About 40 years ago the lipidization of hydrophilic drugs was proposed to induce their brain targeting by transforming them into lipophilic prodrugs. Unfortunately, lipidization often transforms a hydrophilic neuroactive agent into an active efflux transporter (AET) substrate, with consequent rejection from the brain after permeation across the blood brain barrier (BBB). Currently, the prodrug approach has greatly evolved in comparison to lipidization. This review describes the evolution of the prodrug approach for brain targeting considering the design of prodrugs as active influx substrates or molecules able to inhibit or elude AETs. Moreover, the prodrug approach appears strategic in optimization of the encapsulation of neuroactive drugs in nanoparticulate systems that can be designed to induce their receptor-mediated transport (RMT) across the BBB by appropriate decorations on their surface. Nasal administration is described as a valuable alternative to obtain the brain targeting of drugs, evidencing that the prodrug approach can allow the optimization of micro or nanoparticulate nasal formulations of neuroactive agents in order to obtain this goal. Furthermore, nasal administration is also proposed for prodrugs characterized by peripheral instability but potentially able to induce their targeting inside cells of the brain.

Several studies showed that D-Limonene can improve metabolic parameters of obese mice via various mechanisms, including intestinal microbiota modulation. Nevertheless, its effective doses often overcome the acceptable daily intake, rising concerns about toxicity. In this study we administered to C57BL/6 mice for 84 days a food supplement based on D-Limonene, adsorbed on dietary fibers (FLS), not able to reach the bloodstream, to counteract the metabolic effects of a high-fat diet (HFD). Results showed that daily administration of D-Limonene (30 and 60 mg/kg body weight) for 84 days decreased the weight gain of HFD mice. After 84 days we observed a statistically significant difference in weight gain in the group of mice receiving the higher dose of FLS compared to HFD mice (35.24 ± 4.56 g vs. 40.79 ± 3.28 g, p < 0.05). Moreover, FLS at both doses tested was capable of lowering triglyceridemia and also fasting glycemia at the higher dose. Some insights on the relevant fatty acid changes in hepatic tissues were obtained, highlighting the increased polyunsaturated fatty acid (PUFA) levels even at the lowest dose. FLS was also able to positively modulate the gut microbiota and prevent HFD-associated liver steatosis in a dose-dependent manner. These results demonstrate that FLS at these doses can be considered non-toxic and could be an effective tool to counteract diet-induced obesity and ameliorate metabolic profile in mice.

Eugenol, cinnamaldehyde and D-limonene, the main components of natural essential oils, are endowed with antioxidant and anti-inflammatory properties which allow them to induce beneficial effects on intestinal, cardiac and neuronal levels. In order to characterize their pharmacokinetic profiles and aptitude to permeate in the central nervous system after intravenous and oral administration to rats, new analytical procedures, easily achievable with HPLC-UV techniques, were developed. The terminal half-lives of these compounds range from 12.4 ± 0.9 (D-limonene) and 23.1 ± 1.6 min (cinnamaldehyde); their oral bioavailability appears relatively poor, ranging from 4.25 ± 0.11% (eugenol) to 7.33 ± 0.37% (cinnamaldehyde). Eugenol evidences a marked aptitude to permeate in the cerebrospinal fluid (CSF) of rats following both intravenous and oral administrations, whereas cinnamaldehyde appears able to reach the CSF only after intravenous administration; limonene is totally unable to permeate in the CSF. Eugenol was therefore recruited for in vitro studies of viability and time-/dose-dependent dopamine release in neuronal differentiated PC12 cells (a recognized cellular model mimicking dopaminergic neurons), evidencing its ability to increase cell viability and to induce dopamine release according to a U-shaped time-course curve. Moreover, concentration-response data suggest that eugenol may induce beneficial effects against Parkinson’s disease after oral administration.

Solubility and permeability of nitrofurantoin (NITRO) were compared with those of its cocrystals containing isoniazid (ISO), bipyridyl (BIP), or phenanthroline (PHE) as coformers, and their parent mixtures. NITRO dissolution profiles were evaluated via HPLC; we resorted to molecular dynamics (MD) simulations to rationalize the experimental data on the basis of nitrofurantoin–coformers and nitrofurantoin–water intermolecular interactions. Permeation studies were performed by using an in vitro model of the small intestine based on IEC-6 cells. The NITRO water solubility was reduced by its mixture with PHE and BIP but not with ISO. Cocrystallization with BIP induced a slight increase of NITRO solubility; cocrystallization with PHE induced its solubility decrease, even if lower than the physical mixture. The solubility changes were attributed to NITRO solvation shell alterations (MD simulations). Cocrystallization with ISO allowed an increase of the NITRO solubility in the first 30 min of the dissolution pattern. Permeation measurements showed that the NITRO–PHE mixture was detrimental for the monolayer integrity, whereas no alterations were induced by the cocrystal. No effects on NITRO permeability and monolayer integrity were observed either for NITRO–ISO or for NITRO–BIP mixtures. The NITRO–ISO cocrystal increased the NITRO permeability across the monolayer without reducing its integrity.