Effect of concentration and degree of saturation of topical fluocinonide formulations on in vitro membrane transport and in vivo availability on human skin.
OBJECTIVE
The thermodynamic activity of drugs in topical vehicles is considered to significantly influence topical delivery. In vitro diffusion across a synthetic membrane was shown to be correlated to the degree of saturation of the drug in the applied vehicle and therefore offers a potential for increased topical drug delivery. Fluocinonide a topical corticosteroid, was chosen as a model compound to investigate in vitro and in vivo availability from formulations with different degrees of saturation.


METHODS
Sub-, as well as, supersaturated drug solutions were prepared using PVP as an antinucleant agent. In vitro membrane diffusion experiments across silicone membrane and in vivo pharmacodynamic activity assessments, using the human skin blanching assay, were carried out.


RESULTS
Over the concentration range studied, the in vitro membrane transport of fluocinonide was proportional to the degree of saturation of the respective formulations. The in vivo pharmacodynamic response in the human skin blanching assay was related to the concentration of the drug in the vehicle irrespective of the degree of saturation.


CONCLUSIONS
From the membrane permeation experiment it can be concluded, that the drug flux might be increased supra-proportionally with increasing donor concentration, drug (super-)saturation (proportional), beyond what would be anticipated based on ideal donor concentration and partition coefficient considerations only. These findings could not be confirmed in the in vivo investigation, probably due to additional vehicle effects (e.g., enhancement, irritation, drug binding) which have to be expected and could have altered the integrity of the stratum corneum and therewith topical bioavailability of the drug.
Schwarb
F P
FP
Institute of Hospital-Pharmacy and Department of Dermatology, University Hospitals, Basel, Switzerland.
Imanidis
G
G
Smith
E W
EW
Haigh
J M
JM
Surber
C
C
D000287:Administration, Topical; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D002463:Cell Membrane Permeability; D002626:Chemistry, Pharmaceutical; D000431:Ethanol / Q000494:pharmacology; D005447:Fluocinonide / Q000493:pharmacokinetics*; D005938:Glucocorticoids; D005990:Glycerol / Q000494:pharmacology; D006801:Humans; D019946:Propylene Glycol / Q000494:pharmacology; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects; D012996:Solutions / Q000493:pharmacokinetics; D014867:Water / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D012996:Solutions; D014867:Water; D005447:Fluocinonide; D000431:Ethanol; D019946:Propylene Glycol; D005990:Glycerol