Comparative Study of Iontophoresis and Iontophoresis/Microporation-pretreatment of Diclofenac Sodium delivery in Rabbit

Transdermal drug delivery provides an important contribution to medical practice, because of the improved patient compliance, sustained delivery and by-pass of first pass effect. However, it has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. One of the major problems associated with transdermal delivery is the presence of a lag-time and thus the onset of effect is delayed compared to i.v bolus or subcutaneous injections. Iontophoresis increases transdermal delivery by applying a continuous low-voltage current that increase the transport of charged ions across the stratum corneum. Since diclofenac sodium (DS) is ionized at physiological pH, DS is a suitable candidate for iontophoretic delivery as demonstrated by several studies. However, even though iontophoresis increases the rate of delivery across the stratum corneum, it may not be sufficient for applications requiring a very fast onset of effect as for musculoskeletal pain. A conceptually straightforward way to selectively increase the permeabilization of the stratum corneum is to pierce it with very short needles able to open micropores in the SC but too short to reach the sensory nerves. Over the past decade, microneedles have been developed as a means to deliver drugs through the skin in a minimally invasive manner. Solid microneedles pretreatment in conjunction with iontophoresis might speed up even more the delivery of drugs across the stratum corneum. The purpose of this investigation is to study the local (dermis) and systemic delivery of DS form an iontophoresis device without and with pretreatment with a microneedle roller. The skin concentration of DS was determined by cutaneous microdialysis.;Microdialysis is a semi-invasive technique that allows the sampling or the delivery of molecule in vivo, according to the concentration gradient between the solution perfusing the probe and the extracellular fluid surrounding it. DS was quantified in dialysate and plasma samples by a validated HPLC assay. The method consisted of a reversed phase C18 column, flow rate of 0.8ml/min and a detection wavelength of 280 nm. Mobile phase consisted of Acetonitrile: Acetate Buffer (pH: 5.2) in the ratio of 45:55. The retention time was 5.82min and 4.18min in lactated ringer and plasma respectively. The calibration curve for microdialysis samples and plasma were linear in the range of 25-10000ng/ml and 50-10000ng/ml respectively, with a correlation coefficient lager then 0.99. The lower limit of quantification (LLOQ) was found to be 25ng/ml for microdialysis samples and 50ng/ml for plasma samples.;Three female pathogen free New Zealand albino rabbits were selected for the experiments. Each rabbit received on separate occasions iontophoresis (4mA for 20 min (Current Density 300mA/cm2) and iontophoresis with microneedle pretreatment. Microdialysis probes were implanted into upper dorsal shaved skin of the tranquilized rabbit and were perfused with lactated ringer solution at 1 μL/min for 5 hours. Plasma samples were collected from the vein in the ear of rabbit with the help of a catheter. Trans QE pH stabilized Iomed Iontophoretic drug delivery patches were used to apply DS. Phoresor II PM700 equipment was used to give constant electric current i.e. 4mA for 20 min (Current Density 300mA/cm2). Dr. Rollers Derma roller (0.5mm) was used to create the micropores before iontophoresis treatment. Both microdialysis and plasma samples were collected at predetermined interval for 5 hours.;The results show that measurable diclofenac concentrations were reached in the skin and plasma immediately after the onset of the current. Though there was no considerable difference in Cmax and AUC after Iontophoresis alone and Iontophoresis with microneedle pretreatment. A large intra- and inter-subject variability was observed. These studies confirm the suitability of iontophoresis for transdermal delivery of diclofenac sodium, however, the effect of pretreatment with microneedles needs to be further investigated.