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Dedication
I dedicate this book to my wife Stella and
my children Precious-Mary and Treasure-Daniel.
I am grateful for their love and support.
Contents
Listoffigures xiii
Listoftables xv
Preface xvii
Acknowledgment xxi
1. Transcutaneous drug administration 1
Passivetransdermaltherapeuticsystems 3
References 5
2. Anatomy of the human skin 9
References 16
3. Basic principles of transdermal drug delivery 19
Transdermaldrugdeliveryexperiments 21
Selectionoftransdermaldrugdeliverycandidates 24
Physico-chemicaldeterminantsofpercutaneouspenetration 25
Molecularweight 25
Partitioncoefficient 26
Solubility 27
Diffusioncoefficient 27
Ionization 28
Biologicalfactorsandtransdermaldrugdelivery 29
Age 29
Hydration 30
References 31
4. Elastic liposomes and other vesicles 37
Alpha-tocopherol 41
Insulin 42
Sodiumstibogluconate 43
Minoxidilandcaffeine 43
Asenapine 44
Gapjunctionprotein 45
Tetanustoxoid 45
Ondansetron 46
vii
viii Contents
Surfactant-basedelasticvesicles 47
Niosomes 48
Ethosomes 50
Cucurmin 53
Ovalbumin 53
Griseofulvin 54
Terbinafine 55
Transethosomes 56
References 58
5. Chemical permeation enhancers 63
Terpenes 65
Water 70
Azone 70
Pyrrolidoneandderivatives 73
Alcohols 74
Esters 77
Dimethylsulfoxide 80
Fattyacids 81
Glycolethers 82
Surfactants 83
Peptides 86
Aminoacidderivatives 87
Ceramide-likepenetrationenhancers 88
Oleodendrimers 89
Ionicliquidsanddeepeutecticsolvents 90
References 91
6. Microemulsions 97
Transdermaldeliveryofindomethacinwithmicroemulsion 105
Percutaneoustransportofα-santalolthroughbreastskinand
mammarypapilla 106
Skindeliveryofpropranolol-loadedmicroemulsions 107
TheInfluenceofmicroemulsiononthepercutaneoustransportof
tetramethylpyrazine 108
Theinfluenceofmicroemulsiononthetranscutaneousdeliveryof
testosterone 109
Transdermalmicroemulsionloadedwithmethyldihydrojasmonate 110
Theeffectofmicroemulsiononthetranscutaneouspermeationof
dencichine 111
Skindeliveryofclotrimazole-loadedmicroemulsions 112
SkindeliveryofthetetrapeptidePKEKwithmicroemulsions 113
Microemulsionfortheskindeliveryofbee-venomphospholipase
A2(Apim1) 114
Transcutaneousdeliveryofmetronidazolewithmicroemulsion 114
Repaglinidemicroemulsiongelforpercutaneoustransport 115
Contents ix
Theinfluenceofmicroemulsiononthetranscutaneousdeliveryof
cyclosporine 116
Transcutaneousdeliveryoflapacholwithmicroemulsion 116
Microemulsionfortheskintransportofzidovudine 117
Percutaneoustransportofropivacaine-loadedmicroemulsion 117
Celecoxibmicroemulsion-basedgelfortransdermaldelivery 118
Skindeliveryofimiquimodwithmicroemulsion 118
References 119
7. Prodrugs 123
SkindeliveryofsiRNAwithprodrugs 126
Skintransportofbioengineeredcarboxymethyl
cellulose-doxorubicinprodrugs 127
Theeffectofesterpromoietiesonthepercutaneoustransportof
ketorolac 129
Percutaneouspenetrationofapomorphineprodrugs 129
Skindeliveryofpolymerconjugatedprodrugofall-transretinoic
acid 130
Skindeliveryofnaproxenprodrugs 131
Transdermaldeliveryofnatrexoneprodrugs 131
Transcutaneouspermeationofhaloperidolprodrugs 132
Skindeliveryoffexofenadineprodrugs 132
Prodrugsofphenoliccompounds 133
Polyoxyethyleneestersasprodrugsofselectednonsteroidal
antiinflammatorydrugsfortransdermaldelivery 134
Transdermaldeliveryofphenylalanyl-glycineprodrugs 135
