Jean-Philippe Sylvestre

Nanonization of megestrol acetate by laser fragmentation in aqueous milieu

Nanonization is a simple and effective method to improve dissolution rate and oral bioavailability of drugs with poor water solubility. There is growing interest to downscale the nanocrystal production to enable early preclinical evaluation of new drug candidates when compound availability is scarce. The purpose of the present study was to investigate laser fragmentation to form nanosuspensions in aqueous solution of the insoluble model drug megestrol acetate (MA) using very little quantities of the drug. Laser fragmentation was obtained by focusing a femtosecond (fs) or nanosecond (ns) laser radiation on a magnetically stirred MA suspension in water or aqueous solution of a stabilizing agent. The size distribution and physicochemical properties of the drug nanoparticles were characterized, and the in vitro dissolution and in vivo oral pharmacokinetics of a laser fragmented formulation were evaluated. A MA nanosuspension was also prepared by media milling for comparison purpose. For both laser radiations, smaller particles were obtained as the laser power was increased, but at a cost of higher degradation. Significant nanonization was achieved after a 30-minfs laser treatment at 250mW and a 1-hns laser treatment at 2500mW. The degradation induced by the laser process of the drug was primarily oxidative in nature. The crystal phase of the drug was maintained, although partial loss of crystallinity was observed. The in vitro dissolution rate and in vivo bioavailability of the laser fragmented formulation were similar to those obtained with the nanosuspension prepared by media milling, and significantly improved compared to the coarse drug powder. It follows that this laser nanonization method has potential to be used for the preclinical evaluation of new drug candidates.

Fabrication of Paclitaxel Nanocrystals by Femtosecond Laser Ablation and Fragmentation

Nanonization, which involves formulating the drug powder as nanometer-sized particles, is a known method to improve drug absorption and allow the intravenous administration of insoluble drugs. This study investigated a novel femtosecond (fs) laser technique for the fabrication of nanocrystals in aqueous solution of the insoluble model drug paclitaxel. Two distinct methods of this technology, ablation and fragmentation, were investigated and the influence of laser power, focusing position and treatment time on the particle size, drug concentration, and degradation was studied. The colloidal suspensions were characterized with respect to size, chemical composition, morphology, and polymorphic state. Optimal laser fragmentation conditions generated uniformly sized paclitaxel nanoparticles (<500 nm) with quantifiable degradation, while ablation followed by fragmentation was associated with a larger polydispersity. Laser treatment at higher powers produced smaller particles with larger amount of degradation. The crystalline morphology of the drug was retained upon nanonization, but the anhydrous crystals were converted to a hydrated form, a phenomenon also observed during bead milling. These findings suggest that drug nanocrystals can be produced with fs laser technology using very little drug quantities, which may be an asset for preclinical evaluation of new drug candidates.

Nanoparticle size reduction during laser ablation in aqueous solutions of cyclodextrins

The femtosecond laser ablation of gold in aqueous solution has been used to produce colloidal gold nanoparticles. We consider the effect of size reduction through the use of aqueous cyclodextrin (α-CD, β-CD or γ-CD) solutions. Both the size reduction and the colloid stability depend on the type of CD, with the smallest, almost monodispersed and extremely stable particles prepared with β-CD, followed by slightly larger ones fabricated in γ-CD and α-CD. Several studies were carried out to elucidate the nature of the interaction between the gold and CDs. In particular, we studied the influence of pH on the size distribution and the electric charge of the gold particles surface. We examined the gold surface composition and determined the nature of the chemical groups on the gold. This enabled us to develop a model of chemical interactions between the gold and the CDs, which includes both a hydrophobic interaction of the Au0 with the interior cavity of the CD and a hydrogen bonding of -O- groups, on the partially oxidized gold surface, with -OH groups of the CDs. These nanoparticles are of importance in biosensing applications.

Variable porous structure of laser-ablated silicon nanocluster films and its influence on photoluminescence properties

Si/SiOx films were fabricated by Pulsed Laser Ablation from a silicon target in a residual gas. The films were crystalline with minimal grain size of 2-4 nm and had a porous morphology. The film structure was found to be extremely sensitive to deposition conditions with porosity depending on the gas pressure during the deposition. In particular, the increase of helium pressure from 0.2 to 4 Torr in different depositions led to a gradual porosity (P) increase from 10% to 95%. The porosity increase was accompanied by a slight increase of mean crystal size in the deposit. It has been established that photoluminescence (PL) properties were different for films with different porosities. For low porous films (P < 40 %), we observed PL signals with peak energies between 1.6 and 2.12 eV depending on helium deposition pressure. In contrast, PL properties of highly porous films (P > 40%) were mainly determined by post-deposition oxidation phenomena. They led to an enhancement of PL bands around 1.6-1.7 eV and 2.2-2.3 eV, which were independent of deposition conditions. Similar 2.2-2.3 eV signals were observed after strong film oxidation through a thermal annealing of films in air or through a silicon ablation in oxygen-containing atmosphere. Mechanisms of film formation and PL origin are discussed.