Penetration of chlorhexidine into human skin

This study evaluated a model of skin permeation to determine the depth of delivery of chlorhexidine into full-thickness excised human skin following topical application of 2% (wt/vol) aqueous chlorhexidine digluconate. Skin permeation studies were performed on full-thickness human skin using Franz diffusion cells with exposure to chlorhexidine for 2 min, 30 min, and 24 h. The concentration of chlorhexidine extracted from skin sections was determined to a depth of 1,500 µm following serial sectioning of the skin using a microtome and analysis by high-performance liquid chromatography. Poor penetration of chlorhexidine into skin following 2-min and 30-min exposures to chlorhexidine was observed (0.157 ± 0.047 and 0.077 ± 0.015 µg/mg tissue within the top 100 µm), and levels of chlorhexidine were minimal at deeper skin depths (less than 0.002 µg/mg tissue below 300 µm). After 24 h of exposure, there was more chlorhexidine within the upper 100-µm sections (7.88 ± 1.37 µg/mg tissue); however, the levels remained low (less than 1 µg/mg tissue) at depths below 300 µm. There was no detectable penetration through the full-thickness skin. The model presented in this study can be used to assess the permeation of antiseptic agents through various layers of skin in vitro. Aqueous chlorhexidine demonstrated poor permeation into the deeper layers of the skin, which may restrict the efficacy of skin antisepsis with this agent. This study lays the foundation for further research in adopting alternative strategies for enhanced skin antisepsis in clinical practice.

Skin delivery potency and antitumor activities of temozolomide ester prodrugs

Clinical trials have shown temozolomide to be an effective agent for treatment of malignant melanoma. In order to investigate its suitability for delivery via the skin, a series of temozolomide esters was synthesized as prodrugs. In vitro assays demonstrated temozolomide, temozolomide acid and the hexyl ester equi-effective against selected cancer cell lines. The susceptibility of the esters to enzyme hydrolysis and their effectiveness for application to the skin were investigated. The esters effectively diffuse through rat skin and the hexyl ester demonstrated profound potency for penetrating through skin. Topical application of 5% (w/v) hexyl ester in DMSO solution on a mouse model demonstrated a significant inhibition of tumor growth. These results suggest that temozolomide esters could be an effective alternative to temozolomide in the treatment of skin cancer. © 2005 Elsevier Ireland Ltd. All rights reserved.

Azidoprofen as a soft anti-flammatory agent for the topical treatment of Psoriasis

Azidoprofen {2-(4-azidophenyl)propionic acid; AZP}, an azido-substituted arylalkanoic acid, was investigated as a model soft drug candidate for a potential topical non-steroidal anti-inflammatory agent (NSAIA). Reversed-phase high performance liquid chromatography (HPLC) methods were developed for the assay of AZP, a series of ester analogues and their· degradation products. 1H-NMR spectroscopy was also employed as an analytical method in selected cases. Reduction of the azido-group to the corresponding amine has been proposed as a potential detoxification mechanism for compounds bearing this substituent. An in vitro assay to measure the susceptibility of azides towards reduction was developed using dithiothreitol as a model reducing agent. The rate of reduction of AZP was found to be base-dependent, hence supporting the postulated mechanism of thiol-mediated reduction via nucleophilic attack by the thiolate anion. Prodrugs may enhance topical bioavailability through the manipulation of physico-chemical properties of the parent drug. A series of ester derivatives of AZP were investigated for their susceptibility to chemical and enzymatic hydrolysis, which regenerates the parent acid. Use of alcoholic cosolvents with differing alkyl functions to that of the ester resulted in transesterification reactions, which were found to be enzyme-mediated. The skin penetration of AZP was assessed using an in vitro hairless mouse skin model, and silastic membrane in some cases. The rate of permeation of AZP was found to be a similar magnitude to that of the well established NSAIA ibuprofen. Penetration rates were dependent on the vehicle pH and drug concentration when solutions were employed. In contrast, flux was independent of pH when suspension formulations were used. Pretreatment of the skin with various enhancer regimes, including oleic acid and azone in propylene glycol, promoted the penetration of AZP. An intense IR absorption due to the azide group serves as a highly diagnostic marker, enabling azido compounds to be detected in the outer layers of the· stratum corneum following their application to skin, using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). This novel application enabled a non-invasive examination of the percutaneous penetration enhancement of a model azido compound in vivo in man, in the presence of the enhancer oleic acid.