Purpose: Over the counter topical analgesics are used to relieve muscular and joint pains such as arthritis, backache, muscle strains, sprains, and bruises. They are generally preferred by patients and prescribers due to frequent gastrointestinal side effects associated with oral NSAIDs. Topical salicylates are known to be absorbed by the tissue and have been reported to be effective in relieving local pain. Trolamine salicylate (TS) is a derivative of salicylate that inhibits cyclo-oxygenase enzymes and reduces inflammation. Unlike other topical analgesics such as menthol and camphor, it offers many benefits including no distinct odor, low systemic absorption upon dermal or topical administration and low skin irritant properties. Although topical salicylates are widely used, compliance is low due to their frequent dosing regimen (three to four times a day). In this study, the difference between single and multiple dosing of TS across porcine ear skin was determined in in vitro settings.
Methods: All the formulations that were used in this study were prepared in 50:50 (propylene glycol: DI water). To determine the dosing interval of dose frequency study, permeation study was carried out with three different drug concentrations: 0.1%, 1%, and 10% (w/v) for 72 h. In vitro drug permeation studies were performed using vertical Franz diffusion cells and dermatomed porcine ear skin. Formulation was applied on the donor using a positive displacement pipette. For the single dose group, the formulation was only applied once, whereas, in the multiple dose group, skin surface wash was performed carefully, and the new formulation was re-applied every 8 h. Sampling from the receptor solution was performed at predetermined time points. Phosphate buffered saline (10 mM, pH 7.4) was used as the receptor solution. Amount of TS was detected and quantified using HPLC. Statistical analysis was performed using student’s t test and p<0.05 was considered for concluding significant difference between the groups.
Results: The in vitro percutaneous absorption of TS was 8.98 ± 0.39 µg/sq.cm, 57.97 ± 3.42 µg/sq.cm, and 344.77 ± 73.78 µg/sq.cm in 0.1%, 1%, and 10% TS respectively. Percent delivery was the highest in 0.1% TS as 89.78 ± 3.85 %, and it decreased gradually to 65.53 ± 3.27 % in 1% TS group and 44.78 ± 6.07 % in 10% formulation at the end of 72 h. Based on the results of the concentration study, 0.1% TS formulation was selected for dose frequency study as the corresponding flux showed recovery over the 72 h study period, thereby establishing this as a finite dose for investigating effect of multiple applications (maximum flux of 0.55 ± 0.34 µg/sq.cm at 8 h ; minimum flux of 0.01 ± 0.01 µg/sq.cm at 72 h). The amount of TS delivered in the receptor solution after 24 h was found to be 6.46 ± 0.55 µg/sq.cm in the single dose group and 9.56 ± 8.53 µg/sq.cm in multiple dose group. The result showed that there was no significant difference in receptor solution between two groups. The amount of TS observed in viable epidermis and dermis at the end of 24 h was found to be 1.38 ± 0.24 µg/sq.cm and 4.70 ± 1.49 µg/sq.cm in single dose and multiple dose group, respectively. The amount of drug delivered in the skin was not significantly different between the two groups (p>0.05).
Conclusion: In vitro permeation of TS across skin showed a concentration dependent profile over 3 days, and 0.1% formulation provided a finite dose showing flux recovery. Single vs. multiple application of 0.1% TS formulation did not show any significant difference in the amount of drug delivered, into and across skin after 24 h.