffusion into, 380Carcinogens, epidermal assays, 286-287Cat, as animal model, 345-346Cavitation, ultrasound-related, 98-99, 10I
439
Cell culture , as skin substitute, 234Cellulose acetate artificial membrane, 234Center for Drug Evaluation and Research, 419,
420, 421, 423Chemotherapeutic agents, cavitation in
suspensions of, 99Chemotherapy, ultrasound use in, 96Chewing gum, nicotine , 53, 54-56Children , percutaneous absorption/toxicity
relationship in, 167Chimpanzee, as animal model, 345Chiral effects, 418Chromameter,410Chronic exposure absorption studies, 286Cisplatin, uptake in hyperthermia, 216Clinical studies
ofbioequivalence,411FDA guidelines for, 138-139
of comedolytic agents, 411, 428of dermatological products , 229for New Drug Applications, 420-42 Ioftransdermal products, 227
Clonidineconcentration-time profile, 327-329history of, 44pharmacodynamic model, 327-329pharmacokinetic model, 26-28release rate test, 109transdermal systems, 31, 44-47
comparison with other administrationroutes, 422
design, 44-45pharmacodynamics, 46-47pharmacokinetics, 29, 45-46plasma concentration models, 322-324wearing time, 59
Code ofFederal Regulations, 423Co-eluent, 316Comedolytic agents
clinical trials, 411, 428screening test, 133
Compartmental modelof concentration-time profiles
c1onidine, 322-324fentanyl, 320-322indomethacin, 325-326nitroglycerin, 324
of percutaneous absorption, 24-25transdermal, 315
Compliance, in transdermal drug use, 19,59,416
440
Concentration, as permeation factor, 241, 242243
Concentration effects, of dose response, 277,280-283,287-288
Constant delivery, 313Contact dermatitis, transdermal delivery
system-related, 421Corticosteroids; see also Glucorticoids
bioavailability assessment, 351-366in vitro release across synthetic
membranes, 359-362, 364-365in vitrouptake into stratum corneum,
358-359, 364in vivo/in vitrocomparison, 362-364in vivo uptake into stratum corneum, 353
358,364tape stripping technique for, 352-353, 364
bioequivalence assessment, 405-411for generic formulations, 426-428
dose-response relationship, 407-408generic formulations, bioequivalence, 426
428release rate determination, III, 113-115vasoconstrictor assay of: see Vasoconstrictor
assayCortisol, phonophoresis-mediated delivery , 95Cortisone
diffusion cell for, 123percutaneous absorption, in animal models,
338, 339Coumarin, cutaneous permeabiity, 8-9Cow, as animal model, 346Cream
compositional stability, 375corticosteroid release from , 361-362, 363,
364-365release rate determination, 110-115"vanishing", 264vehicle concentration, 244vehicle residue, 370
p-Cresol , methyl-substitutedfree energy of transfer, 76, 77octanol/water partition coefficients, 76, 77,
78structure, 75
Croton Oil-Kerosene Test, 427Crystalline energy changes, in maximum flux,
82-84, 85, 86Crystalline state
comparison with stratum corneum barriermicroenvironment, 84
INDEX
Crystalline state (COni .)permeants' escape from, 70effect on thermodynamic activity, 387
Cyano group-bearing molecules , detection of,140
DDT, percutaneous absorption, 6, 8, IItime of exposure effect on , 287
Decontamination, of skinin alachlor testing, 198, 199,201-206from hydrophilic compounds, 190, 191, 193partition coefficient relationship of, 189-190,
191Deficiency disorders, transdermal replacement
therapy for, 431-432Dehydration, enhancer-related, 261, 268-269Deponit
design, 39plasma levels, 42release profile, 112
Dermatological productsamount of drug per unit area, 376, 377, 378application, 107application site, disease manifestations and ,
376application thickness, 374, 376, 378bioavailabilityassessment, 136-137,376bioequivalence assessment, 136-137,376-
378definition, 226delivery enhancement, 251delivery systems, types of, 374development, 228-229evaporation, 375formulation studies, 228-229high activity maintenance of, 388-389in vitro release method for, 110-115kinetic determinants of delivery of, 378-385
evaporation, 375, 383-385film dry-down rate, 381-382, 383
norms of operation, 374-378quality control of, 107-116,235reapplication frequency , 375-376solution attributes measurement, 388-390systemic accumulation, 371, 376-377, 403-
405measurement, 374
thermodynamic activity, 375-376, 380, 383,385-390
Dermatopharmacokinetic study , ofbioequivalence, 402-403, 404
INDEX
Dermatosis, animal models of, 137, 138Detergents, percutaneous absorption, 285Diaflo ultrafiltration membrane, 234Diethylene glycol, 425Diethyltoluamide, percutaneous absorption, in
animal models, 343-344Diffusion, 379-380
of electrolytes, ultrasound-enhanced, 100electron paramagnetic resonance of, 140lipid pathway, 72-73models, 317as percutaneous absorption process, 314-315polar pathway, 72-73in polymers, 78, 79Stokes-Einstein equation of, 78from thin films, 381, 382-383transbilayer , 73-74, 76, 78, 79ultrasound-enhanced, 99, 100-101
Diffusion cell design, 117-125for cream release profile determination, Ill,
113,114for dissolution testing, 398-400excised skin, 5-7flow-through, 119-124modifications, 123-124one-chambered cell, 118-122two-chambered cell, 117
Diffusion coefficient, 313-314Diffusion resistance, Fick's law of, 6, 117, 313,
314-315,319Dilution, dose-response relationship, 287-288,
409,410Dimeth yl sulfoxide, as vehicle, 244, 245Dinoseb, percutaneous absorption, in animal
models, 279-280, 341-342Diquat, percutaneous absorption, in animal
models, 345Diseased skin
animal models of, 137, 138bioavailability measurement of, 137topical drug concentration in, 139
Dissolution , in vitro, 397-400
Dog, as animal model, 345-346hairless, mosquito repellent testing on, 282,
283Dopamine agonists, transdermal delivery
systems, 60-61Dose response, 277-289
accountability, 277, 279-280, 288in animal models, 340-342
441
Dose response (Cant .)
