Philip G. Green

Convective solvent flow across the skin during iontophoresis.

AbstractEnhanced flux of neutral solutes during transdermal iontophoresis is attributed largely to electroosmotic volume flow. In this study, the iontophoretic fluxes of tritiated water (3H2O) and 14C-labeled mannitol through hairless mouse skin (HMS) were determined. The following questions were addressed: (i) What is the variability of water flux during iontophoresis? (ii) To what extent is the iontophoretic flux of a neutral solute correlated with water flux? (iii) Does the intrinsic permeability of the skin to neutral solutes change following iontophoresis? (iv) What is the effect of low pH on electroosmotic volume flow? and (v) Does the skin remain permselective after removal of the stratum corneum? Transport of both water and mannitol reached steady-state levels during 10 hr of constant-current iontophoresis (0.36 mA/cm2). Anodal fluxes exceeded cathodal values. Cathodal mannitol flux was retarded, relative to passive transport, by net volume flow in the opposite direction, such that transport of this molecule increased significantly after the termination of current passage. Anodal equivalent volume flows for water and mannitol, respectively, were 2.7 (±1.3) and 1.23 (±0.59) µL/hr cm2, indicating that only ~50% of the water flux participated in the electroosmosis of mannitol. The passive permeability of water and mannitol after 10 hr of iontophoresis was, respectively, 6 and 30 times greater than the pretreatment values. At pH 7, the cationic permselectivity of HMS was marginal [the Na+ transport number (

Iontophoretic delivery of amino acids and amino acid derivatives across the skin in vitro.

t_{Na} +

lontophoretic Delivery of a Series of Tripeptides Across the Skin in Vitro

) was determined to be 0.46] and less than that reported for human skin. Lowering the pH values of the solutions on either side of the skin to slightly less than 4 reversed the direction of net volume flow; cathodal flux was greater than anodal flux. When the donor solution was at pH 3.8 and the receptor was pH 7.4, the flux profile was complicated and net volume flow was not obvious. Finally, it was found that electroosmosis from anode to cathode was retained even following removal of the stratum corneum by tape-stripping.

Facilitated transfer of cationic drugs across a lipoidal membrane by oleic acid and lauric acid

Abstract The effect of two fatty acids (oleic and lauric) on the transport of the cationic drug naphazoline, neutral caffeine, and an anionic model drug salicylate, across excised human skin was studied using Franz diffusion cells. Oleic and lauric acids both increased the in vitro skin permeation of all penetrants. Oil/water partitioning data and rotating diffusion cell measurements, in the presence of the fatty acids, suggested that the enhanced flux of the cationic naphazoline could be accounted for by an increase in lipophilicity through ion pairing with the carboxylate anion of the acid. Caffeine and sodium salicylate were incapable of forming ion pairs consequently, increases in skin permeability are also due to a disruption of the stratum corneum. This conclusion was further supported by (a) increased transepidermal water loss, and (b) increased in-vivo skin permeation of the non ion-pairing methyl nicotinate, at skin sites pretreated with the fatty acids.

In vitro and in vivo iontophoresis of a tripeptide across nude rat skin

The effects of penetrant properties (lipophilicity and charge) and of vehicle pH on the iontophoretically enhanced delivery of amino acids and their N-acetylated derivatives have been examined in vitro. The penetrants were nine amino acids (five were zwitterionic, two positively charged, and two negatively charged) and four N-acetylated amino acids, which carry a net negative charge at pH 7.4. Iontophoresis at constant current (0.36 mA/cm2), using Ag/AgCl electrodes, was conducted across freshly excised hairless mouse skin. Iontophoretic flux of the zwitterions was significantly greater than passive transport. Delivery from the anode was greater than from the cathode for all zwitterions. The level of enhancement was inversely proportional to permeant octanol/pH 7.4 buffer distribution coefficient. Cathodal iontophoresis of the negatively charged amino acids and of the N-acetylated derivatives produced degrees of enhancement which were significantly greater than those measured for the “neutral” zwitterions. Furthermore, the enhanced flux reached a steady-state level within a few hours for the negatively charged species, whereas the transport of the zwitterions continued to increase with time. Anodal iontophoresis of histidine and lysine, the two positively charged amino acids studied, induced substantial enhancement which was sensitive to the pH of the delivery vehicle. For example, the flux of histidine from an applied solution at pH 4 (where the amino acid carries a net positive charge) was significantly greater than that from a vehicle at pH 7.4 (where histidine is essentially neutral). The behavior of lysine was more complex and suggested a certain degree of neutralization of the skins net negative charge.

