Topical Pentravan(r) Based Compositions with Naproxen and Its Proline Ester Derivative--A Comparative Study of Physical Properties and Permeation of Naproxen Through the Human Skin  
[PERSON]  
1 Department of Chemical Organic Technology and Polymeric Materials, Faculty of Chemical Technology and Engineering, West Pomeranian University of Technology, Pulaskiego 10, 70325 Szczecin, Poland; [EMAIL_ADDRESS] (E.K. ); [EMAIL_ADDRESS] (P.O.-R.); [EMAIL_ADDRESS] (K.W.) [PERSON]  
1 Department of Pharmacoslichenics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70111 Szczecin, Poland; [EMAIL_ADDRESS] (U.A.-G.); [EMAIL_ADDRESS] (M.B.) [PERSON]  
2 Department of Pharmaceutical Chemistry, Pomeranian Medical University, Powstaroow Wielkopolskich Ave. 72, 70-111 Szczecin, Poland; [EMAIL_ADDRESS] (A.N. ); [EMAIL_ADDRESS] (L.K. ); [EMAIL_ADDRESS] (L.M.-S.)  
[PERSON]  
3 Department of Chemical Organic Technology and Polymeric Materials, Faculty of Chemical Technology and Engineering, West Pomeranian University of Technology, Pulaskiego 10, 70325 Szczecin, Poland; [EMAIL_ADDRESS] (F.K. ); [EMAIL_ADDRESS] (P.O.-R.); [EMAIL_ADDRESS] (K.W.) creating the local anti-inflammatory and analgesic effects. Various enhancers' approaches, allows for enhanced drug concentration mainly locally in tissues, e.g., in the structures of joint, in tendinous cots, and in the bursa [3; 4; 5]. Advantages associated with the skin application include non-invasive delivery and low levels of the drug in the plasma, which minimizes a first-pass metabolism and enables easier termination the drug exposure at any time as well as reduced drug toxicity [2]. It is estimated that the plasma concentration of NSAIDs after topical skin administration states that only 5% of the concentration is achieved after systemic administration. However, concentration of NSAIDs in the joint cartilage and synovial fluid is higher after topical than after oral administration [6]. Besides the skin barrier, important factors, limiting the permeation of drugs through the skin, include the physicochemical properties of the drug (molecular weight, ionization, solubility, and lipophilicity) as well as the properties of the drug vehicle and excipients [2]. (_S_)-Naproxen, i.e., (+)-(25)-2-(6-methoxynaphth-2-yl)propionic acid, classified as an NSAID, has analgesic and antipyretic properties. Its skin administration is recommended in rheumatic diseases or degenerative changes in both peripheral joints and the spine. Applied on specific area of the human body surface, it can effectively reduce the symptoms of post-traumatic changes or inflammation of the tissues in this area. Various attempts are being made to increase the permeation rate and amount of permeated naproxen through the skin for greater therapeutic efficacy. Both the chemical form of the drug and the composition of formulation, i.e., the vehicle and excipients, affect the penetration through the difficult-to-penetrate barrier of the skin, and above all the _stratum corneum_ layer [7; 8; 9; 10; 11]. Salt formation is one of the important and simple solutions that not only increases the solubility of ionizable compounds, as naproxen, but also increases the drug permeation through the skin barrier. The type of counterion is important in this matter [7; 10]. Various neutralizing agents, such as alkali metal hydroxides, ammonia, diethylamine, triethanolamine, and any combinations thereof were used with naproxen in topical gel compositions to produce the corresponding salt form of naproxen in situ. Among all used, the ammonia and diethylamine have been found to enhance significantly the permeation and the accumulation of naproxen in human skin [8]. Recently, we have shown that salts of the naproxen with alkyl esters of amino acids such as Gly, Ser, Leu and Pro increase the solubility of drug in water and PBS pH 7,4 solution.