Transdermal iontophoresis of hydromorphone hydrochloride

The objective of the present investigation was to evaluate the effect of various electronic and formulation variables on the enhancement of transdermal delivery rate of hydromorphone across hairless rat skin, and to investigate if therapeutically effective analgesic concentrations of hydromorphone for the management of cancer-related pain can be achieved with transdermal iontophoresis.;The effects of electrode material, electrode polarity, current strength, current duration, current on/off ratio, solution pH, presence of buffer ions, drug concentration, and solution ionic strength on the in vitro permeation profiles and rate of hydromorphone across freshly-excised full-thickness hairless rat skin were evaluated using side-by-side permeation cells. Also, the stability of the hydromorphone hydrochloride solution to the skin enzymes was determined. Furthermore, the effects of current strength and drug concentration on the pharmacokinetics and pharmacodynamics of hydromorphone were evaluated in vivo in hairless rats. Current was supplied by Phoresor II(TM) and the Trans Q1 GS patches were used in the in vivo studies.;Hydromorphone hydrochloride solution was observed to be stable to the enzymes present on the hairless rat skin. Silver/silver chloride electrodes were found to be effective in delivering hydromorphone by iontophoresis. Modal iontophoresis of a 0.10 M hydromorphone hydrochloride solution at 0.30 mA delivered a 21-fold higher cumulative amount of hydromorphone across hairless rat skin in 12 hours as compared to cathodal iontophoresis. The in vitro permeation flux of hydromorphone was observed to significantly increase (P < 0.0.5) from 72.04 to 280.30 mug/cm2/h with an increase in current strength from 0.10 to 0.50 mA. A linear relationship (r2 = 0.9984) was observed between the total hydromorphone flux and current strength in vitro. No significant difference in the flux of hydromorphone with increase in the duration of current application from 2 to 12 hours was observed. Also, the application of current in a continuous mode resulted in a significantly greater (P < 0.05) flux of hydromorphone. Solution pH was found to have a significant effect on the iontophoretic permeation of hydromorphone as it affected the ionization state of hydromorphone as well as the permselectivity of the skin. Citrate-phosphate buffered hydromorphone hydrochloride solutions resulted in lower flux of hydromorphone as compared to the phosphate buffered hydromorphone hydrochloride solution. With a 10-fold increase in the hydromorphone hydrochloride concentration from 0.01 to 0.10 M, the in vitro iontophoretic flux of hydromorphone was observed to significantly increase (P < 0.05). However, with further increase in hydromorphone hydrochloride concentration to 0.50 M, there was no significant difference in the iontophoretic flux. The addition of increasing amounts of sodium chloride to a hydromorphone hydrochloride solution resulted in a decrease in the amount, flux and transport number of hydromorphone across the hairless rat skin.;The plasma hydromorphone concentrations following an intravenous bolus dose were observed to decrease rapidly. Iontophoresis was observed to enhance the hydromorphone absorption as compared to passive condition in vivo in hairless rats. Increase in current strength resulted in a significant increase (P < 0.05) in the plasma hydromorphone concentrations at both 0.10 and 0.50 M hydromorphone hydrochloride solutions. However, a drug-concentration effect on the plasma hydromorphone concentrations was observed only at high current levels (i.e., 4.0 mA). In addition, the pharmacodynamic effect of hydromorphone evaluated by the tail-flick test showed a delay in the time taken for the rat to withdraw its tail from the hot water following iontophoretic application as compared to passive condition. However, no direct correlation was observed between the plasma hydromorphone concentrations and the antinociceptive effects of hydromorphone in hairless rats.;These results showed that by manipulating the electronic and formulation variables the transdermal iontophoretic delivery of hydromorphone hydrochloride can be controlled, and the possibility of obtaining therapeutically effective hydromorphone concentrations for the management of cancer-related pain is feasible by transdermal iontophoresis.