Transdermal delivery of diclofenac salts from saturated aqueous solutions

Diclofenac is a relatively safe and tolerable NSAID, that has a potent anti-inflammatory effect, but it is poorly soluble and is almost always formulated as a salt. Serious gastrointestinal adverse effects occasionally appear after oral administration: owing to its adverse effects, its high portion of hepatic first-pass metabolism (∼50%) as well as its short biological half-life, the topical application of diclofenac provides, therefore, a preferred alternative to the oral dosage forms. Despite salts are reported not to penetrate well through skin and not to reach an effective concentration at the site of action after transdermal application, the diethylammoniun salt of diclofenac in a topical medication has been reported to be particularly suitable for musculoskeletal pain and localized forms of non-articular rheumatism and inflammations of well-defined areas near the body surface; moreover recently appeared on the pharmaceutical market a patch for transdermal administration of diclofenac in the form of a N-(2-hydroxyethyl) pyrrolidine salt, with satisfactory efficiency. For this reason, we wanted to explore the possibility to use alternative salts for transdermal application of diclofenac. The following bases: monoethylamine (EtA), diethylamine (diEtA), triethylamine (triEtA); monoethanolamine (MEA), diethanolamine (DEA), triethanolamine (TEA); pyrrolidine, piperidine, morpholine, piperazine and their N-2-hydroxyethyl analogues were employed to prepare diclofenac salts. The salts were re-crystallized from water in order to employ into the donor compartment the form stable in the presence of water: these compounds in fact are known to exist in different hydrate or polymorph forms. Vertical Franz-type diffusion cells with a diffusional surface area of 9.62 cm2 were used to study the permeability of diclofenac salts from their saturated solutions: membrane samples were excised from the internal pig ear, after suitable preparation. They were then placed between the donor and receptor compartments of the cells, containing 100 mL of phosphate buffer (pH 7.4), in the receptor compartment and a saturated solution (5 ml) of each salt in the donor compartment, at 37±0.5°C, using a thermostatic water bath. The aliquots were withdrawn at predetermined time intervals (for 25 h) and then immediately analyzed by HPLC. Three replicates of each experiment were performed. Fluxes were determined as usual plotting the permeated amount, normalised for the membrane surface area, against time. The plot shows an example of ex-vivo permeation of sodium naproxen from a 0.5% w/v aqueous solution. After a lag time (≈1 h) the naproxen concentration linearly increases in the receptor compartment