Carbamazepine-loaded solid lipid nanoparticles and nanostructured lipid carriers: Physicochemical characterization and in vitro/in vivo evaluation.

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) represent promising alternatives for drug delivery to the central nervous system. In the present work, four different nanoformulations of the antiepileptic drug Carbamazepine (CBZ) were designed and prepared by the homogenization/ultrasonication method, with encapsulation efficiencies ranging from 82.8 to 93.8%. The formulations remained stable at 4 °C for at least 3 months. Physicochemical and microscopic characterization were performed by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), atomic force microscopy (AFM); thermal properties by differential scanning calorimetry (DSC), thermogravimetry (TGA) and X-ray diffraction analysis (XRD). The results indicated the presence of spherical shape nanoparticles with a mean particle diameter around 160 nm in a narrow size distribution; the entrapped CBZ displayed an amorphous state. The in vitro release profile of CBZ fitted into a Baker-Lonsdale model for spherical matrices and almost the 100% of the encapsulated drug was released in a controlled manner during the first 24 h. The apparent permeability of CBZ-loaded nanoparticles through a cell monolayer model was similar to that of the free drug. In vivo experiments in a mice model of seizure suggested protection by CBZ-NLC against seizures for at least 2 h after intraperitoneal administration. The developed CBZ-loaded lipid nanocarriers displayed optimal characteristics of size, shape and drug release and possibly represent a promising tool to improve the treatment of refractory epilepsy linked to efflux transporters upregulation.

Hybrid inhalable microparticles for dual controlled release of levofloxacin and DNase: physicochemical characterization and in vivo targeted delivery to the lungs.

Current medical treatments against recurrent pulmonary infections caused by Pseudomonas aeruginosa, such as cystic fibrosis (CF) disorder, involve the administration of inhalable antibiotics. The main challenge is, however, the eradication of microbial biofilms immersed in dense mucus that requires high and recurrent antibiotic doses. Accordingly, the development of novel drug delivery systems capable of providing local and controlled drug release in the lungs is a key factor to improve the therapeutic outcome of such therapeutic molecules. Inhalable hybrid carriers were prepared by co-precipitation of CaCO3 in the presence of alginate and the resulting microparticles were treated with alginate lyase (AL) in order to modify their porosity and enhance the drug loading. The hybrid microparticles were loaded with DNase (mucolytic agent) and levofloxacin (LV, wide-spectrum antibiotic) in the range of 20-40% for LV and 28-67% for DNase, depending on the AL treatment. In vitro studies demonstrated that microparticles were able to control the DNase release for 24 h, while 30-50% of LV was released in 3 days. The morphological characterization was performed by optical, fluorescence and scanning electron microscopies, showing a narrow size distribution (5 µm). FTIR, XRD, DSC and nitrogen adsorption isotherm studies revealed the presence of the drugs in a non-crystalline state. A microcidal effect of microparticles was found on P. aeruginosa in agar plates and corroborated by Live/Dead kit and TEM observations. Finally, to study whether the microparticles improved the localization of LV in the lungs, in vivo studies were performed by pulmonary administration of microparticles to healthy mice via nebulization and dry powder inhalation, followed by the quantification of LV in lung tissue. The results showed that microparticles loaded with LV delivered the antibiotic at least 3 times more efficiently than free LV. The developed system opens the gateway to new drug delivery systems that may provide enhanced therapeutic solutions against bacterial infections and in particular as a potential tool in CF pathology.

CNS drug development - lost in translation?

CNS drug development is characterized by an especially high attrition rate, despite clear unmet medical needs in the field of neuro-pharmacology and significant investment in R of novel CNS drug treatments. Here, we overview the issues underlying the intrinsic difficulty of CNS drugs development, including obstacles of pharmacokinetic nature and lack of predictivity of preclinical tests. We highlight current efforts to overcome these limitations, with an emphasis on modeling opportunities towards early recognition of CNS candidates (stressing the possibilities of multi-target directed ligands or "magic shotguns") and different approaches to improve CNS bioavailability.

Design, synthesis, and anticonvulsant activity of some sulfamides.

As part of our search for potential anticonvulsant agents, a set of compounds were designed, synthesized, and evaluated against MES and PTZ tests. Bioisosteric functional group information was used to design a new functionality, sulfamides, that complies with the requirements of the pharmacophore previously defined. Some of the molecules showed a promising anticonvulsant profile as selective anti-MES drugs, being active at low concentrations (30mg/kg). The biological data were confirmed in Phase II of the Anticonvulsant Drug Development Program of the National Institute of Health.