Transdermal delivery of tricyclic antidepressants using iontophoresis, chemical enhancers and superporous hydrogels

Tricyclic antidepressants (TCAS) are indicated for treatment of atypical depression. With conventional oral tablet administration, relatively narrow therapeutic index, potentially serious side effects and different metabolizing enzyme activities in the population make safe administration of TCAS an important challenge. One solution to this problem can be iontophoretic transdermal delivery of TCAS. This can be beneficial due to bypassing TCAS' metabolism in the liver, providing zero-order delivery throughout 24 hours with once a day application, and improved patient compliance.; The purpose of this study was to investigate iontophoretic transdermal delivery of TCAS (amitriptyline HCl, clomipramine HCl, and nortriptyline HCl) and to develop appropriate formulations. Effects of current density and drug concentration on iontophoretic drug permeation were evaluated. In addition, fatty acids and terpenes were used to enhance drug delivery. Furthermore, superporous hydrogels (SPHS) were synthesized and tested as drug carriers for the delivery of TCAS.; Fatty acids and terpenes were shown to open up the stratum corneum cell layers and reduce skin resistance. Linoleic acid was observed to decrease the transition temperature of the stratum corneum (SC) lipids as shown by a DSC study. However, linoleic acid did not produce any drug enhancement effect when dissolved in H2O:EtOH (40:60) with nortriptyline HCl during iontophoresis while terpenes increased the drug permeation about 30%.; Poly(acrylamid-co-acrylic acid) SPHS were synthesized using a gas-blowing technique. SPHS showed significantly better drug release properties than either agarose gel or hydroxy propylmethyl cellulose (HPMC) gel under the same experimental conditions. SPHS also have the advantage of being able to carry lipophilic enhancers compared to agarose gel and HPMC gel. Using SPH400 with a surface area of 10 cm2 for a patch, the delivery amount of nortriptyline HCl with 4% menthol by iontophoresis with a current density of 0.3 mA/cm 2 can reach about 50.5 mg/day, which is in the range of estimated therapeutically effective amount of nortriptyline HCl if delivered through the skin.