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The nasal pathway represents an alternative route for non-invasive systemic administration of drugs. The main advantages of nasal drug delivery are the rapid onset of action, the avoidance of the first-pass metabolism in the liver and the easy applicability. In vitro cell culture systems offer an opportunity to model biological barriers. Our aim was to develop and characterize an in vitro model based on confluent layers of the human RPMI 2650 cell line. Retinoic acid, hydrocortisone and cyclic adenosine monophosphate, which influence cell attachment, growth and differentiation have been investigated on the barrier formation and function of the nasal epithelial cell layers. Real-time cell microelectronic sensing, a novel label-free technique was used for dynamic monitoring of cell growth and barrier properties of RPMI 2650 cells. Treatments enhanced the formation of adherens and tight intercellular junctions visualized by electron microscopy, the presence and localization of junctional proteins ZO-1 and b-catenin demonstrated by fluorescent immunohistochemistry, and the barrier function of nasal epithelial cell layers. The transepithelial resistance of the RPMI 2650 cell model reached 50 to 200 X 9 cm 2 , the permeability coefficient for 4.4 kDa FITC-dextran was 9.3 to 17 9 10 -6 cm/s, in agreement with values measured on nasal mucosa from in vivo and ex vivo experiments. Based on these results human RPMI 2650 cells seem to be a suitable nasal epithelial model to test different pharmaceutical excipients and various novel formulations, such as nanoparticles for toxicity and permeability.

Co-grinding is a procedure for the preparation of nanoparticles in which the drug is ground together with one or more excipients. The grinding of meloxicam, a crystalline solid, together with amorphous polyvinylpyrrolidone (PVP) or semi-crystalline polyethylene glycol (PEG) as excipients, is expected to lead to a drastic reduction in particle size. We optimized meloxicam grinding using a three level full factorial response surface design. In the case of PVP the optimum co-grinding parameter set in our study proved to be a meloxicam to PVP-C30 ratio of 1:1, and a rotation frequency of 400 rpm. The best size reduction was achieved at a meloxicam to PEG 6000 ratio = 1:2 at a rotation frequency of 400 rpm: nanoparticles averaging d SEM = 174 nm in diameter and with a very narrow size distribution (standard deviation 35% of mean) were obtained. X-ray powder diffraction analysis indicated that the optimized products contained amorphous meloxicam nanoparticles in the PVP-C30 composition, although meloxicam nanocrystals could also be detected in the samples which contained PEG 6000. The dissolution properties were significantly increased under nasal conditions (pH 5.1, temperature 30°C), especially in the case of the amorphous product. Such dry powder systems can offer novel opportunities in systemic nasal drug delivery.

(1) Intranasal administration is a non-invasive and effective way for the delivery of drugs to brain that circumvents the blood-brain barrier. The aims of the study were to test a nasal delivery system for human beta-amyloid (A beta) peptides, to measure the delivery of the peptides to brain regions, and to test their biological activity in rats. (2) A beta(1-42), in the form of a mixture of oligomers, protofibrils, and fibrils was dissolved in a nasal formulation containing hydrophobic, hydrophylic, and mucoadhesive components. The peptide solution was administered intranasally to rats as a single dose or in repeated doses. (3) Nasally injected A beta labeled with the blue fluorescent dye amino-methyl coumarinyl acetic acid (AMCA) could be detected by fluorescent microscopy in the olfactory bulb and frontal cortex. The concentration of the peptide was quantified by fluorescent spectroscopy, and a significant amount of AMCA-A beta peptide could be detected in the olfactory bulb. Unlabeled A beta also reached the olfactory bulb and frontal cortex of rats as evidenced by intense immunostaining. (4) In behavioral experiments, nasal A beta treatment did not affect anxiety levels (open-field test) and short-term memory (Y-maze test), but significantly impaired long-term spatial memory in the Morris water maze. The treatments did not result in A beta immunization. (5) The tested intranasal delivery system could successfully target a bioactive peptide into the central nervous system and provides a basis for developing a non-invasive and cost effective, new model to study amyloid-induced dysfunctions in the brain.

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