Over the past decades, topical salicylates are still a popular drug candidate for investigations, especially in advanced technology and development in the field of drug delivery to the skin [36]. There are many products in different application forms intended for the topical administration of salicylates, containing salicylic acid, salicylate esters (methyl, glycol) or salicylate salts (triethanolamine, diethylamine) available on the market for use in human, veterinary and sports medicine and cosmetics.

Topical salicylates are used to treat skin conditions that involve scaling or overgrowth of skin cells such as psoriasis, ichthyoses, dandruff, corns, calluses, and warts on the hands or feet by softening and loosening dry, scaly, or thickened skin so that it falls off or can be removed easily[12], [35]. One of the important indications of salicylates is musculoskeletal pain treatment, such as delaying the onset of muscle soreness (DOMS)[5], [19].

Already in the 1990s, studies demonstrating direct penetration of topically applied salicylate into underlying tissues with subsequent extensive metabolism to salicylic acid were published[7], [20]. However, at the same time, the steady-state salicylate plasma concentrations were found to be extremely low and unlikely to result in any real systemic effect. The usefulness of topical salicylate-containing products in drug therapy is therefore limited primarily to their local effect. Local adverse effects have occurred in only 2 % of subjects and without a significant difference between the treatment and the placebo group [17].

In addition to salicylic acid, the main therapeutically used substance from the group of non-acetylated salicylates is methyl salicylate (MS). Methyl salicylate is contained in high concentrations in commonly available over-the-counter topical agents[21] used for pain and inflammatory conditions affecting muscles and joints. MS is converted to pharmacologically effective salicylic acid by the skin carboxyesterases [27]. Under certain conditions, chemical hydrolysis of MS can occur too, usually at pH > 7[4]. Since the skin is typically pH 5.5, hydrolysis of MS is expected to be mediated by skin esterases or to occur in the subcutaneous tissue at physiological pH[33].

A fundamental prerequisite for the effective topical delivery of any active pharmaceutical ingredient (API) is to ensure that the formulation remains at the site of application. Film-forming systems (FFSs) represent an alternative to conventional topical preparations – especially solutions, emulsions, gels, creams, but also medicated plasters. FFSs are described as a non-solid dosage form that produces a film in situ, i.e., after its application to the skin. These systems are composed of an active substance and film-forming ingredients diffused in a vehicle, which evaporates or absorbs rapidly in the stratum corneum, leaving behind an adhesive film of excipients along with the drug.

Besides the fact that FFSs overcome some of the drawbacks of conventional topical products, such as occlusion of sweat ducts and painful removal (patches) or easy wipe-off leading to subtherapeutic drug levels (creams, ointments, gels), they can also act as a drug reservoir, reducing the frequency of necessary applications and thus improving the patient compliance[18], [32]. Additionally, their cosmetic aspects may be more appealing than those of semisolids as they are fast drying, less greasy and more discrete thanks to their transparency[10].

Despite the frequent use of PLGA in the formulation of micro- and nanoparticles, the number of PLGA-based FFSs for topical drug delivery reported in the literature is limited. Kim et al. tested films with commercially available PLGA of different molecular weights in combination with ethyl 2-cyanoacrylate for the delivery of trolamine salicylate[14]. On the contrary, Snejdrova et al. prepared terbinafine hydrochloride-loaded FFSs with in-house optimized PLGA derivatives[29]. Other relevant information on FFSs is summarized in a number of review articles [23], [34].

The primary objective of this formulation study is to optimize the composition and properties of poly(lactic-co-glycolic acid) (PLGA) in situ formed films to achieve sustained and prolonged release of salicylates. Based on our previous studies [30], we carefully selected a non-commercial PLGA derivative branched on poly(acrylic acid). Thanks to its chain architecture, lower molar mass, and acid-terminated branches, this polymer carrier exhibits lower swelling, reduced hydrophobicity, and increased drug loading capacity, which makes it a suitable carrier for local sustained drug delivery. As a source of salicylates, salicylic acid itself and – especially – methyl salicylate were used. The latter acting also as a plasticizer of the PLGA carrier[28], which should reduce the glass transition temperature of amorphous PLGA towards skin temperature, solve the problem of PLGA film fragility and, last but not least, contribute to the optimization of the drug release profile. Such multifunctional drug and excipients are particularly valued in the formulation of drug delivery systems[13]. The PLGA films were characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectrometry (FT-IR), rheological tests, and scanning electron microscopy (SEM). The emphasis was placed on salicylic acid and methyl salicylate dissolution testing, which finally revealed the optimal formulation.