In vitro and in vivo evaluation of polyoxyethylene esters as dermal prodrugs of ketoprofen, naproxen and diclofenac.

Novel polyoxyethylene esters of ketoprofen (1(a-e)), naproxen (2(a-e)) and diclofenac (3(a-e)) were synthesized and evaluated as potential dermal prodrugs of naproxen, ketoprofen and diclofenac. These esters were obtained by coupling these drugs with polyoxyethylene glycols by a succinic acid spacer. The aqueous solubilities, lipophilicities and hydrolysis rates of esters 1(a-e), 2(a-e) and 3(a-e) were determined in a buffered solution and in porcine esterase. The permeation of these prodrugs through excised human skin was studied in vitro. Furthermore we investigated the in vivo topical anti-inflammatory activity of esters 1(d), 2(e) and 3(e), which showed the best in vitro profile, evaluating the ability of these compounds to inhibit methyl nicotinate (MN)-induced skin erythema on healthy human volunteers. Esters 1(a-e), 2(a-e) and 3(a-e) showed good water stability and rapid enzymatic cleavage and their hydrolysis rates, both chemical and enzymatic, were not significantly affected by the length of the polyoxyethylenic chain used as promoiety. Concerning in vitro percutaneous absorption studies, only esters 1(d-e), 2(d-e) and 3(c-e) showed an increased flux through stratum corneum and epidermis membranes compared to their respective parent drugs. In vivo results showed an interesting delayed and sustained activity of esters 1(d) and 3(e) compared to the parent drugs. In conclusion polyoxyethylene glycols could prove to be suitable promoieties for ketoprofen, naproxen and diclofenac design since esters 1(d-e), 2(d-e) and 3(c-e) showed some requirements (chemical stability, enzymatic lability and an increased skin permeation) needed to obtain successful dermal prodrugs. Furthermore, was observed an appreciable and sustained in vivo topical anti-inflammatory activity of esters 1(d) and 3(e), compared to the parent drugs, using MN-induced erythema in human volunteers as inflammation model.

In vitro and in vivo evaluation of caffeic and ferulic acids as topical photoprotective agents.

Topically-applied antioxidant drugs represent a successful strategy for protecting the skin against UV-mediated oxidative damage. However, they can afford to the skin a satisfactory photoprotection only if able to permeate through the stratum corneum and thus to reach deeper cutaneous layers. Caffeic and ferulic acids, dissolved in saturated aqueous solutions at pH 3 or 7.2, have been tested for their capability to permeate through excised human skin mounted in Franz cells. At both pH values, ferulic and, at a lower degree, caffeic acids appeared able to permeate through the stratum corneum. The known higher lipophilicity of ferulic acid may explain the fact that it permeates through the stratum corneum better than caffeic acid. However, vehicle pH values proved to have no influence on biophenol skin permeation profile; this observed lack of pH effect may reflect the drug higher concentration attainable in saturated solutions at high pH. On the basis of the findings obtained in these in vitro experiments, we designed the schedule of a series of in vivo experiments, carried out to evaluate the ability of caffeic and ferulic acids to reduce, in healthy human volunteers, UVB-induced skin erythema, monitored by means of reflectance spectrophotometry. Caffeic and ferulic acids, dissolved in saturated aqueous solution pH 7.2, proved to afford a significant protection to the skin against UVB-induced erythema. To conclude, we have confirmed, by means of in vitro and in vivo experiments, that caffeic and ferulic acids may be successfully employed as topical protective agents against UV radiation-induced skin damage; however their skin absorption is not influenced by the pH of the formulation.