In vitro percutaneous absorption of arildone, a highly lipophilic drug, and the apparent no-effect of the penetration enhancer Azone in excised human skin.

PURPOSE: Arildone, a novel lipophilic antiviral drug when evaluated in Clinical Trials showed limited skin absorption and antiviral efficacy. These studies were conducted to explain the apparent poor absorption characteristics and attempt to promote skin absorption by using Azone, a penetration enhancer.
METHODS: Standard in vitro skin permeation methods using excised human skin were employed to characterise the absorption of Arildone. 14C-Arildone was used to estimate the distribution in skin layers by scintigraphic and autoradiographic procedures.
RESULTS: The aqueous solubility and distribution constant values for Arildone were 2 micrograms ml-1 and 5 x 10(5) (isopropyl myristate/water), respectively. Absorption through full thickness skin or stratum corneum-viable epidermal membranes (diffusional resistant dermis removed), from a propylene glycol vehicle, was slow and the addition of Azone had no effect on the permeation rate. Distribution studies showed accumulation of Arildone in the stratum corneum. The concentration of Arildone in the viable epidermis was estimated from sectioning the skin and was found to be in sufficient amounts (400 micrograms cm-3) to have potential antiviral activity.
CONCLUSIONS: The apparent accumulation of Arildone in the stratum corneum suggested that the hydrophilic skin region presented the main barrier to permeation. Azone which affected the permeability of the stratum corneum was therefore not effective at enhancing Arildone absorption. Vehicles which readily permeate and enhance the transfer of lipophilic drugs from the stratum corneum into the viable epidermis were recommended.