Dependence of skin drug permeation on microstructure and time dependent alterations following application of more-phasic dermatological formulations studied by the continuous phase drug concentration concept

In this work, the dependence of transdermal delivery of hydrophilic drugs on mass fraction and
microstructure of dispersed phase of multi-phase dermatological o/w formulations was studied.
Permeation of sodium nicotinate, caffeine and benzyltrimethylammonium chloride (BTA-Cl),
used as model drugs, was studied under occlusive conditions. Sodium nicotinate permeation
was also investigated non-occlusively taking especially into consideration alterations these
formulations may undergo due to evaporation of volatile components. The study formulations
included a typical emulsion (E) consisting of triglycerides, emulsifier (polysorbate 20) aqueous
buffer pH 7.4 and ethanol, a typical liposomal dispersion (LD) consisting of phospholipids,
aqueous buffer pH 7.4 and ethanol and two complex formulations, CF10 and CF50, each
consisting of all these components. These formulations were designed in order to consider not
only diversity in their composition but also widely varying ratios of dispersed to continuous
phase. CF50 and E contained a high amount of dispersed phase of 50 weight-% and LD and
CF10 a comparatively low amount of dispersed phase of 10 weight-%. Permeation was studied
in-vitro using Franz-type diffusion cells across excised full-thickness pig ear skin. A concept is
proposed for the interpretation of the permeation data. This concept postulates that continuous
phase drug concentration of the formulations is the only parameter governing permeation
kinetics. As reference, purely aqueous or aqueous/ethanolic gel formulations were used.
Coexisting dispersed structures of the formulations were fractionated using ultracentrifugation.
The received fractions of all formulations were characterised by chemical component analysis,
scanning electron microscopy and particle size measurements. Emulsion droplets were
creaming and liposomes sedimenting, as attested by formulation E and LD, respectively. CF50
comprised emulsion droplets and a microemulsion that consisted of 13 weight-%
phospholipids, 13 weight-% triglycerides, 10 weight-% polysorbate 20 and of 64 weight-%
hydrophilic phase. NMR-diffusion measurements demonstrated a droplet-like o/w structure for
this system. Particle size measurements following different dilution steps indicated a stable
droplet size of 20-24 nm. No liposomal structures were detected within CF50. For CF10, a
coexistence of liposomes, emulsion droplets and small quantity of microemulsion aggregates
was found. The continuous phase of all formulations consisted of aqueous buffer and the total
amount of ethanol, independently of dispersed structures. Distribution of the drugs between
distinct phases of the formulations was studied using the shake-flask method and ultrafiltration.
Sodium nicotinate and BTA-Cl distributed completely into the hydrophilic phase of the
formulations, according to their solubility properties, while caffeine showed moderate
distribution into triglycerides. Based on these observations, continuous phase drug
concentrations were calculated.
Caffeine permeation from the formulations across a silicon membrane gave equal permeability
coefficients, calculated with continuous phase drug concentration, clearly demonstrating the
validity of the proposed concept. Permeability coefficients across skin, however, were different,
depending on the formulation. The same was true also for BTA-Cl and sodium nicotinate. This
was not due to variable molecular mobility of drug within the formulations, as attested with
sodium nicotinate NMR diffusion experiments. The possible effect of formulations on the
barrier function of the skin was investigated by measuring distribution of drugs between the
stratum corneum and continuous phase of the formulations and calculating the diffusion
coefficients within the stratum corneum. This demonstrated clearly that CF10 and CF50 were
able to increase drug diffusion coefficients within the stratum corneum statistical significantly
for all model drugs. Furthermore, a reduction of drug distribution between stratum corneum
and formulation with increasing amount of dispersed phase of all formulations was observed
which was responsible for retardation of skin permeation. Drug permeation was ultimately the
combined result of these two contrasting formulation effects on skin barrier function. The
diffusion enhancing effect of CF10 and CF50 was shown to be due to the microemulsions
contained in these formulations. The presence of ethanol was found to be essential for this
effect, demonstrating a synergism of the microemulsions with the ethanol.
During evaporation of volatile formulation compounds, several phase transitions were
detected, such as: vesicle to microemulsion in case of CF10, phase inversion from o/w to w/o
in case of CF50 and drug precipitation due to exceeded maximum solubility in case of E. For
LD and CF10, sodium nicotinate fluxes were continuously increasing in course of the
permeation experiments. The emulsion yielded a constant flux, while the phase inversion
observed in case of CF50 very likely caused a decrease in permeation. For quantitative
interpretation of the permeation data, the continuous phase drug concentration concept was
expanded to the situation of non-occlusive application. The increase of permeability for nonocclusively
applied formulations was up to tenfold, compared to an occlusively applied purely
aqueous gel. This could be explained by the resulting continuous phase drug concentrations,
independently of arising microstructures. Hence, this concentration governed sodium
nicotinate permeation in this situation alone, without the need to consider formulation effects
on skin barrier function. This is in good agreement with the observed synergism of the ethanol
with the microemulsions, because ethanol evaporated very quickly from the formulations
following non-occlusive application.
To conclude, taking into account continuous phase drug concentration of multi-phase
formulations provides a predictive tool in order to delineate the effect of physicochemical
formulation parameters and of formulation effects on skin barrier function on delivery rate. This
is true for occlusive and non-occlusive application.