Skinpermeationofatenololandpropranololesters 135
Thetranscutaneouspenetrationoftheophyllineprodrugs 136
Transdermaldeliveryofacyclicnucleosidephosphonates 137
Percutaneoustransportofthalidomideprodrugs 137
Transdermaldeliveryofcytarabineprodrugs 138
Transdermalpermeationofacetylsalicylicacidprodrugs 138
References 139
8. Microneedles 143
Solidmicroneedles 144
Fabrication 144
Transdermaldrugdeliverywithsolidmicroneedles 149
Dissolvingmicroneedles 152
Hollowmicroneedles 160
Coatedmicroneedles 163
Dipcoating 164
Electrohydrodynamicatomization 165
Inkjetprinting 166
Three-dimensionalprinting 167
Spraycoating 168
x Contents
Partialimmersion 169
Nitrogengasjetcoating 169
Polyelectrolytemultilayerassembly 170
Hydrogel-formingmicroneedles 170
References 173
9. Iontophoresis, magnetophoresis, and electroporation 183
Transdermaliontophoreticdeliveryoftherapeuticagents 191
Ranitidine 191
Methotrexate 191
Penbutololsulfate 192
Almotriptanmalate 192
3-Fluoroamphetamine 193
Acyclovir 193
Granisetron 195
Memantine 196
Ketoprofen 196
Dexamethasone 199
Donepezil 201
3-Fluoroamphetamine 202
Magnetophoresis 203
ETP-mediatedtransdermaldeliveryofdoxepin 209
UsingETPtotransportcalcein 210
DeliveringfentanylacrossthehumanskinwithETP 210
PercutaneoustransportofmetoprololwithETP 211
ETP-mediatedtransdermaldeliveryofnalbuphine 212
TheeffectofETPonthetransdermalpermeationofdoxorubicin 212
DeliveryofironwithETP 213
ETP-mediatedtransdermaldeliveryofKb-binding
ovalbumin-peptideSIINFEKL 213
TranscutaneoustransportofneostigmineviaETP 214
SkindeliveryofsinomeninehydrochloridebyETP 215
SkindeliveryofmethotrexateviaETP 215
PercutaneoustransportoftetracaineviaETP 216
ETP-mediatedtranscutaneouspermeationofalniditan 216
ETP-assistedskinpermeationofheparin 217
TransdermaldeliveryofdomperidoneviaETP 217
ETP-mediatedtransdermalpenetrationofdiphtheriatoxoid 217
PercutaneoustransportofinsulinviaETP 218
ETP-mediatedpercutaneousdeliveryofandrographolide 218
TheeffectofETPonthepercutaneousabsorptionofgenistein 219
ETP-assistedskintransportofinsulin 220
TheinfluenceofETPonthetranscutaneouspenetrationofterazosin 221
ETP-mediateddeliveryofvaccinesagainstTrypanosomacruzi 221
ETP-mediatedskindeliveryofpDNAvaccinethatcodesforthe
influenzanucleoprotein(PR8) 222
References 223
Contents xi
10. Sonophoresis 231
Mechanismoftransdermalsonophoresis 234
Acousticstreaming 234
Cavitation 235
Rectifieddiffusion 237
Cellular-leveleffect 238
Thermaleffect 238
Transdermalsonophoreticdeliveryoftherapeuticagents 239
Methotrexate 240
Gemcitabine 240
Sinomenine 242
Penbutolol 242
Propranolol 242
Ketoprofen 243
Diclofenac 244
Galantamine 245
Rivastigmine 245
Lercanidipinehydrochloride 246
Insulin 246
Heparin 248
Histamine 248
Caffeine 249
References 250
11. Laser and other ablation technologies 257
Heat 268
References 272
12. Mathematical modeling of transdermal drug delivery 275
Artificialneuralnetwork 279
Macroscopicmodels 280
References 282
Index 285
List of figures
Figure1.1 Aschematicrepresentationofatransdermalpatch. 3
Figure2.1 Anatomyofthehumanskin. 10
Figure4.1 Invitroskinpermeationstudies:amountoftocopherolaccumulated 42
intheskinlayers(SC,stratumcorneum;Ep,epidermis;D,dermis)
andreceptorfluid(RF)after8hofnonocclusiveapplicationofthe
transfersomes.