application frequency, 277, 285-286toxicity-related, 286-287
concentration effects, 277, 280-283, 287-288dilution and , 287-288, 409,410surface area in, 277time of exposure in, 277, 284, 287
Dose-response relationship model,bioequivalence applications of, 406,407,410-411
Drug concentrationas drug permeation factor, 241, 242-243See also Concentration effects
Drug delivery systemsareas of drug delivery of, 370design, 227See also Topical delivery systems;
Transdermal delivery systemsDrug disposition , in systemic circulation, 318Drug EfficacyStudy Implementation Program,
395, 396Drug Price Competition and Patent Term
Restoration Act, 426Drug release, from transdermal systems, 313
314Drug release profile
determination of, 107-116FDA assessment method, 109, 110, Ill ,
112, 113,420product/brand-specific, 109
Drug transp ortfactors affecting, 236-251
age factors, 246-247application site, 246concentration, 241, 242-243enhancers, 247-251hydration , 238lipophilicity, 238-241molecular weight, 240-241racial factors, 247recommendations for, 251-252sex factors, 247solubility, 241-243vehicle/dosage form effects, 243-245, 247
pathwayslipid pathway, 71-72, 73-80, 235, 236polar pathway, 71-74, 235, 236tissue pathway, 235, 236
See also Percutaneous absorption
442
Drug uptakemodels of. 231-235See also Percutaneous absorption
Drug uptake studiesin vivoversus in vitro. 229-231rationale and objectives. 229
Dry-down . formulation activity maintenanceduring. 388. 391; see also Film drydown rate
Duhring Chamber Test. 427Duragesic : see Fentanyl
Ear edema. animal model of. 133Edge loss. 318Efficacy
definition. 327DrugEfficacy Study Implementation
Program, 395. 396in vivoassessment. 133-136regulatory requirements, 421
Electric enhancement. 62-63. 250Electron paramagnetic resonance. 140Emla cream. phonophoresis-mediated delivery.
95Emulsion. 264-266
multiple. 264. 266. 267oil-in-water (o/w). 264-265. 269
evaporative concentration. 375water-in-oil (w/o) . 264. 265-266. 269
Enantiomer ratio . 418Endocrine drugs. transdermal. 431Enhancement
chemical approach. 248. 250-251 ; see alsoEnhancers
electrical. 62-63. 250physical approach, 250
Enhancement factor, 316Enhancer effect, versus vehicle effect, 244, 250
251Enhancers, 261-276, 417
animal model testing of, 344-345bioequivalence and, 422-423as dehydration cause, 261. 268-269effect of, 316-317emulsions, 264
multiple, 264, 266, 267oil-in-water (o/w) , 264-265. 269. 375water-in-oil (w/o), 264, 265-266, 269
liquid preparations, 262-263penetration, 270-275simple suspensions, 263-264
INDEX
Enhancers (COni ,)
stratum corneum effects of. 267-275horny layer mod ified, 261, 268-275horny layer unmodified, 261. 267-268
transdermal drug delivery devices and , 266267
See also VehiclesEnzymes. epidermal. as drug metabolizers. 291,
317Ephedrines, percutaneous pharmacokinetics.
23-24Epidermis. use in permeability studies. 22. 251.
252Erythema inhibition model. 133Estraderm, 48-49. 316Estradiol
diffusion/metabolism model. 317dose accountability assessment. 186. 187.
189.191-192history of. 47-48pharmacokinetics. 29singJe-dose absorption. 286stratum corneum reservoir . 191-192transdermal delivery systems. 31. 47-50.
432-435advantages. 433disadvantages. 433. 434-435enhancers. 316. 372ethanol-driven. 372oral estrogen versus. 58plasma concentration-time profile models.
