title: Effect of controlled laser microporation on drug transport kinetics into and across the skin.
abstract: The objectives of this study were to investigate a novel laser microporation technology ( P.L.E.A.S.E. Painless Laser Epidermal System) and to determine the effect of pore number and depth on the rate and extent of drug delivery across the skin. In addition, the micropores were visualized by confocal laser scanning microscopy and histological studies were used to determine the effect of laser fluence (energy applied per unit area) on pore depth. Porcine ear skin was used as the membrane for both the pore characterization and drug transport studies. Confocal images in the XY-plane revealed that the pores were typically 150-200 microm in diameter. Histological sections confirmed that fluence could be used to effectively control pore depth - low energy application (4.53 and 13.59 J/cm(2)) resulted in selective removal of the stratum corneum (20-30 microm), intermediate energies (e.g., 22.65 J/cm(2)) produced pores that penetrated the viable epidermis (60-100 microm) and higher application energies created pores that reached the dermis (>150-200 microm). The effects of pore number and pore depth on molecular transport were quantified by comparing lidocaine delivery kinetics across intact and porated skin samples. After 24h, cumulative skin permeation of lidocaine with 0 (control), 150, 300, 450 and 900 pores was 107+/-46, 774+/-110, 1400+/-344, 1653+/-437 and 1811+/-642 microg/cm(2), respectively; there was no statistically significant difference between 300, 450 and 900 pore data - probably due to the effect of drug depletion since >50% of the applied dose was delivered. Importantly, increasing fluence did not produce a statistically significant increase in lidocaine permeation; after 24h, cumulative lidocaine permeation was 1180+/-448, 1350+/-445, 1240+/-483 and 1653+/-436 microg/cm(2) at fluences of 22.65, 45.3, 90.6 and 135.9 J/cm(2), respectively. Thus, shallow pores were equally effective in delivering lidocaine. Increasing lidocaine concentration in the formulation from 10 to 25mg/ml produced a corresponding increase in permeation (at 24h, 1650+/-437 and 4005+/-1389 microg/cm(2), respectively). The validity of the porcine skin model was confirmed as transport across porcine and human skins was shown to be statistically equivalent (at 24h, 1811+/-642 and 2663+/-208 microg/cm(2), respectively). The clinical potential of the technology and its capacity to provide significantly faster delivery than conventional passive administration was demonstrated in short duration experiments involving application of a marketed lidocaine cream (LMX4) to laser-porated skin; after only 5 min of formulation application, lidocaine deposition was measured at 61.3+/-7.5 microg/cm(2). In conclusion, the results demonstrate the ability of P.L.E.A.S.E.(R) (i) to create well-defined conduits in the skin, (ii) to provide a controlled enhancement of transdermal transport and (iii) to enable improvement in both the rate and extent of drug delivery.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, 30 Quai Ernest Ansermet, 1211 Geneva 4, Switzerland.
authors.forename: Y G
authors.initials: YG
authors.lastname: Bachhav
authors.forename: S
authors.initials: S
authors.lastname: Summer
authors.forename: A
authors.initials: A
authors.lastname: Heinrich
authors.forename: T
authors.initials: T
authors.lastname: Bragagna
authors.forename: C
authors.initials: C
authors.lastname: Böhler
authors.forename: Y N
authors.initials: YN
authors.lastname: Kalia
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems / Q000379:methods*; D066298:In Vitro Techniques; D007834:Lasers; D008012:Lidocaine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D018613:Microscopy, Confocal; D016062:Porosity; D012867:Skin / Q000378:metabolism* / Q000528:radiation effects / Q000648:ultrastructure; D012869:Skin Absorption; D013552:Swine; D014018:Tissue Distribution
chemical_list: D008012:Lidocaine