Enhanced in vitro skin permeation of cationic drugs

Abstract The utility of iontophoresis, the electrically assisted delivery of drugs across the skin, to overcome some of the obstacles of peptide delivery has been widely reported in the literature. Iontophoresis offers similar advantages to passive transdermal delivery in that it is non-invasive and can deliver drugs in a continuous fashion over a prolonged period of time. However, unlike passive delivery iontophoresis is capable of delivering larger hydrophilic molecules, such as peptides, in a variety of complex dosing scenarios. Human studies have been performed to demonstrate the safe, effective and reproducible delivery of intact peptides to the systemic circulation. Plasma concentration-time profiles from these studies indicate that steady-state plasma levels are achieved rapidly and the decline in plasma levels appears to be absorption limited rather like an intramuscular bolus injection. However, short lag times are observed which are consistent with diffusion across the outermost layers of the skin but shorter than those typically associated with passive transdermal diffusion. In all reported human clinical trials iontophoretic patches appeared to be well tolerated. Iontophoretic drug delivery offers non-invasive, continuous and pulsatile delivery as well as preprogrammed complex dosing regimes. Small battery powered wearable systems for peptide drugs are currently being developed. The non-invasiveness and wide utility of iontophoresis offer a real benefit in convenient drug delivery for the patient.

Iontophoretic delivery of piroxicam across the skin in vitro

The iontophoresis of eight tripeptides, of the general structure alanine–X–alanine, has been measured across hairless mouse skin in vitro. The peptides were blocked (a) at the carboxyl terminus using the mixed anhydride reaction with t-butylamine and (b) at the amino terminus by acetylation with 14C-acetic anhydride. The nature of the central residue (X) was varied by selecting one of five neutral amino acids, two negatively chargeable moieties (aspartic and glutamic acids), and a positively chargeable species (histidine). Constant current iontophoresis at 0.36 mA/cm2, using Ag/AgCl electrodes, was performed for 24 hr in diffusion cells, which allowed both anode and cathode to be situated on the same (epidermal) side of a single piece of skin. Due to a combination of osmotic and electroosmotic forces, the anodal iontophoretic flux of neutral peptides was significantly greater than passive transport. Steady-state fluxes were not achieved, however, suggesting that time-dependent changes in the properties of the skin barrier may be occurring. Limited, further experiments confirmed that, on a 24-hr time scale, these changes were not fully reversible. The cathodal delivery of anionic permeants was well controlled at a steady and highly enhanced rate by the current flow. This behavior closely paralleled earlier work using simple negatively charged amino acids and N-acetylated amino acid derivatives. It appears that the normalized iontophoretic flux of these anionic species is independent of lipophilicity but may be inversely related to molecular weight. The positively charged peptide, Ac–Ala–His–Ala–NH(But), showed greater anodal iontophoretic enhancement when delivered from a donor solution at pH 4.0 than from a solution at pH 7.4. This was consistent with (a) the corresponding behavior of histidine alone and (b) the existence of a pKa for these compounds at ∼6. Steady-state delivery was not achieved, although the levels of enhancement, especially at pH 4, were the largest observed. A preliminary investigation of tripeptide stability to either (i) electrolysis in the donor compartment or (ii) cutaneous metabolism revealed very little degradation under the conditions of the experiment. Overall, this research supports the principle of enhanced peptide delivery across the skin by iontophoresis and indicates a number of areas (e.g., mechanism and extent of current-induced changes in skin barrier function, molecular size dependence, pathways of current flow) on which further work should be focused.

Transdermal iontophoresis of amino acids and peptides in vitro

Abstract The transfer of four β-adrenoceptor blocking agents of different lipophilicity across an artificial lipid membrane was measured using the rotating diffusion cells (RDC). A facilitated transport mechanism was established when oleic acid and lauric acid were incorporated in the membrane, using an appropriate pH gradient. The diffusion of metoprolol, oxprenolol and to a lesser extent propranolol was enhanced by an ion-pair mechanism in the presence of the fatty acids. The transfer of atenolol, the most hydrophilic of the drugs under investigation, was not enhanced. The results are useful in understanding the way in which charged molecules may be transported across biological membranes by ion pair mechanisms and also for the development of solid supported liquid membranes in separation technology.