## 4 Discussion
At first we demonstrated higher permeability of ibuprofen and its derivatives, with Pentravan(r) as vehicle compared to commercial preparations [2,29]. In other studies, Pentravan(r) was used as a vaginal delivery vehicle for hormonal medications [34]. The presented studies first allowed us to assess the possibility of combining naproxen and its salt with Pentravan(r) as a vehicle also with substances commonly used as penetration enhancers--method and TinCap. The menthol or capsaicin has an analgesic effect confirmed in experimental and clinical models. Both are sensates which provide a cooling (menthol) or warming (capsaicin) sensation when used in topical applications. They have been described previously in other studies [35,36]. Menthol is a specific terpene often used as an agent to increase skin penetration. The action of terpenes mainly involves changes in the SC barrier structure and interactions with intercellular lipids [37]. Terpenes loosen the ceramide structure, which is the main component of SC [38], thus increasing drug penetration [37,39,40,41,42]. Whereas capsaicin, classified as an alkaloid, stimulates sensory nerve endings, causes local skin hyperaemia and induces a warming sensation, which is beneficial in neuralgia pharmacotherapy [43]. It turned out that naproxen in the unmodified acid form is compatible with the Pentravan(r) vehicle used, also with the addition of both penetration enhancers. However, menthol shortens the time remaining the compositions homogeneous. The naproxen salt--[ProOiPr][NAP], also forms stable emulsions based on Pentravan(r), without and with addition of TinCap, while with menthol the composition is unstable and the liquid phase separates from the emulsion immediately after preparation. Moreover, the viscosity of the compositions with naproxen salt were lower than with naproxen acid, which may also affect the spreadability and thickness of the composition layer on the skin. The influence of these factors should be verified by in vivo tests. Our study showed that both unmodifiedNAP and [ProOiPr][NAP] combined with the Pentravan(r) vehicle are effectively released from the vehicle and penetrate through the human skin. However, the naproxen salt [ProOiPr][NAP] used in the Pentravan(r) based compositions provides much faster penetration the skin by the drug. Additionally, after 24 h, almost 2.5 times higher amount of permeated drug was demonstrated for salt than for the unmodified acid form of naproxen from Pentravan(r) based topical composition without any penetration enhancer. Moreover, the addition of TinCap to the composition comprising naproxen modified with proline isopropyl ester, significantly affects the steady drug permeation throughout the entire range of time tested. After 24 h, the cumulated mass of the drug in the receptor fluid was twice as high with TinCap as without it. The developed topical compositions based on the Pentravan(r), the registered pharmaceutical raw material, can be contribution for the prescription preparations prescribed by a physicians, made in compounding pharmacies for individual patients in the pharmacotherapy of pain of various origins, e.g., in diseases of the musculoskeletal system and rheumatic diseases and soft tissue pain. The presented results of the in vitro human skin permeation studies may be a starting point for the clinical trials and approving process.