Controlled transport of timolol maleate through artificial membranes under passive and iontophoretic conditions.

The passive and iontophoretic permeability of timolol maleate (TM) through porous and dense artificial membranes was investigated in order to select the most optimal membrane for a transdermal drug delivery system. For the meso-porous membranes (pore diameter 2-50 nm), the TM permeability for passive diffusion and iontophoresis was practically the same. For the micro-porous membranes (pore diameter<2 nm), a significant transport contribution of iontophoresis was observed, which was more pronounced when higher current densities were applied. The electrical resistance of all the porous membranes was lower than the electrical resistance of human skin. For dense membranes, passive and iontophoretic TM permeability was significantly lower than for porous membranes and in most cases their electrical resistance was comparable or even higher than the resistance of human skin. For most of the membranes studied the average adsorption of TM at 37 degrees C was low (0.02-0.33 mg/cm(2)) and independent of the TM concentration. For the meso-porous mixed cellulose acetate-cellulose nitrate membrane the TM adsorption was significantly higher and increased with the TM concentration. Based on our results, the optimum membrane for an iontophoretic transdermal TM delivery system is the LFC 1 micro-porous membrane because it mainly controls the TM delivery (TM iontophoretic permeability: 0.86 x 10(-6) cm/s), has very low electrical resistance (0.9-1.5 komega cm(2)) and the TM adsorption to it is low (0.15 mg/cm(2)). The therapeutic plasma TM concentration is achievable by application of this membrane in realistic sizes (5-64 cm(2)) and by application of current densities between 0.13 and 0.5 mA/cm(2).

Delivery of timolol through artificial membranes and pig stratum corneum.

The in vitro passive and iontophoretic (applied current density: 0.5 mA/cm(2)) timolol (TM) permeability from a liquid solution through pig stratum corneum (SC) is found to be 0.9 +/- 0.5 x 10(-6) and 3.9 +/- 0.9 x 10(-6) cm/s, respectively. The in vitro iontophoretic TM delivery through the combination of artificial porous membranes with pig SC is investigated as well. When the meso-porous PES-30 membrane is applied, the SC mainly controls the TM delivery. When the microporous NF-PES-10 membrane is applied, both the membrane and the SC contribute to controlling the delivery of TM. When the microporous LFC 1 membrane is applied, the TM delivery is membrane controlled. In all cases, however, the efficiency of the TM delivery is low and would need to be improved for the development of a commercially viable product.

Passive and iontophoretic controlled delivery of salmon calcitonin through artificial membranes.

The development of a transdermal delivery system for drug molecules of high molecular weight (peptides or proteins) is nowadays a great scientific and commercial challenge. For these molecules, the passive transport through the skin is generally very low and should be enhanced by the application of the electrical current (a method called iontophoresis). A very important component of a transdermal iontophoretic system is the artificial membrane, which acts as the interface between the drug reservoir and the skin. The optimum membrane should (i) provide an effective drug delivery; (ii) have low electrical resistance and (ii) have low drug adsorption. In this work, the selection of membrane(s) for a transdermal iontophoretic salmon calcitonin (sCT, MW approximately 3500) system is performed. The passive and iontophoretic transport of sCT through porous artificial membranes, the sCT adsorption to them and the electrical resistance of all porous membranes in iontophoretic experiments is studied. The sCT transport through the membranes is compared with that through human skin, and based on the above three criteria the optimum membranes are selected for the sCT transdermal system.

In vitro evaluation of a hydroxypropyl cellulose gel system for transdermal delivery of timolol.

In this work, the development of a gel reservoir for a timolol (TM) transdermal iontophoretic delivery system is investigated. TM gel is prepared using hydroxypropyl cellulose (HPC) and the permeability of TM from the gel through an artificial membrane (Polyflux) and pig stratum corneum (SC) is studied. For a constant TM donor concentration, the TM transport across the Polyflux membrane alone decreases when the concentration of the gel increases due to increase of the gel viscosity. For constant gel concentration, however, the TM permeation across the membrane increases when the TM donor concentration increases. In addition, no effect of the electrical current (iontophoresis, current density 0.5 mA cm-2) on the TM permeation is found. For the combination of the Polyflux membrane with pig SC, the TM transport is much lower than for the membrane alone and the SC fully controls the TM delivery. In this case, the application of electrical current enhances the TM delivery 13-15 times in comparison to passive (no current) transport. According to our estimation, the daily TM dose (10-60 mg) can be delivered by an iontophoretic patch with Polyflux membrane area of 6-36 cm2 containing 20% (w/w) HPC gel and 15 mg cm-3 of TM.