**1. Introduction**

Nanomedicine offers highly valuable research and practical application tools in the medical field, for improving the current methods of prevention, diagnosis, and targeted therapy in various pathological conditions, from simple inflammatory to neoplastic diseases [1]. Nano-sized carrier systems exhibit new or improved physical, chemical, and biological characteristics, and the obtained innovative compounds having the same dimensions as biological structures can interact more quickly at the bio-molecular level, both on the surface and inside the cell [2].

Contemporary papers highlight many medical applications of nanotechnology in the pharmaceutical field, given the design of new nanoparticulate systems for the transport and release of active substances, as well as in the field of regenerative medicine (nano-robots and

**Citation:** Mititelu-Tartau, L.; Bogdan, M.; Pricop, D.A.; Buca, B.R.; Hilitanu, L.; Pauna, A.-M.; Dijmarescu, L.A.; Popa, E.G. Biocompatibility and Pharmacological Effects of Innovative Systems for Prolonged Drug Release Containing Dexketoprofen in Rats. *Polymers* **2021**, *13*, 1010. https:// doi.org/10.3390/polym13071010

Academic Editors: José Miguel Ferri, Vicent Fombuena Borràs and Miguel Fernando Aldás Carrasco

Received: 26 February 2021 Accepted: 22 March 2021 Published: 25 March 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

devices used in cell regeneration), in preventive medicine, diagnosis, and treatment of diseases [3]. Researchers have historically tried to incorporate different agents into nano-systems: thus, analgesic–antipyretic agents, non-steroidal anti-inflammatory drugs, or analgesics belonging to the opioid group were loaded into nanoparticles through various methods [4–9].

Dexketoprofen (DEX) is a dextro-enantiomer of the non-steroidal anti-inflammatory drug ketoprofen, acting through the inhibition of the prostaglandin biosynthesis by blocking both cyclooxygenases (COX-1 and COX-2) [10–12]. The water-soluble salt of this non-steroidal anti-inflammatory drug, the (+)-(S)-2-(3-benzoylphenyl) propionic acid tromethamine derivative (dexketoprofen tromethamine), possesses analgesic, antipyretic, and anti-inflammatory properties, and is used in the treatment of acute and chronic pain in medical, as well as in post-surgery, conditions [13–15].

The pharmacodynamic effects of DEX are manifested 30 min after oral administration (when the maximum plasma concentration is reached), with a half-life of 4–6 h [16]. It has a high capacity to bind the plasma proteins, and the apparent volume of distribution is less than 0.25 L/kg. The liver plays a central role in DEX biotransformation, and it is excreted urinarily, with a terminal half-life around 1.65 h [17]. Due to its short half-life and need to be administered frequently over 24 h, much research has been conducted aiming to obtain prolonged-release compounds. Moreover, the design of such formulations loading this non-steroidal anti-inflammatory agent aims to reduce its adverse effects [18].

Chitosan is obtained by the partial de-acetylation of chitin. It has various properties, due to different values of molecular weight, de-acetylation degree, and sequencing pattern (random or block distribution of de-acetylated residues along the main chain) [19]. Chitosan has a high content of primary amines, which induce a cationic polyelectrolyte behavior, interacting easily with cellular membranes, but also with the lipid bilayer of the vesicles [20]. Positive charging of chitosan-coated lipid vesicles is possible due to pH-dependent protonation/deprotonation processes [21]. At low pH values, chitosan is a water-soluble cationic polyelectrolyte, due to protonated amino groups; at high values of pH, the polymer becomes water-insoluble, losing its charge [22]. In the latter case, the electrostatic repulsion of chitosan is low, facilitating the formation of interpolymer bonds (liquid crystal domains or network bonding) [23]. Thus, fibers, films or hydrogels are formed, depending on the preset conditions for the initiation of transition from the soluble state to insoluble state; this transition takes place usually at pH values between 6 and 6.5, which is a convenient interval for biological applications.

A variety of nanoparticles consist of DEX-coated zinc oxide quantum dots, which demonstrated good penetrability of the drug through rats' skin after transdermal application [24]. In order to improve the pharmacokinetic properties and to decrease adverse effects, nanoparticles containing DEX entrapped in montmorillonite (a natural layered structure of phyllosilicate) were prepared, which proved to deliver the active substance in the body after oral use in acute postoperative pain [25].

Different solid formulations based on lipids (such as triglycerides, fatty acids, steroids, waxes), surfactant and water have been prepared, using the ultrasonication technique, in order to obtain DEX-loaded nano-systems for the sustained release of the drug in different diseases accompanied with pain [26]. A new design of analgesic-loaded nanosystems consists of the encapsulation of DEX-trometamol in nanovesicles based on the polysaccharide chitosan, using a spray-drying method [27].

The aim of our study was to obtain original formulations of DEX-loaded nanoparticle systems with chitosan and phosphatidylcholine, and also the experimental investigation of the biocompatibility and the pharmacological effects of nanovesicles containing DEX in rats.