324, 325release rate test. 109. I 13wearing time . 59
Estradiol-containing products. micronizationof,432
~-Estradiol. in vivopermeation model. 315316
Estrogen. conjugated. 396. 403, 433Estrogen, transdermal delivery systems.
comparison with other administrationroutes , 422
See also Estradiol , transdermal deliverysystems
Estrogen replacement therapy. 422, 431, 432435; see also Estradiol. transdermaldelivery systems
cardiovascular effects of. 433-434Ethanol
as enhancer, 316-317for estradiol. 372
INDEX
Ethanol (Cont.)as enhancer (Cont.)
for fentanyl, 321, 372stratum corneum effects of, 273
permeability coefficient, 248as vehicle, 244
Etofenamate, transdermal delivery system, 31Evaporation
of dermatological products, 375film thickness correlation, 381-382
Excised skin method, 5-7Excreta, radioactivity assays of, 12-13, 139
140,184Excretion rate, as drug delivery indicator, 12
13,23-24, 139-140, 184
Fat, hydration effects of, 269Feasibility studies, of transdermal products,
227Federal Register, bioavailabilityJbioequivalence
definitions of, 130, 136-137Feedback process
in dermatological product development, 229in transdermal product development, 227
228Feldman-Maibach method, 165, 176, 177Fenitrothion, percutaneous absorption, in
animal models, 343-344Fentanyl
concentration-time profile model , 320-322enhancer, 316history of, 50-51pharmacokinetics, 29, 30transdermal delivery systems, 30, 31, 50-52
ethanol-driven, 372wearing time , 59
Fick's law, of diffusion resistance, 6, 117,313,314-315,319
Film dry-down rate, 381-382First-order equation, 3 I3First-pass effect, 19, 28Flow-through diffusion cell, 119-124Fluocinolone, solubility measurement, 389-
390Fluorine group-bearing molecules, detect ion,
140Aux rate, 27
estimation of, 28, 30maximum, 268
prodrug enhancement of, 80-86steady-state equation of, 268
443
Follicleas drug penetration pathway, 136, 137, 138,
379-380radioactivity distribution in, 135, 136
Food, Drug, and Cosmetic Actgeneric drug regulations of, 395-3961938 amendments, 396,4251962 amendments, 396, 4251984 amendments, 396,411 ,426,429
Food and Drug Administration (FDA)Abbreviated New Drug Applications, 108,
394-395,397,422-423,426Approved DrugProducts with Therapeutic
Equivalence Ratings, 397, 423bioavailabilityJbioequivalence definitions of,
130bioequivalence documentation requirement
of, 393, 394, 396-397bioequivalence study guidelines of, 138-139Drug Efficacy Study Implementation
Program , 395, 396drug evaluation responsibility of, 425generic drug bioequivalence requirements of,
396-397New Drug Applications, 108,393,416-422,
426biopharmaceutical issues of, 416-4 I7clinical pharmacology requirements of,
420-421efficacy and safety requirements of, 421in vitro studies for, 4 I9-420in vivostudies for, 419pharmacokinetic issues in, 417-420
Office of Generic Drugs, 423topically-applied drug products testing
requirements of, 107-108transdermal delivery systems regulations
assessment guidelines, 109, 110, I II, 112,113,420
blood-level requirements, 35Food and Drug Administration method, of
transdermal drug release determination,109,110,111 ,112,113,420
Forehead, as percutaneous absorption site, 282Formatand Control of the Clinical and
StatisticalSections 0/an New DrugApplication, 420
Formulation studiesof dermatological products, 228-229of transdermal products, 227
Fourier transform infrared spectroscopy, 140
444
Franz diffusion cell, 118-119Functional groups , free energy of transfer, 76,
77
Gastrointestinal tractas drug absorption barrier, 417-418drug metabolism in, 19oral controlled-release formulations
absorption in, 416-417permeability of, 417-418
Gelcompositional stability , 375release rate determination, 110-115
Generic drugsAbbreviated New Drug Applications for,
394-395,397,422-423,426ApprovedDrugProducts with Therapeutic
Equivalence Ratings for, 423bioequivalence, 131, 393-413
animal models for, 401-402clinical trials of, 411criteria for generic substitution of, 396
397dermatopharmacokinetic studies of, 402-
403in vivodissolution testing for, 397-400in vivo documentation of, 401-411pharmacodynamic detector of, 407pharmacodynamic studies of, 405-407pharmacokinetic assessment methodology,
402,403-405regulatory history of, 395-396test sensit ivity for, 407-408test specificity for, 408validation procedures for, 409vasoconstrictor assay of, 409-411
plasma levels of, 140price competition of, 426projected retail sales of, 429
Glove juice test, 429Glucorticoids
Stoughton-McKenzie assay of: seeVasoconstri ctor assay
stratum corneum reservoir of, 190-191Goat, as animal model, 345-346Grafted skin models , 210-212, 345
intact rodent, 210-211limitations, 401-402rat/human skin flap system , 211-212
Griseofulvin, cutaneous permeabiity, 8-9
INDEX
Guinea pig, as animal model , 338, 339-340,344
hairless, as transdermal drug screeningmodel ,251
Habitrol, 53-:54Herpes simplex virus, antiviral agents' efficacy
against , 167Hertzer,39Hexanol, permeability coefficient, 249High-density lipoproteins, sex steroids '
interaction with, 433-434Hill equation, 327Hormone replacement, transdermal delivery
systems, 47-50, 60-61 ; see alsoEstradiol , transdermal delivery systems ;Testosterone, transdermal deliverysystems
