Ion-pair formation as a strategy to enhance topical delivery of salicylic acid.

An in-vitro study was carried out to determine the possibility of improving the efficiency of transdermal delivery of salicylate through human epidermis by ion-pair formers (alkylamines and quaternary ammonium ions). Further, the relationship between the physicochemical properties of the counter-ions and salicylate flux was examined. It was found that flux can be related to the conductivity associated with the penetrant solution, molecular size of the counter-ion and lipophilicity expressed as either octanol/water partition coefficient of the ion pairs or the carbon chain-length of the counter-ions. Equations have been developed to predict salicylate flux from these physicochemical parameters.

Effect of ion pairing with alkylamines on the in-vitro dermal penetration and local tissue disposition of salicylates.

Hydrophilic ionic drugs can be rendered lipophilic by ion-pair formation with hydrophobic counter-ions. This study examines the value of forming ion pairs between anionic salicylate and a series of amines as model cationic counter-ions to facilitate topical delivery and skin penetration. The in-vitro translocation of salicylate ions from a nonaqueous vehicle through human epidermis was estimated in the presence or absence of amines. The distribution into, and accumulation of the salicylate ion in various tissues following topical application to anaesthetised rats were also investigated. Although the epidermal permeation constants of the salicylate-amine ion pairs were lower than that of salicylate itself (enhancement ratios: 0.74-0.87), salicylate retention and localisation in the underlying rat tissues increased in the presence of some of the counter-ions studied. Salicylate concentrations (microg (g tissue)(-1)) in the dermis were 877.2+/-78.6 for salicylate alone and 1098+/-121.9-2586+/-332.5 for salicylate-amine ion pairs. The levels of salicylate in tissues up to the top muscle layer were 1.2-3.7-fold higher in the presence of the counter-ions. It is concluded that, although amine counter-ions have the ability to influence the penetration of salicylate, in-vitro permeability studies do not reflect the in-vivo increases in tissue concentrations resulting from probable changes in systemic clearance.

Self promotion of deep tissue penetration and distribution of methylsalicylate after topical application.

PURPOSE: To determine how changes in cutaneous blood flow induced in-vivo by methylsalicylate (MeSA), compared to non-rubefacient triethanolamine salicylate (TSA), affected topical salicylate absorption and distribution, and to assess formulation therapeutic potential by comparing tissue concentrations to published antiinflammatory concentrations. METHODS: Flux of salicylate from MeSA and TSA formulations applied to full-thickness rat skin was determined using in vitro diffusion cells. Anaesthetised rats were then used to quantify salicylate concentrations in plasma and tissues underlying the application site for the two formulations over a 6h period. In vitro and in vivo absorption profiles were then compared and the effect of MeSA on cutaneous blood flow assessed. RESULTS: In vitro flux of salicylate from the MeSA formulation was 40% higher, though after correcting for differences in formulation concentrations the ratio of permeability coefficients was reversed. Contrary to the in vitro predictions, in vivo tissue and plasma concentrations of salicylate in rats rose rapidly in the first 1 hr and were more than the predicted 1.4-fold higher for MeSA. This effect was mirrored by the increase in blood flow induced by MeSA in human cutaneous vessels and that reported in the literature. Potential therapeutic levels were not seen below superficial muscle layers. CONCLUSIONS: Direct tissue penetration of salicylate occurs below application sites from both MeSA and TSA formulations. Tissue concentrations of MeSA were higher than predicted due to its rapid distribution in the blood.

Percutaneous absorption of salicylates from some commercially available topical products containing methyl salicylate or salicylate salts in rats.

Studies to determine the extent of local tissue penetration of topically applied, commercially available salicylate esters and salts were conducted in male Wistar rats. The salicylate concentration in plasma, tissues underlying the site of drug application, and similar tissues on the contralateral (control) side were measured. The plasma and tissue salicylate levels suggest that direct penetration of salicylate was predominant to the top muscle level on the treated site. Results also suggest that the drugs were first absorbed into the bloodstream and subsequently distributed to both the deeper tissues on the treated site and the contralateral tissues. The topical application of formulations of ester methyl salicylate and salts triethanolamine salicylate and diethylamine salicylate containing comparable salicylate concentrations yielded similar salicylate concentrations in the various tissues. The salicylate concentrations in the deeper tissues approached concentrations observed in the contralateral tissues suggesting that salicylate present in these tissues was due to the systemic blood supply.