Microprocessor controlled transdermal drug delivery.

Transdermal drug delivery via iontophoresis is reviewed with special focus on the delivery of lidocaine for local anesthesia and fentanyl for patient controlled acute therapy such as postoperative pain. The role of the microprocessor controller in achieving dosimetry, alternating/reverse polarity, pre-programmed, and sensor-based delivery is highlighted. Unique features such as the use of tactile signaling, telemetry control, and pulsatile waveforms in iontophoretic drug delivery are described briefly.

Scanning electrochemical microscopy of iontophoretic transport in hairless mouse skin. Analysis of the relative contributions of diffusion, migration, and electroosmosis to transport in hair follicles.

Scanning electrochemical microscopy (SECM) is used to measure spatially localized diffusive and iontophoretic transport rates in hairless mouse skin. Molecular fluxes within individual hair follicles are quantified by measuring the rate at which redox-active probe molecules emerge from the follicle. The influence of an applied current on the flux of an anion (ascorbate), a cation (ferrocenylmethyltrimethylammonium), and a neutral molecule (acetaminophen) is used to determine the contributions of diffusion, migration, and electroosmosis to iontophoretic transport. The direction of electroosmotic transport is consistent with hair follicles possessing a net negative charge at neutral pH. Electroosmosis results in a modest increase in the transport rate of the neutral molecule (a factor of approximately 2.4x at an iontophoretic current density of 0.1 mA/cm(2)). Larger enhancements in the flux of the electrically charged species are associated with migration. The electroosmotic flow velocity within hair follicles is established to be 0.5 (+/-0.1) microm/s at 0.1 mA/cm(2), independent of the electrical charge of permeant. The net volume flow rate across skin resulting from electroosmosis in hair follicles is estimated to be 0.3 microL/cm(2)h. The results suggest that hair follicles are a significant pathway for electroosmotic solution flow during iontophoresis. The radius of the hair follicle openings in hairless mouse skin is measured to be 21 +/- 5 microm.

Direct imaging of molecular transport through skin.

Scanning electrochemical microscopy (SECM) was used to image spatial variations in the molecular flux of Fe(CN)6(-4) across excised hairless and nude mouse skin. The SECM response is specific to electroactive molecules, allowing selective imaging of the flux of Fe(CN)6(-4) in multicomponent ionic solutions. Quantitative SECM image analysis demonstrated that 40% to 60% of the total Fe(CN)6(-4) flux occurred through appendages in the skin. SECM analysis of skin samples exposed to a known transport enhancer, sodium dodecylsulfate, indicated that the increase in the ion transport rate occurred exclusively in nonporous skin tissue.

Transport of ionic species in skin: contribution of pores to the overall skin conductance.

Two methods are reported that allow visualization of high conductance paths in skin at current densities typically used during clinical iontophoretic drug delivery (10-200 microA/cm2). In the first method, the counter-directional iontophoretic transport of Fe(CN)6(4-) and Fe3+ across skin results in the precipitation of colloidal prussian blue, Fe4[Fe(CN)6]3, at sites of high iontophoretic flux. The appearance of localized deposits of Fe4[Fe(CN)6]3 is recorded by video microscopy and used to document the activation of low-resistance paths. In the second method, the ionic flux of Fe(CN)6(4-) through pores is directly imaged by scanning electrochemical microscopy (SECM). Both methods demonstrate that the iontophoretic flux across skin is highly localized. Activation of low-resistance pores in hairless mouse skin is shown to occur during iontophoresis. The spatial density of current carrying pores increases from 0 to 100-600 pores/cm2 during the first 30-60 min of iontophoresis. At longer times, the active pore density approaches a quasi-steady-state value that is proportional to the applied current density. The total conductance of the skin is proportional to the number of pores, consistent with a model of conduction in skin that is comprised of low-resistivity pores in parallel with a high-resistivity bulk phase. The contribution of pores to the total skin conductance during iontophoresis increases from an initial value of 0-5% to a quasi-steady-state value of 50-95%.

Iontophoretic transport through porous membranes using scanning electrochemical microscopy: application to in vitro studies of ion fluxes through skin.

Scanning electrochemical microscopy (SECM) is used to map localized iontophoretic fluxes of electroactive species through porous membranes. A method is described that allows both the rate of transport of species from a microscopic pore and the pore's diameter to be measured. SECM images and analyses of synthetic porous membranes (track-etched polycarbonate and mica membranes) and hairless mouse skin are reported. Preliminary analysis of SECM images of the mouse skin indicates that a significant percentage of the iontophoretic flux occurs through pores associated with hair follicles.

Iontophoretic delivery of model inorganic and drug ions.

The in vitro delivery of the inorganic ions Li+, Na+, K+, Mg2+, and Ca2+, and the model organic ions pyridostigmine and propranolol through various types of excised skin was investigated using a constant current iontophoretic system. The drug delivery rate was found to be linearly dependent on current for each ion. The slope of this linear dependence is defined as the iontophoretic flux and was used to calculate the efficiency of drug delivery which was found to be virtually independent of the type of skin employed. However, the efficiency of drug delivery was affected by the anode material and drug counterion employed in the iontophoretic system. In addition, the efficiency of delivery for divalent magnesium and calcium ions was found to be less than half that observed for the monovalent sodium and potassium ions. The in vivo iontophoretic delivery of pyridostigmine using the domestic weanling pig is also reported. The in vivo results were found to be similar to those observed in vitro.

STUDIES IN CRATAEGUS (ROSACEAE: MALOIDEAE) XIV. THE BREEDING SYSTEM OF CRATAEGUS CRUS-GALLI SENSU LATO IN ONTARIO.

Crataegus crus-galli L. sensu lato in southern Ontario is a complex of taxa, two of which appear to consist exclusively of both triploid and tetraploid individuals. While pollen fertility is reduced in triploids, both ploidy levels are characterized by production of eight nucleate aposporous embryo-sacs and hence remain seed-fertile; in addition, single, apparently sexual, embryo-sacs are found in the ovules of tetraploids. Agamospermy is shown experimentally to be pseudogamous. Polyploidy in C. crus-galli s.l. is accompanied by self-compatibility, in contrast to the self-incompatibility of diploid Crataegus species such as C. punctata, with which comparison is made. The weediness of the component taxa of C. crus-galli s.l., in general, and their tendency toward uniparental reproduction, in particular, may explain the homogeneity of their topodemes, and the way in which these topodemes may be markedly differentiated from one another even within a single taxon.