Horse, as animal model , 345-346Human models, for bioavailability/
bioequivalence assessment, 123, 251Hydration
as drug transport and permeation factor , 238enhancer-related, 261, 268-269
Hydrocortisonecutaneous concentration, 404dose accountability assessment, 186, 187,
189,190,191-192,194dose response, 280-281percutaneous absorption
in animal models, 341application frequency effect on, 285-286
phonophoresis-mediated penetration, 94, 95release rate profile, 113, 114-115stratum corneum reservoir of, 190, 191-192vasoconstrictor assay of, 141
Hydrocortisone estersalkane solubility, 82, 83flux enhancement factor , 84, 85free energy of transfer, 77maximum flux, 85, 86octanol solubility, 83octanol/water partition coefficients, 76, 77,
78skin penetration data, 84, 86structure, 74water solubility , 83
Hydrophilic compounds, decontamination of,190, 191, 193
Hydrophobic drugs , diffusion, 380
INDEX
Hydroxybenzoic acid, stratum corneumreservoir of, 192
Hypersensitivity reactions, to transdermaldelivery systems, 417, 421
Hypertension, transdermal drug therapy: seeClonidine, transdermal delivery systems
Hyperthermia, cisplatin uptake in, 216
Immunosuppressed animals, as grafted skinmodel,210-211
Indomethacinplasma concentration-time profile models,
325-326ultrasound-mediated transdermal delivery,
96Inflammation models, in vivo, 133Insulin , ultrasound-mediated delivery , 96-97Intermittent application, effect on percutaneous
absorption, 285-286Intermittent delivery, transdermal, 61-62Intravenous administration
blood-level profile, 21, 22comparison with drug excretion data, 140comparison with transdermal formulations,
419kinetic models, 318, 320-322radiolabeled elimination profile, 184therapeutic window, 21, 22
In vitrodissolution testing , 107-108,397-400In vitro drug uptake studies, versus in vivo
studies, 229-231In vitromodels, of drug permeation and
uptake, 231-232In vitropercutaneous absorption methods, 5-7In vitroquality control methods, 107-108,
419-420In vitro release method, 107-116
for dermatological products, 110-115for transdermal patches, 109-110, 115
In vitroshort -term skin exposure method, 9-10In vivodrug uptake studies, versus in vitro
studies, 229-231In vivogeneric drug bioequivalence
measurement, 401-411In vivopercutaneous absorption methods, lO-
IIIontophoresis, 62-63, 250ISDN, pharmacokinetics of, 29Isolated perfused porcine skin flap, 11-12,
212-216,336
445
Isopropyl myristate, as vehicle, 244, 245Isosorbide dinitrate, transdermal delivery
system, 31
Jungle. The (Sinclair) , 425
Key Pharmaceuticals, 20
Lag time , pharmacokinetic, 25-26Laser Doppler imaging, of blood flow, 140Leuprolide, iontophoresis-mediated delivery,
62-63Levonorgestrol, enhancer form ulations, 344
345Lidocaine, phonophoresis-mediated delivery,
95Lidocaine hydrochloride, skin flap transdermal
flux, 215Lignocaine, phonophoresis-rnediated delivery,
95Lindane, dose response, 281Lipid pathway, of drug transport, 71-72, 73
80,235,236Lipid-protein-partitioning concept, 270, 274
275Lipophilic compounds, passive diffusion, 72-73Lipophilicity
as drug permeation factor , 238-241hydrophilic compounds' permeability
coefficients and , 71models , 238-240
Lipophilic solute , permeability, 72-73permeability coefficients, 71
Lipoproteins, sex steroids' interaction with ,433-434
Liquid preparations, micellar systems of, 262263
Lotion, compositional stability, 375Low-density lipoproteins, sex steroids'
interaction with, 433-434
Malathion, percutaneous absorption, 284single-dose absorption, 286
Mannitol, ultrasound-mediated delivery, 96-97Marmoset, as animal model , 345Mass-balance procedures, 183-195
under nonoccluded exposure conditions,185, 186, 187-188, 189-194
under occluded exposure conditions, 185,186, 187-188, 189-194
446
Mass-balance procedures (Cont .)part itioning/stratum corneum retent ion
relationsh ip, 190-192partitioning/surface recovery relationship,
189-190 , 191Mass selectivity coefficient, 79Matrix systems, 266-267
drug release from, 314edge loss from, 318
McKenzie-Stoughton assay: seeVasoconstrictor assay
Membranesbiological, diffusion in, 78, 79for diffusion studies, 110for drug release quality control , 110, IIIfor drug uptake/permeation studies, 232-235
animal skin, 232-234artificial membranes, 234-235human skin, 232skin culture s, 234
edge loss of, 318release rate-controlling, 30, 266, 267, 313,
373synthetic, 234-235, 251
dissolution test for, 398-400in vitro corticosteroid release across, 359
362,.364-365Menopause, estrogen therapy during: see
Estradiol, transdermal delivery systems;Estrogen, transdermal delivery systems
2-Mercaptobenzothiazole, percutaneousabsorption, in animal models, 339
Metabolic drugs, transdermal, 431Metabolism
cutaneous, 291-293dose-response relationship of, 287enhancers' effects on, 317implicat ions for drug regulatory
requirements, 418-419models, 317
hepatic, 317Methane, permeability coefficient, 248Micelles, of oil-in-water (o/w) emulsions, 264
265Micronization, of estradiol-containing
products, 432Miglyol products, as vehicle, 244Mineral oil, as vehicle, 244Minitran, 39
INDEX
Minoxidil , 403, 405kinetic determinants of delivery of, 383-385propylene glycol solvent for, 383-385
Mitomycin C, flux rate, 81, 82Modeling