Figure5.1 Effectofpenetrationenhancersontheintercellularlipiddomain. 64
Figure5.2 Steady-statefluxvaluesoftheophylline(A)andindomethacin(B) 72
throughmodelmembranesofvariouscompositionandthrough
porcineskin.
Figure6.1 Schematicrepresentationofthethreemostcommonlyencountered 98
microemulsionmicrostructures:oil-in-water,bicontinuous,and
water-in-oilmicroemulsion.
Figure6.2 Representativepseudo-ternaryphasediagramsofsystemscontaining 103
ME-1,ME-2,ME-3andME-4.
Figure6.3 Cumulativeamountpermeatedofmethyldihydrojasmonateperunit 111
areafromselectedmicroemulsionsystems.
Figure7.1 Theprecursors,reaction,andcarboxymethylcellulose-doxorubicin 128
conjugateproduct.
Figure8.1 Typesofmicroneedles,step-by-stepprocessoftheirapplication,and 145
correspondingmechanismsofdrugdeliveryacrossatissuebarrier.
Figure8.2 Theschematicrepresentationofsumatriptan-loadeddissolvable 154
microneedles.
Figure8.3 Permeationprofilesofsumatriptansuccinate(cid:1)loadedmicroneedles 155
after32h:(A)F1microneedles,F1control(microneedleinvertedon
skin),F1control+tapestrip(153),andreferencesolution(5mg/mL
sumatriptansuccinate);(B)F2microneedles,F2control,F2control
+tapestrip(153),andreferencesolution;(C)F3microneedlesand
referencesolution.
Figure9.1 Representationofaninvitroiontophoreticsetup. 185
Figure9.2 ITPusinganAg/AgClelectrodesystem.EMtransportsthecations, 187
includingthedrugmolecule,fromtheanodalcompartmentandinto
2
theskin.Atthesametime,endogenousanions,primarilyCl ,move
intotheanodalcompartment.
Figure9.3 EffectofITPandablativelasertreatmentontransdermalpermeation 194
of3-fluoroamphetamine(PAL-353)acrossdermatomedhumanskin.
Figure9.4 Comparisonofdifferentpulseprotocolsandtheireffectonskinand 210
subsequentpassivecalceindeliverythroughpigskin.
Figure10.1 Theexperimentalsetupforsonophoresis. 232
Figure10.2 Acommerciallyavailablesonophoreticdevice(Sonoprep). 232
Figure10.3 Effectofdifferentultrasoundamplitudeontheskinpermeationof 241
gemcitabinehydrochloride.
xiii
List of tables
Table4.1 Transdermaldeliveryoftherapeuticagentsfromelasticliposomes. 39
Table4.2 Percutaneoustransportofdrugsfromelasticvesicles,niosomes, 40
ethosomes,(ESMs)andtransethosomes(TELs).
Table5.1 Effectofchemicalpermeationenhancersontransdermaldrug 66
delivery.
Table6.1 Theinfluenceofmicroemulsionsontransdermaldrugdelivery. 104
Table8.1 Microneedle-assistedpercutaneousdrugdelivery. 146
Table9.1 TheeffectofITP,magnetophoresis,andETPontransdermaldrug 184
delivery.
Table10.1 Effectofultrasoundontranscutaneousdrugtransport. 239
Table11.1 Theinfluenceoflasertreatmentonpercutaneousdrugdelivery. 260
xv
