Recent advances in carrier mediated nose-to-brain delivery of pharmaceutics.

Central nervous system (CNS) disorders (e.g., multiple sclerosis, Alzheimer's disease, etc.) represent a growing public health issue, primarily due to the increased life expectancy and the aging population. The treatment of such disorders is notably elaborate and requires the delivery of therapeutics to the brain in appropriate amounts to elicit a pharmacological response. However, despite the major advances both in neuroscience and drug delivery research, the administration of drugs to the CNS still remains elusive. It is commonly accepted that effectiveness-related issues arise due to the inability of parenterally administered macromolecules to cross the Blood-Brain Barrier (BBB) in order to access the CNS, thus impeding their successful delivery to brain tissues. As a result, the direct Nose-to-Brain delivery has emerged as a powerful strategy to circumvent the BBB and deliver drugs to the brain. The present review article attempts to highlight the different experimental and computational approaches pursued so far to attain and enhance the direct delivery of therapeutic agents to the brain and shed some light on the underlying mechanisms involved in the pathogenesis and treatment of neurological disorders.

Recent developments in nanocarrier-aided mucosal vaccination.

To date, most of the licensed vaccines for mucosal delivery are based on live-attenuated viruses which carry the risk of regaining their pathogenicity. Therefore, the development of efficient nonviral vectors allowing the induction of potent humoral and cell-mediated immunity is regarded as an imperative scientific challenge as well as a commercial breakthrough for the pharma industries. For a successful translation to the clinic, such nanocarriers should protect the antigens from mucosal enzymes, facilitate antigen uptake by microfold cells and allow the copresentation of robust, safe for human use, mucosal adjuvants to antigen-presenting cells. Finally, the developed formulations should exhibit accuracy regarding the administered dose, a major drawback of mucosal vaccines in comparison with parenteral ones.

Polyelectrolyte complexes as prospective carriers for the oral delivery of protein therapeutics.

The oral administration of protein therapeutics is hindered by the multitude of barriers confronted by these molecules along the gastrointestinal tract (i.e., acidic environment, proteolytic degradation, mucosal barrier, etc.). Their unique properties (e.g., high molecular weight, hydrophilicity, charge, etc.) and labile structure are mainly responsible for their instability in the harsh conditions along the gastrointestinal tract (GIT) and dictate the employment of alternative routes for their administration (e.g., parenteral). The association of proteins with colloidal carriers represents an interesting approach to overcome the aforementioned issues. However, certain requirements, such as stability in the GIT, stimuli-responsiveness, protection of the encapsulated biomolecule from enzymatic degradation and permeability of the mucosa, have to be met in order to efficiently deliver the sensitive payload to the intended site of action, thus resulting in enhanced bioavailability. The formation of colloidal polyelectrolyte complexes (PECs) seems to be a promising strategy towards this direction, and the present review aims to provide an insight into PECs (e.g., preparation methods, characteristics) along with their advantages and drawbacks as drug delivery vehicles for the oral administration of protein-based therapeutics.

Lipid-based nanocarriers for the oral administration of biopharmaceutics.

Biopharmaceutics have been recognized as the drugs of choice for the treatment of several diseases, mainly due to their high selectivity and potent action. Nonetheless, their oral administration is a rather challenging problem, since their bioavailability is significantly hindered by various physiological barriers along the GI tract, including their acid-induced hydrolysis in the stomach, their enzymatic degradation throughout the GI tract and their poor mucosa permeability. Lipid-based nanocarriers represent a viable means for enhancing the oral bioavailability of biomolecules while diminishing toxicity-related issues. The present review describes the main physiological barriers limiting the oral bioavailability of macromolecules and highlights recent advances in the field of lipid-based carriers as well as the respective lipid intestinal absorption mechanisms.

Effective incorporation of insulin in mucus permeating self-nanoemulsifying drug delivery systems.

The development of a novel, mucus permeating SNEDDS formulation for oral insulin delivery containing a hydrophobic ion pair of insulin/dimyristoyl phosphatidylglycerol (INS/DMPG) is presented. Three oil/surfactant/cosurfactant combinations and 27 weight ratios of oil, surfactant and cosurfactant for each combination were evaluated with the aid of ternary phase diagrams, for the incorporation of the protein/phospholipid complex. The developed formulation was characterized by an average droplet diameter of 30-45 nm. Depending on the initial protein concentration, the loading of insulin in SNEDDS varied between 0.27 and 1.13 wt%. The therapeutic protein was found to be efficiently protected from enzymatic degradation by intestinal enzymes (i.e., trypsin, α-chymotrypsin). The SNEDDS formulation exhibited increased mucus permeability and did not appear to be affected by ionic strength. The incorporation of INS/DMPG in SNEDDS prevented an initial burst release of insulin. INS/DMPG loaded SNEDDS were found to be non-cytotoxic up to a concentration of 2mg/ml. According to the reported results, the incorporation of the hydrophobic ion pair of INS/DMPG in SNEDDS could be regarded as a promising strategy for the oral delivery of insulin.

On the synthesis of mucus permeating nanocarriers.

The synthesis of nanocarriers with "slippery" surface (i.e., poly(lactide-co-glycolide)-polyethylene glycol (PLGA-PEG) nanoparticles (NPs) and polyelectrolyte complexes (PECs) of polyacrylic acid (PAA) with poly-L-lysine (PLL) and/or polyarginine (PArg)) and of nanocarriers (i.e., PLGA NPs, PLGA-PEG NPs, liposomes) containing a mucolytic agent (i.e., 4-mercaptobenzoic acid (4MBA)) is presented. Depending on the molecular weight (MW) of PEG (i.e., 2, 5 kDa), PLGA-PEG NPs with a "brush" or "dense brush" PEG configuration were prepared. The PLGA-PEG NPs exhibited increased mucus permeability in comparison with non-pegylated PLGA NPs when tested in fresh porcine intestinal mucus. The NPs that were prepared using PEG with a MW equal to 5 kDa and had a "dense brush" PEG configuration, were found to exhibit the highest mucus permeability. The average size and the surface charge of PECs could be effectively tuned by varying the PAA/polycation charge ratio, thus resulting in the synthesis of neutral as well as positively and negatively charged PECs. The PECs with negative surface charges were found to exhibit the highest mucus permeability followed by the neutral and finally the positively charged PECs. Depending on the initial concentration of the mucolytic agent, 4MBA loadings up to 13.65, 13.1 and 18.43 wt% were achieved for PLGA NPs, PLGA-PEG NPs and liposomes, respectively. PLGA and PLGA-PEG NPs were characterized by a rapid release of the mucolytic agent (i.e., >80 wt% of 4MBA was released in 20 min) whereas, its encapsulation in liposomes allowed a more controlled release (i.e., up to 30 wt% of 4MBA was released in 45 min). 4MBA loaded liposomes were found to exhibit increased mucus permeability depending on the composition of the phospholipid bilayer.