for drug uptake and permeation, 231-235pharmacodynamic, 311-312, 326-329pharmacokinetic, 311, 312-316
cutaneous metabolism, 317-318drug absorption rate, 312-313drug release, 313-314examples , 318-326plasma drug concentration, 312skin absorption, 314-317
Molar dose, for bioequivalent products, 130Molecular weight, as drug permeation factor ,
240-241Monkey
as percutaneous absorption model, 334, 335,337,338,339,341-342, 343-344, 345346
SeealsoRhesus monkeyMorphine, iontophoretically-administered, 62Mosquito repellents, dose-response-related
percutaneous absorption, 282, 283Motion sickness, transdermal drug therapy : see
Scopolamine, transdermal deliverysystems
Mouseas animal model, 335-336, 339-340, 344skin thickness, 234
Mult imembrane systems, 234
Natural moisturizing factor, 268-269Newborn , percutaneous absorption in, 283New Drug Application , 108,393,426
regulatory requirements for, 416-422biopharmaceutical issues in, 416-417clinical pharmacology requirements, 420-
421efficacyand safety requirements, 421in vitro studies, 419-420in vivo studies, 419pharmacokinetic issues in, 417-420
Nicoderm , 53-54, 56Nicotinates, phonophoresis-mediated delivery,
95Nicotine
chewing gum, 53, 54-56pharmacokinetics, 29
INDEX
Nicotine (Cont .)transdermal delivery systems , 31, 52-57
design, 53-54edge loss of, 318with intermittent delivery, 62pharmacodynamics, 56-57pharmacokinetics, 54-56wearing time, 59
Nicotinic acid , percutaneous absorption,application time effects, 174-175
Nicotrol, 53-54, 55-56Nitrate dependence, 37p-Nitroaniline
dose response, 282, 283, 284in vitro short-term skin exposure, 10
Nitro-Bid ointment, 28Nitroderrn, release profile, 112Nitrodisc, 42
design, 38-39exercise tolerance to, 43-44release profile, 39-40, I 12
Nitro-Our, 42, 43design, 38exercise tolerance to, 44release profile, 39-40, 112
Nitroglycerincream , 107cutaneous metabolism, 292history of, 37metabolite-to-parent ratio, 418ointment, 19,37-38,40-41pharmacokinetics, 29properties, 387surface area of dosage , 285systemic bioavailability, 13transdermal delivery systems, 31, 37-44
blood-flow dependence, 317blood-level profile, 58-59concentration-time profile models , 324crystallinity, 387design, 37-40drug excess of, 372-373with intermittent delivery, 6290-cm 2 system, 20percentage of drug delivered by, 372-373pharmacodynamics, 43-44pharmacokinetics, 40-43release-rate profile, brand comparison,
III , 112release-rate test, 109
447
Nitroglycerin (Cont .)transdermal delivery systems (Cont .)
saturation point, 387tolerance to, 422wearing time , 59
Nitrol , 40-41Norepinephrine, co-iontophoresis, 215
Occlus ion , 371-372adverse effects, 421bioavailability and, 417effect on percutaneous absorption, 185, 186,
187-188,189-194effect on skin blanching response, 365
Occlusive vehicle, 269Octanol, permeability coefficient, 249Octanol/water partition coefficient , 79, 82n-Octylamine, temperature-related
percutaneous absorption, 283-284Oestrogel , 48, 49Ointment
compositional stabil ity, 374-375corticosteroid release from, 360-361 , 362-
363, 364-365nitroglycerin, 19, 37-38, 40-41release rate determination, 110-115vehicle concentration, 244
Oral administrationblood-level profiles attained with, 22comparison with transdermal delivery
systems, 18, 19Oral controlled-release formulations
comparison with transdermal deliverysystems , 416-417
release rate, 417Ornithine decarboxylase, inhibition, 133Osteoporosis, estrogen replacement therapy for,
433Oxygen diffusion, ultrasound-enhanced, 99
Pain control, with transdermal drug therapy:see Fentanyl, transdermal deliverysystems
Paraquat, percutaneous absorption, in animalmodels, 344
Parathionbiotransformation, 216dose response, 281
Part itioning, 379-380, 383drug solubility and , 386
448
Patch delivery : seeTransdennal deliverysystems
Patentsdecrease of, 429extension of, 426
Peak effect, assessment, 409Penetration enhancers, 270-275Pentadeconic acid , percutaneous absorption, 7Percutaneous absorption, 3-15, 379-380
anatomical application site effect on , 175177,179,282
animal models of: see Animal models, ofpercutaneous absorption
application frequency effect on , 285-287application time effect on , 174-175bioavailability/bioequivalence relationship
of, 132biological response assay of, 13-14in vitro individual and regional variat ion of,
7-9in vitro percutaneous absorption methods
for, 5-7in vitroshort-term skin exposure test of, 9
10in vivo percutaneous absorption methods for,
10-11pharmacokinetic model, 314-316pharmacokinetics, 22-28powdered human stratum corneum model,
4-5
process of, 22-28in skin flaps, 11-12,214-216stratum corneum concentration relationship,
164-180application conditions, 166-177in vivorelationship, 164-166
surface disappearance determinant of, 13systemic bioava ilability assessment of, 12-13
transepidermal route, 379, 380transfollicular route, 379-380
ultrasound-enhanced, 91- 104clinical studies, 94-96
mechanisms, 98- 10Inonhuman in vivo studies, 96
for transdermal delivery systems , 96- 10 Iultrasound characteristics and, 92-94
Permeability coefficientsof n-alkanols, 235-236alkyl chain length versus, 239-240, 241, 242,
243, 244, 248-249
INDEX
Permeability coefficients (Cont .)
