Uptake and Transport of Ultrafine Nanoparticles (Quantum Dots) in the Nasal Mucosa.

A wide variety of colloidal delivery systems, including polymeric nanoparticles, metal colloids, liposomes, and microemulsions have been reported to enhance the delivery of therapeutic agents across the nasal mucosa. The mechanisms involved in the uptake of these nanomaterials, especially ultrafine nanomaterials (diameters < 20 nm) through the nasal mucosa are not well understood. Fluorescent quantum dots (QDs) were used to investigate the uptake of ultrafine nanoparticles by bovine respiratory and olfactory mucosal tissues following in vitro exposure, and an inductively coupled plasma optical emission spectroscopy method was developed to quantify the amount of QDs localized within the tissues. QDs do not biodegrade or release their core materials and, as a result, this method allowed for the direct quantification of the nanoparticles themselves, rather than the measurement of a potentially dissociated drug or label. The results demonstrated that carboxylate-modified QDs (COOH-QDs) showed ∼2.5-fold greater accumulation in the epithelial and submucosal regions of olfactory tissues compared to that in respiratory tissues. Endocytic inhibitory studies showed that clathrin-dependent endocytosis, macropinocytosis, and caveolae-dependent endocytic process are all involved in the uptake of COOH-QDs into the respiratory tissues. In olfactory tissues, clathrin-dependent endocytosis is the major endocytic pathway involved in the uptake of COOH-QDs. Additional energy-independent pathways also appeared to allow the transfer of COOH-QDs within the olfactory mucosa. When polyethylene glycol-modified QDs known as PEGylated QDs (PEG-QDs) of similar size, ∼15 nm, were investigated, no nanoparticles were detected in the tissues suggesting that the PEG corona limits the interactions with endocytic and other uptake processes in the nasal epithelium. The capacity for nanoparticle uptake observed in the nasal mucosa, along with the ability of significant numbers of nanoparticles to enter the olfactory tissues using nonenergy-dependent pathways show that the pathways for ultrafine nanoparticle uptake in the nasal tissues have both drug delivery and toxicologic consequences. This places an increased importance on the careful selection of nanoparticle components and drugs intended for intranasal administration.

Acyclovir chemical kinetics with the discovery and identification of newly reported degradants and degradation pathways involving formaldehyde as a degradant and reactant intermediate.

The purpose of this research was to determine acyclovir (ACV) acidic degradation kinetics which is relevant to gastric retentive device product design. A stability-indicating method revealed two unknown degradation products which have been identified by mass spectrometry as ACV and guanine formaldehyde adducts. In addition to the formation of these adducts, a proposed degradation scheme identifies the formation of methyl acetal ethylene glycol, formaldehyde, ethylene glycol, and guanine as additional ACV degradation products. pH-rate profiles were explained by using a rate law which assumed acid-catalyzed hydrolysis of protonated and unprotonated ACV. The predicted and observed rate constants were in good agreement. Data-driven excipient selection recommendations were based on the chemical kinetic study results, degradation scheme, and pH-rate profiles. The average activation energy for the degradation reaction was determined to be 31.3±1.6kcal/mol. The predicted ACV t90% at 37°C and pH 1.2 was calculated to be 7.2days. As a first approximation, this suggests that ACV gastric retentive devices designed to deliver drug for 7days should have acceptable drug product stability in the stomach.