title: Dissolving polymeric microneedle arrays for electrically assisted transdermal drug delivery.
abstract: It has recently been proposed that the combination of skin barrier impairment using microneedles (MNs) coupled with iontophoresis (ITP) may broaden the range of drugs suitable for transdermal delivery, as well as enabling the rate of delivery to be achieved with precise electronic control. However, no reports exist on the combination of ITP with in situ drug loaded polymeric MN delivery systems. Furthermore, although a number of studies have highlighted the importance of MN design for transdermal drug delivery enhancement, to date, there has been no systematic investigation of the influence of MN geometry on the performance of polymeric MN arrays which are designed to remain in contact with the skin during the period of drug delivery. As such, for the first time, this study reports on the effect of MN heigth and MN density upon the transdermal delivery of small hydrophilic compounds (theophylline, methylene blue, and fluorescein sodium) across neonatal porcine skin in vitro, with the optimised MN array design evaluated for its potential in the electrically faciliatated delivery of peptide (bovine insulin) and protein (fluorescein isothiocyanate-labelled bovine serum albumin (FTIC-BSA)) macromolecules. The results of the in vitro drug release investigations revealed that the extent of transdermal delivery was dependent upon the design of the MN array employed, whereby an increase in MN height and an increase in MN density led to an increase in the extent of transdermal drug delivery achieved 6h after MN application. Overall, the in vitro permeation studies revealed that the MN design containing 361 MNs/cm(2) of 600 μm height resulted in the greatest extent of transdermal drug delivery. As such, this design was evaluated for its potential in the MN mediated iontophoretic transdermal delivery. Whilst the combination of MN and ITP did not further enhance the extent of small molecular weight solute delivery, the extent of peptide/protein release was significantly enhanced when ITP was used in combination of the soluble PMVE/MA MN arrays. For example, the cumulative amount of insulin permeated across neonatal porcine skin at 6h was found to be approximately 150 μg (3.25%), 227 μg (4.85%) and 462 μg (9.87%) for ITP, MN, and MN/ITP delivery strategies, respectively. Similarly, the cumulative amount of FTIC-BSA delivered across neonatal porcine skin after a 6h period was found to be approximately 110 μg (4.53%) for MN alone and 326 μg (13.40%) for MN in combination with anodal ITP (p<0.001). As such, drug loaded soluble PMVE/MA MN arrays show promise for the electrically controlled transdermal delivery of biomacromolecules in a simple, one-step approach.
authors.affiliation: School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, UK
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Garland
authors.forename: Ester
authors.initials: E
authors.lastname: Caffarel-Salvador
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Migalska
authors.forename: A David
authors.initials: AD
authors.lastname: Woolfson
authors.forename: Ryan F
authors.initials: RF
authors.lastname: Donnelly
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000831:Animals, Newborn; D016503:Drug Delivery Systems; D019793:Fluorescein / Q000008:administration & dosage; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000031:analogs & derivatives; D061389:Insulin, Regular, Pork / Q000008:administration & dosage; D007478:Iontophoresis / Q000379:methods*; D008298:Maleates; D008751:Methylene Blue / Q000008:administration & dosage; D008845:Microinjections; D009339:Needles; D011095:Polyethylenes; D012710:Serum Albumin, Bovine / Q000008:administration & dosage; D012867:Skin / Q000378:metabolism; D013552:Swine; D013806:Theophylline / Q000008:administration & dosage
chemical_list: D061389:Insulin, Regular, Pork; D008298:Maleates; D011095:Polyethylenes; C039217:fluorescein isothiocyanate bovine serum albumin; C557837:insulin, regular, beef-pork; D012710:Serum Albumin, Bovine; C043105:poly(methyl vinyl ether-co-maleic anhydride); D013806:Theophylline; D016650:Fluorescein-5-isothiocyanate; D008751:Methylene Blue; D019793:Fluorescein