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