Strategies to promote the delivery of anti-inflammatory agents through different nanotechnological approaches

Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are some of the most widely prescribed drugs in the world and are commonly used to treat inflammatory disorders and the related effects (e.g. fever and pain), but also inflammation in chronic diseases such as rheumatoid arthritis and osteoarthritis. However, some of these active ingredients are characterized by poor aqueous solubility, low bioavailability and poor stability. In order to overcome these limits, different technological approaches have been studied in this thesis to enhance delivery of poorly soluble drugs with anti-inflammatory activity, i.e., production of nanosuspensions (Part 1), liposomes and polymeric nanofibers (Part 2). Part 1 of this thesis investigates the potential of nanocrystals suspension for inhalation drug delivery. More in detail, Chapter 1 focuses on the ability of electronic nicotine delivery systems (ENDS) to deliver drug nanocrystals through the produced aerosol. A nanocrystal nanosuspension of beclomethasone dipropionate, using Poloxamer 188 as stabilizer, was prepared with a wet ball media milling technique and thoroughly characterized by different techniques. The nanosuspension was then loaded in an electronic cigarette and the produced aerosol was collected and analysed, confirming the presence of drug nanocrystals. The results of this study suggested the possible alternative use of ENDS as medical device for the delivery of poorly soluble drugs. In Chapter 2, the combination of a conventional glucocorticoid drug and a natural active compound was studied. Curcumin has shown a potential extraordinary activity as an add-on ingredient in asthma treatment, due to its immunomodulatory and anti-inflammatory mechanism of action. However, its low water solubility and bioavailability lead to a poor therapeutic effect. Therefore, the aim of this study was to prepare a multicomponent formulation for the delivery of curcumin and beclomethasone dipropionate into the lungs as water-based nanosuspensions. Single component formulations and a multi-component formulation were prepared through a wet ball media milling technique, using P188 as a non-toxic stabilizer. The different formulations were characterized, and the inhalation delivery efficiency was studied with Next Generation Impactor (NGI, Apparatus E Ph. Eu). The three formulations exhibited a nanocrystal mean diameter in the range 200-240 nm and a homogenous particle size distribution. Finally, the nebulization tests of the three samples showed optimal aerodynamic parameters and MMAD < 5 µm. In Part 2 of the thesis, a combination of two different technological approaches, namely liposomes and nanofibers, was used to improve the delivery of the poorly soluble drug simvastatin. Simvastatin, as part of the statins group, is mostly used for its lipid lowering effect. However, recent studies have highlighted the anti-inflammatory and immunomodulatory activity of the drug both in vitro and in vivo. At first, simvastatin was encapsulated in liposomes through the direct sonication methods. The different formulations were characterized in terms of size, size distribution, zeta potential, drug content and encapsulation efficiency. Three formulations were chosen for the preparation of the polymeric solutions and anofibers were prepared through a green electrospinning technique. The liposomes-composite nanofibrous systems were characterized for drug content and entrapment efficiency, drug release (both in sink and non-sink conditions), protection of the active compound by the antioxidant. Moreover, Multi-Angle Dynamic Light Scattering Technology (MADLS) was used to investigate the release of liposomes from the nanofibrous mats. Finally, in vitro tests were carried out to study the cytotoxicity of the different formulations on human keratinocytes and their ability to inhibit lymphocytes proliferation.