of lipophilic solutes, 71of polar permeants, 72
Permeationelectrically-enhanced, 62-63, 250models, 231-235
Permeation studies, 229-230factors affecting permeation in, 236-251
age of skin , 246-247application site, 246concentration: 241, 242-243enhancers, 247-251hydration, 238lipophilicity, 238-241molecular weight, 240-241racial factors , 247recommendations for, 251-252sex factors, 247solubility, 241-243vehicle/dosage form , 243-245, 247
membranes for, 232-235animal skin , 232-234artificial membranes, 234-235human skin , 232skin cultures, 234
test compounds for, 235-236Pesticides, percutaneous absorption
in animal models, 336-337time of exposure effect, 284See also specific pesticides
Pharmacodynamic activity, 21-22Pharmacodynamics
definition, 311modeling, 311-312, 326-329
Pharmacodynamic studiesofbioequivalence, 405-411detector in, 406-407
Pharmacokinetics, 21-28definition, 31 1modeling, 311, 312-326
cutaneous metabolism, 317-318drug absorption rate, 312-313drug release, 313-314examples, 318-326plasma drug concentration, 312skin absorption, 314-317
Pharmacokinetic studies, for New DrugApplications, 420-421
Pharmacokinetic techniques, forbioequivalence evaluation, 402 , 403405
INDE X
Phenolsdose accountability, 186, 188, 189stratum corneum reservoir of, 191- 192
Physostigmine, ultrasound-mediated delivery,96, 97
Pig, as animal model, 334-336, 346Pig skin flap: see Skin flap, isolated perfused
porcinePK-PD model, 326-327Plasma, radioactivity assay of, 12Plasters, 371Poison Ivy Test, 427Polar path way, of drug transport , 71-74, 235,
236permea nt selectivity of, 71, 72
Polychlorinated biphenyls, skindecontam ination of, 206
Polycyclic aromatic hydrocarb ons, cutaneousmetabolism, 292
Polyethylene 400, as vehicle, 244Polymers, diffusion in, 78, 89Polyurethane artificial membrane, 234Polyvinylidene difluoride membrane, drug
release across, 359-362, 364-365Pore pathway: see Polar path wayPotency, pharma codynamic, 327Poultice, 371Prilocaine, phonophoresis-mediated delivery,
95Primates, nonhuman, as animal mode ls, 334,
335, 337, 338, 339, 341-342, 343-344,345-346
Principles and Pract ices of In VitroPercutaneous Penetration StudiesConference, 110
Prodru gsdefinition, 69-70formul ation process, 69-70for maximum flux, 80-86
crystalline energy changes in, 82-84, 85,86
drug molecular size effects in, 72, 76, 84lipid pathway, 71-72, 73-80lipophil icity in, 70-71 , 84, 86permeability coefficients of, 71, 72, 80polar pathway, 71, 72-73, 74
Progesteronedose accountability assessment , 186, 187,
189,1 91-1 92transdermal delivery system, 31
Progestogens, 434
449
Propranolol, cutaneous permeabiity. 8-9sex factors in. 247
Propylene glycolas enhance r. 271, 273. 383-385evapo ration. 384-385. 386formula, 27 1as rninoxidil solvent, 383-385as vehicle. 244. 245
Prostaglandin(s), cutaneous metabolism, 292Prostagland in Ez• synthetic: see ViprostolProstep, 53. 54Protein synthesis. conjugated estrogens and ,
433Psoriasis Plaque Test, 427Pyrexal Erythema Test. 427
Qualit y controlof dermatological products. 107-116,235in vitro method s, 107-1 08,41 9-420of transd ermal delivery systems, 419-420
Rabbit , as animal model, 337, 344, 346Racial factors, in permea bility, 247Radioactive tracers, 12-1 3, 134-1 36, 184, 192
193ethics of use of, 178use in hum ans, 139, 140, 178
Raoult's law, 388Rat , as ani mal model , 336-337, 341-342, 346
of dinoseb percuta neous absorp tion, 279280
hairless, 339-3 40, 344Rat/human skin flap system (RHSFS), 2 11
2 12Regional delivery, definition , 371Release rate-cont rolling membranes: see
Membranes, release rate-cont rollingReplacement therapy, transdermal, 431; see
also Estradiol, transdermal deliverysystems; Testosterone, transdermaldelivery systems
Reservoir, of stratum corneum, 30, 190-192,402
lipophil icity-dependence of, 191, 193as matrix system, 266relationship to percutaneous absorption,
164-1 66anatom ical site application effects, 175
177application time effects, 174-175
450
Reservoir (COni .)
relationship to percutaneous absorption(COni .)
dosage effects. 167vehicle effects. 167-174
relationship to stratum corneum barriereffect. 165. 177-178
for transdermal systems. 313-314Retin-A. clinical trials. 428Retinoic acid. cutaneous metabolism. 292Retinoic acid derivatives. clinical trials. 411Retinoids . anti proliferative activity
measurement. 133Rhesus monkey. as animal model. 334. 337.
