NANOTECHNOLOGICAL STRATEGIES FOR ADMINISTRATION OF POORLY SOLUBLE NEUROACTIVE DRUGS

Many neuroactive drugs are characterized by poor solubility, hampering their therapeutic potential and clinical research studies. For instance, the lipophilic molecules dimethylfumarate, retinyl palmitate, progesterone and URB597 can be employed in the treatment of relapsing remitting multiple, early brain injury, learning deficits and/or traumatic brain injuries. In this study the possibility to encapsulate these drugs in lipid nanoparticles is investigated. Solid lipid nanoparticles and nanostructured lipid carriers have been produced by melt and ultrasonication of stearic triglyceride or a mixture of stearic triglyceride and caprylic/capric triglycerides. Mean diameters and morphology of lipid particles were studied by photon correlation spectroscopy, cryo-transmission electron microscopy and x-ray diffraction, while encapsulation efficiency and in vitro drug release have been determined by HPLC. A behavioural study was conducted in rats to study the capability of lipid nanoparticles containing URB597 to alter behaviours relevant to psychiatric disorders after intranasal administration. At this regard the nanoparticle surface has been modified by polysorbate 80, in order to obtain “stealth” nanoparticles. The nanoencapsulation strategy allowed to increase drug solubility with respect to unphysiological solvent or solvent mixtures usually employed for animal and clinical studies. In particular, retinyl palmitate solubility in nanostructured lipid carriers has been increased up to 8-fold. Moreover rat behavioral effects observed by nanoencapsulated URB597 administered intranasally suggest the therapeutic potential of this non-invasive route to treat social dysfunctions, such as autism.