CHARACTERIZATION OF COMPLEX COACERVATES OF SOME TRICYCLIC ANTIDEPRESSANTS AND EVALUATION OF THEIR POTENTIAL FOR ENHANCING TRANSDERMAL FLUX

Complex coacervation is the separation of an aqueous mixture of opposi tely charged ions into a dense coacervate oil phase, rich in ionic com plex, and a dilute equilibrium phase. Coacervation was investigated be tween cationic tricyclic antidepressants (amitriptyline, imipramine an d doxepin) and counter-ions of anionic bile salts sodium cholate (NaC) and sodium deoxycholate (NaD), and the surfactant sodium lauryl sulfa te (SLS). Systems were analyzed by microscopy, HPLC, Karl Fischer titr ation, thermogravimetric analysis and particle size analysis. Two syst ems were selected to investigate the potential of this formulation for enhancing transdermal flux of charged species - amitriptyline (AMI) w ith NaD, which separates into two distinct phases, and AMI with SLS wh ich remains as a sol. Octanol/vehicle partition coefficients were dete rmined and the AMI:NaD coacervate produced an 18-fold increase and AMI :SLS 22-fold compared with aqueous solution. Permeation experiments we re performed using human epidermal membrane with an aqueous receptor a nd the flux from a 0.025 M aqueous solution which is above the critica l micelle concentration (0.015 M) was 3.0 +/- 0.54 mu g/cm(2)/h (S.E.M ., n = 10). The flux from an AMI:NaD coacervate donor was 6.6 +/- 0.71 mu g/cm(2)/h (S.E.M., n = 8), which represents a significant 2.2-fold increase (t-test, P = 0.01). The AMI:SLS system, however, reduced the flux compared with the aqueous solution. Permeation studies were repe ated using silastic membrane to exclude simple enhancing effects of th e counterions and similar differences in flux were obtained indicating that the changes were due to the formulation. The results indicate th at the increased lipophilicity of the coacervate oil phase can increas e the transdermal flux of charged species.