Transdermal macromolecular delivery: real-time visualization of iontophoretic and chemically enhanced transport using two-photon excitation microscopy.
OBJECTIVE
To investigate the transdermal delivery of a model macromolecule by passive and iontophoretic means following pretreatment with C12-penetration enhancers and to visualise transport across human stratum corneum (SC) in real time.


METHODS
Transport studies of dextran, labelled with fluorescent Cascade Blue (D-CB: M(R) = 3 kDa) across human stratum corneum, were conducted during passive and iontophoretic modes of delivery following pretreatment with either dodecyltrimethylammonium bromide (DTAB), sodium dodecyl sulphate (SDS) or Azone. Size-exclusion chromatography was used to assess maintenance of dextran structural integrity throughout experimental lifetime. Two-photon excitation microscopy was employed to visualise real-time dextran transport during current application.


RESULTS
The positively charged C12-enhancer DTAB elevated passive D-CB steady-state flux (J(ss)) and was the only enhancer to do so above control during iontophoresis. The negatively charged SDS had the least effect during both stages. On-line macromolecular transport was visualised, indicating both inter- and intra-cellular pathways across SC during current application. No transport was visible across untreated SC during passive transport.


CONCLUSIONS
Use of a positively charged enhancer may improve J(ss) of anionic macromolecular penetrants during passive and iontophoretic delivery. On-line visualisation of iontophoresis across SC was possible and can provide mechanistic insight into SC transport pathways.
Grewal
B S
BS
Pharmaceutical Sciences Research Institute, Aston Pharmacy School, Aston University, Birmingham, UK.
Naik
A
A
Irwin
W J
WJ
Gooris
G
G
de Grauw
C J
CJ
Gerritsen
H G
HG
Bouwstra
J A
JA
D000279:Administration, Cutaneous; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics; D001381:Azepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003911:Dextrans / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007478:Iontophoresis / Q000379:methods*; D008856:Microscopy, Fluorescence / Q000379:methods; D017785:Photons; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012869:Skin Absorption / Q000502:physiology*; D012967:Sodium Dodecyl Sulfate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013501:Surface-Active Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors
D000925:Anticoagulants; D001381:Azepines; D003911:Dextrans; D005456:Fluorescent Dyes; D000644:Quaternary Ammonium Compounds; D013501:Surface-Active Agents; C013912:decyltrimethylammonium; C035229:laurocapram; D012967:Sodium Dodecyl Sulfate