Targeted dermal delivery of highly potent anti-varicella zoster virus nucleoside analogues from saturated solutions and ethanolic oil-in-water creams.
Varicella zoster virus (VZV) is responsible for causing chickenpox and shingles infections, the latter of which can lead to long-term post-herpetic neuralgia (PHN), the most common complication of VZV infections. A class of anti-VZV nucleoside analogues has been synthesised that shows up to 30,000 times the potency of aciclovir in vitro. The relatively high lipophilicities exhibited by the compounds led them to be selected for dermal delivery. The aim was to assess the relative penetration and permeation of the compounds into and through the skin, ideally targeting the region of skin in which the reactivated virus replicates. By targeting the skin it should be possible to reduce the viral load that causes damage to the nerves, thereby limiting zoster-associated pain, in particular PHN. Three compounds, as saturated solutions or as ethanol-based creams, were applied to full-thickness pig ear skin in Franz-type diffusion cells. An ethanolic and water receptor phases were compared. Samples of the receptor phase were taken at specific intervals, followed by tape stripping and separation of the remaining membrane at the end of the experiment. Analysis of the samples showed that all three compounds penetrated into the ethanolic receptor phase to a considerable degree, while only the least lipophilic compound entered the water receptor phase. The effects of the organic solvent in the receptor phase were visible in both the penetration and permeation of the compounds. All three compounds were distributed throughout the membrane in a manner that indicates that the site of viral replication in the skin is reached.
Jarvis
Chris A
CA
Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3XF, UK.
Heard
Charles M
CM
McGuigan
Chris
C
D000279:Administration, Cutaneous; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D004431:Ear, External / Q000378:metabolism; D000431:Ethanol; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D066298:In Vitro Techniques; D009705:Nucleosides / Q000008:administration & dosage* / Q000627:therapeutic use*; D009824:Ointments; D019999:Pharmaceutical Solutions; D012869:Skin Absorption; D013552:Swine; D014867:Water
D000998:Antiviral Agents; D009705:Nucleosides; D009824:Ointments; D019999:Pharmaceutical Solutions; D014867:Water; D000431:Ethanol