N6-cyclopentyladenosine : selective brain targeting by nasal administration of microparticles

The adenosine derivative N6-cyclopentyladenosine (CPA) has been proposed as a potent antiischemic drug for the central nervous system (CNS).1 On the other hand, this compound has not yet entered in the clinical use being (i) quickly degraded in blood; (ii) unable to reach the brain by the systemic way; (iii) able to induce relevant side effects at other organs.1 Recently, the nasal route has been proposed as a promising way to directly deliver into the brain those drugs unable to overcome the physiologic barriers between blood and CNS.2,3 Here, we report a study regarding the preparation of powder formulations containing CPA for nasal delivery. The powders have been obtained by spray-drying in the presence either of mannitol and lecithin, or chitosan as carriers. The drug content was detected by UV-spectrophotometric analysis, morphology by scanning electronic spectroscopy and particle size by laser diffraction. In vitro drug release studies from microspheres were carried out according to USP 24. Ex vivo mucoadhesive tests were performed on sheep nasal mucosa blowing an air stream over the microspheres spread onto the mucosa and calculating the detection of drug content by HPLC, upon dissolution in water of microparticles still adhered onto the mucosa. The permeability of both free and microencapsulated drug was studied across sheep nasal mucosa using phosphate buffer (pH 6.5) as receptor solution. Male Wistar rats received an intravenous infusion of drug. Nasal administration was also performed using insufflators Monopowder P® (Valois Dispray, France). After the administration, blood and liquor samples, as well as the olfactory bulb and ventricular sections of the brain were withdrawn and the respective drug amounts analysed by HPLC. According to our results, the drug influenced the particle size and morphology in comparison with blank microparticles. The drug dissolution rate increased or decreased after loading in mannitol or chitosan microparticles, respectively. About 60% of chitosan microspheres was recovered from mucoadhesive tests. The permeation rate of free drug was lower or higher than that of the encapsulated drug in mannitol or chitosan microspheres, respectively. The drug was not found in the central nervous system (CNS) after intravenous administration, which led to blood concentrations in the micromolar range. However, after nasal administration of the same dose, the drug was found in the CNS (up to micromolar range in the liquor, up to 0.2 ng/mg tissue in the brain sections). The CPA amounts detected in rat blood after nasal administration of the powders appeared negligible with respect to the amounts detected after intravenous administration. We can conclude that nasal administration of microparticles prepared by spray-drying appears a promising strategy to obtain the selective CNS targeting of antiischemic adenosine derivatives.