338.339.341-342. 343-344. 346alachlor testing in. 197-207
percutaneous absorption. 198-199. 200201.204-205
scintillation counting. 199-200skin decontamination. 198. 199.201-206
dinoseb percutaneous absorption in. 279280
Rodentsimmunosuppressed. as human skin graft
host. 210-211See also Guinea pig; Mouse; Rat
Safetyin vivo assessment. 133-136regulatory requirements. 421
Salicyclic acid. ultrasound-mediated delivery.97
Sampling. dermatological . 403Scalp, as percutaneous absorption site, 282Scopolamine
definition, 35pharmacokinetics. 29release rate test, 109transdermal delivery systems, 31, 35-37
comparison with other administrationroutes, 422
design, 35-36pharmacodynamics, 37pharmacokinetics, 36-37two-eompartment model, 25wearing time, 59
Sebum, drug partitioning in, 379, 380Semisolidity, of dermatological products. 389Sex factors, in permeability, 247Silastic artificial membrane, 234
INDEX
Skinanimal models of. 138. 232-234
physical and chemical parameters. 345-346
use in bioequivalence testing. 400as drug absorption barrier . 417-418washing of: see DecontaminationSee also Stratum corneum
Skin biopsy. for dermatological samples. 403Skin blanching assay: see Vasoconstrictor assaySkin cultures. 234Skin exposure. in vitro short-term. 9-10Skin flaps. 11-12
isolated perfused porcine. 212-219. 336isolated perfusion protocols. 213-214percutaneous absorption studies of. 214
216procedure for creating. 212-213
Skin grafts: seeGrafted skin modelsSkin sandwich flap. 12Skin scraping. for dermatological samples. 403Skin stripping technique. 163-181
for antiviral agent testing. 167application conditions. 166-177
anatomical application site. 175-177 . 179application time. 174-175dosage applied. 167. 179vehicle effect. 167-174. 179
comparison with in vivo techniques, 165. 178for corticosteroid bioavailability assessment.
352-353. 364for dermatological samples. 403experimental protocol. 180short-term exposure. 10-11weight of stratum corneum removed by.
352-353Skin substitutes. 235Skin thickness. of animal models. 342-343Smoking cessation: seeNicotine. chewing gum;
Nicotine . transdermal delivery systemsSnake skin. as animal model. 345Soap and water. as skin decontaminant, 198.
199.201-206Solubility
as drug permeation factor. 241-243measurement. 389-390in solvents. 386-390
Solute. bilayer concentration, 73-74Sonophoresis, 92, 250; seealso UltrasoundSquare-root-of-time. 313. 314
INDEX
Static diffusion cell, 118-119, 122-123Steady-state plasma concentration, 27Steroids
cutaneous metabolism , 292dose accountability, 186, 187, 189-192fluorinated , stratum corneum reservoir of,
190Stokes-Einstein equation, 78, 79Stratum corneum
barrier effectcorrelation with reservoir effect, 165, 177
178selectivity of, 70, 71-80
drug concentration in, 140drug partitioning in, 379- 380, 383
drug solubility and , 386lipid domain, 71powdered human, 4-5prodrug-enhanced drug transport across, 69-
89lipid pathway, 71-72, 73-80maximum flux, 80-86permea nt selectivity and ; 71-80polar pathway, 71-74
protein domain, 71remova l methods, 137reservoir function : see Reservoir, of stratum
corneumtopical compound retent ion in, 190-192,
193Stripp ing: seeSkin stripp ing techn iqueSucrose, permeability coefficient, 72Sulfoxides, as vehicles, 244Supersaturated systems, 268Supor artificial membrane, 234Surface area, in percutaneous absorption, 285Surface disappearance, as percutaneous
absorption determ inant, 13Surfactants, of micellar systems, 262Surgical scrubbing agents , 428-429Suspension , simple, 263-264Sustained -release formulations, bioavailabi lity
testing regulations, 146Synthetic membrane dissolution test method,
398-400Syntheti c membranes, 234-235, 25 1, 359-362,
364-365Systemic circulation
dermatological product accumulation in,371,374,376-377,403-405
451
Systemic circulation (COni.)
