Puchun Liu

The effects of ethanol on the transport of lipophilic and polar permeants across hairless mouse skin: Methods/validation of a novel approach

The influence of ethanol on the in vitro transport behavior of some lipophilic and polar/ionic permeants in hairless mouse skin has been investigated over a 0–100% ethanol/saline concentration range in a two-chamber diffusion cell. The lipophilic permeants were employed in probing the transport enhancing effects of ethanol upon the lipoidal pathway of the stratum corneum, and the polar/ionic permeants were used to quantify the influence of ethanol on thepore pathway of the stratum corneum over the entire range of ethanol concentrations. The following were the important interpretations of the data. The lipophilic permeants (estrone, s-estradiol, and hydrocortisone) were mainly transported via the lipoidal pathway up to around 50% ethanol. The permeation enhancement factor, E, for the lipoidal pathway was calcuklated from the transport data for the three lipophilic permeants. In order to calculate the E values, it was first necessary to establish the validity of Henrys law by comparing the ratios of permeant solubilities (in different ethanol/saline solutions) to ratios of permeant partition coefficients (in hexadecane/ethanol-saline systems). The calculated E values were found to be about the same for all three permeants: E = 7.0 ± 2.0 at 25% ethanol and E = 112 ± 19 at 50% ethanol. These large enhancing effects of ethanol upon the lipoidal pathway were somewhat surprising, and it is suggested that ethanol (< 50%) may work as an effective ‘fluidizing’ agent at some locus in the stratum corneum lipid bilayer at or near the polar head plane, but not in the bilayer hydrocarbon interiors. The polar/ionic permeants (tetraethylammonium bromide, mannitol, estrone ammonium sulfate, and vidarabine) all were transported via the pore pathway at all ethanol concentrations. Ethanol up to around 25% had little effect upon the pore pathway; however, at higher concentrations (∼ 50%), ethanol greatly enhanced pore transport and, at very high ethanol levels (t~ 75%), the pore pathway appeared to dominate the transport of all permeants including the lipophilic permeants.

Enhanced transdermal delivery of estradiol in vitro using binary vehicles of isopropyl myristate and short-chain alkanols

Abstract The effect of binary vehicles of isopropyl myristate (IPM) and short-chain alkanols on the enhancement of skin permeation of estradiol (E 2 ) was studied in vitro using human epidermal membrane. The steady-state fluxes of E 2 and solvents across the skin were determined from saturated solutions of neat and binary solvents of IPM and ethanol (EtOH), n -propanol ( n -PrOH), n -octanol ( n -OcOH), or isopropanol (i-PrOH). While the neat solvents modestly increased the E 2 flux, addition of IPM to the alkanols resulted in a synergistic enhancement of the E 2 flux. Among the (1:1) binary cosolvents evaluated, i-PrOH produced the highest E 2 flux (1.1 μg/cm 2 per h), which was 35-fold greater than from water and over 15-fold greater than from the neat solvents. This combination was also the best in terms of relative compositions of the IPM/i-PrOH cosolvents. A strong correlation between E 2 and i-PrOH fluxes suggested the enhancement for both permeants. While i-PrOH traversed the skin, IPM was retained in the stratum corneum. The uptake of both IPM and E 2 in the stratum corneum was largely increased by adding i-PrOH (up to 50%) to IPM.

Variation of human skin permeation in vitro: Ionic vs neutral compounds

Abstract The variation of skin permeation data has been investigated for ionic vs neutral permeants through human cadaver skin. In contrast to neutral ones, ionic permeants produced highly variable flux data with a positively skewed asymmetrical distribution. This permeant-dependent flux variation may suggest that different mechanisms are involved in the in vitro skin transport for ionic and neutral compounds.

Flow-Through System Effects on in Vitro Analysis of Transdermal Systems

The development of transdermal therapeutic systems (TTS) often involves in vitro evaluation of formulations and prototypes using flow-through diffusion cells. The apparent flux obtained from such methodologies does not accurately represent the actual (intrinsic) permeation of the compound through the skin. Flow-through system parameters, i.e., fraction collector tube volume, receiver cell volume, flow rate, and sampling interval, modify the flux yielding an apparent flux. Both finite-dose flux profiles and infinite-dose diffusional lag times are modified by these parameters. In this study, a transfer function is derived which describes the effect of these parameters. The intrinsic flux is calculated from apparent flux data using the transfer function and experimental flow-through system parameters. This allows the calculation of permeant flux profiles devoid of modification by the experimental methodology.

An in vivo investigation of the rabbit skin responses to transdermal iontophoresis.

To optimize the benefits of transdermal iontophoresis, it is necessary to develop a suitable animal model that would allow for extensive assessments of the biological effects associated with electro-transport. Rabbit skin responses to iontophoresis treatments were evaluated by visual scoring and by non-invasive bioengineering parameters and compared with available human data. In the current density range 0.1-1.0 mA/cm(2) applied for 1 h using 0.9% w/v NaCl and 0.5 mA/cm(2) for up to 4 h, no significant irritation was observed. 2 mA/cm(2) applied through an area of 1 cm(2) for 1 h resulted in slight erythema at both active electrode sites but without significant changes in transepidermal water loss (TEWL) and laser Doppler velocimetry (LDV). A value of 4 mA/cm(2) under similar conditions caused moderate erythema at the anode and cathode with TEWL and LDV being significantly elevated at both sites; 1 mA/cm(2) current applied for 4 h, caused moderate erythema at both anode and cathode; and 1 mA/cm(2) applied for 1 h caused no irritation when the area of exposure was increased from 1 to 4.5 cm(2). When significant irritation and barrier impairment occurred, the erythema was resolved within 24 h with barrier recovery complete 3-5 days post-treatment. Rabbit skin thus shows promise as an acceptable model for iontophoresis experiments.

Transdermal iontophoretic delivery of methylphenidate HCl in vitro

Methylphenidate is prescribed orally for Attention Deficit Disorder in children and adults, and for narcolepsy patients. Methylphenidate has a short plasma half-life (1-2 h) and thus needs to be frequently administered for effective therapy. Such therapy has limitations in terms of patient compliance, particularly in young children. For such reasons, the development of a transdermal dosage form of methylphenidate may be useful. This study was undertaken to evaluate the passive and electrically assisted transport (iontophoresis) of methylphenidate from aqueous methylphenidate hydrochloride solutions across excised human skin. A maximum flux of 12.0 micrograms/(cm2 h) of protonated methylphenidate was estimated from the passive transport data at pH 3.5. Iontophoresis significantly enhanced protonated methylphenidate transport as compared with passive delivery. From the present experiments, the efficiency of iontophoretic delivery of methylphenidate was approximately 700 micrograms/(mA h). Based on in vitro skin flux data, the daily dose of 15-40 mg methylphenidate can be achieved using a current density of 0.5 mA/cm2 and a minimum transport area of 2-5 cm2 for 24-h application, or an area of 4-10 cm2 for 12-h (daytime) application. From methylphenidate skin flux values, methylphenidate mobility of 2.2 x 10(-4) cm2/(V s) was estimated, which compares reasonably with its free solution mobility of 6.6 x 10(-4) cm2/(V s).