drug disposition in, 318transdermal drug accumulation in, 371
Systemic drugs, bioequ ivalence, 426
Tape stripp ing: seeSkin stripping techniqueTaurocholic acid, percutaneous absorption, 7-8Terpenes, as penetration enhancers, 272Test compounds , for permeation studies , 235
236Testosterone
dose accountability assessment , 186, 187,189, 191-192
dose response, 280-281flow-through diffusion, 122percut aneous absorption
in animal models, 341, 343-344applica tion frequency effects, 286
pharmacokinetics, 29transdermal delivery systems, 435-436
comparison with other administrationroute s, 422
Testosterone proprionate, flow-throughdiffusion, 122
Thalidom ide, 425Theophylline
percuta neous absorption, application timeeffects, 174-175
transdermal delivery systems, 60-61Therapeutic index, narrow , 421Therapeutic window, 21, 22Thermodynamic activity, 267-268
alkane solubility as indicator of, 82-84crystallinity and, 387of dermatological products, 375-376, 380,
383, 385-390of topicai delivery systems, 370of transdermal delivery systems, 417
Thin-film phenomenon, 381-383Thomas diffusion cell, 119Timolol, pharmacokinetics, 29Tissue pathway, of drug transport, 235, 236Tolazoline, co-iontophoresis, 215Topical delivery, definition , 371Topical delivery systems
film spread area of, 370history of, 17-19purpose , 415shallowness of drug delivery of, 370thermodynamic activity, 370
452
To pical delivery systems (COni.)
types of, 107, 37 1See also Dermatological produ cts;
Tra nsdennal delivery systemsToxicity
application frequency relationship, 286-287in children , 167percuta neous absorptio n relationship, 167
Toxicological studies, ani mal models for, 134136
Tra nsdermal delivery systems, 17-68adhesives, 421advan tages, 57, 416application sites, 373backing materials, 372 .bioequivalency measurement, 373blood levels attained with, 373classification , 30, 32-33clinica l consideratio ns with, 431- 436com mercial systems, 35-57
adva ntage over current dosage forms, 57c1onidi ne, 44-47estradiol, 47-50fentanyl, 50-52medical rationale for, 19nicotine, 52-57nitroglycerin, 37-44performance of, 57-63scopolamine, 35-37
comparison with oral dosage, 18, 19definit ion, 19, 226, 371delivery environment stability , 373delivery rate estimation for, 373development of, 226-228differentiated from topical systems, 369-391drug candidate selectio n for, 20, 28-30dru g delivery process, 369-370dru g permea tio n process, 22-28dru g release mechan isms, 33-34with electrica lly-enhanced perm eat ion , 62-
63form ulation studies, 227limitat ions, 20matrix systems, 266-267microbial growth und erneath , 372,42 1norm s of operation, 37 1-3 73as occlusive system, 37 1-372patient compliance with, 19,59,4 16phannacokinetic considerations of
delivery system design, 30-34regulatory considerations , 34-35
INDEX
Tra nsderma l delivery systems (COni.)
pha nnacokinetic interpretation and , 21-28product profile, 20purp ose, 107regulatory approval, 34-35with release-rate controlli ng membrane, 373release rate determination, 109-110, III,
112, 113, 115size, 33, 373
blood level corre lation, 59maxim um , 20
systemic effects, 4 15vehicle effect, 245wearing time, 59
Transderm- Nitro, blood-level profiles, 41-42,43
design, 38release profile, 3{}, 40, 112
Tret inoin, 428solubility measuremen t, 389, 390
Tricloca rban, percuta neous absorption , 5-6Triprolidine, pha rmacokinetics, 29T umor model, 216
Ultrasou nd, 9 1-104characteristics, 92-94clinica l studies of, 94-96mechanisms , 98-101nonhuman in vivo studies of, 96use with transdennal delivery systems , 96
101United States Pharmacopeia
in vivo dissolution requiremen ts of, 397-398transdennal patch release rate assessment
guidelines of, 109Urea-base d penetra tion enha ncers, 272Urea-based penetrat ion solvents, 272Urine, dru g levels in, 12-1 3, 23- 24, 139-1 40
Vascular system, dru g absorptio n into , 380Vasoconstric tio n, glucocorticoid-re lated, 405
406; see also Vasoco nstrictor assayVasoconstrictor assay, 141, 155-1 62,405-407,
408,427-428bioavailability corre latio n, 356-358, 365clinical efficacy corre lation, 356, 357clinical equivalency of form ulations, 159-
16 1concentration effect, 282eye versus inst rument observations in, 158,
159
INDEX
Vasoconstrictor assay (Cont.)modification, 409-411observer training for, 159occlusion effects on , 365single versus multiple observations in, 157-
158subjectivity of, 351test models, 155thermodynamic princip le of, 268trial methodology , 156- 157
Vehicle effect, 245enhancer effect versus, 244, 250-251
Vehiclesco-permeation, 243for dermatological produ cts, 228as drug permeation factors, 243-245, 246,
247effect on percutaneous absorption, 167- 174,
179occlusive, 269
Vidarabine- 5-valerate, 3 17Viprostol, 292- 306
percutaneous absorption, 293-294, 295skin deposition , 294- 297, 298, 299
453
Viprostol (Cont.)
skin metabo lism, 297, 300-306first-pass metaboli sm, 303-306in vitro studies, 300-301 , 302-303in vivo studies, 300-302
structure, 292-293transdermal systemic circulation release,
293-294, 295Volatile compounds
percutaneous absorptio n, 7transdermal delivery systems, 58
Washing, of skin: see DecontaminationWatch glass-patch-Teflon mesh screen
assembly, for release rate determination ,109,110, I ll, 112, 113,420
Waterpermeabi lity coefficient, 248as vehicle, 244
Water temperature, effect on percutaneousabsorption, 283- 284
Waxman -Hatch Act, 35, 426, 429
Zeolite artificial membrane, 234
Recommended