The potential of nasal application for delivery to the central brain-a microdialysis study of fluorescein in rats.

Previous animal studies have shown that various types of nasally administered drugs and model substances can access the central nervous system (CNS) via direct transport across the olfactory epithelium, and thereby circumventing the blood-brain barrier (BBB). These compounds, however, have mainly been identified in the cerebrospinal fluid and the olfactory bulbs which are usually not pharmacologically relevant targets. The aim of the present study was to evaluate the potential of targeting the central brain by olfactory absorption by use of sodium fluorescein as a hydrophilic model substance with limited permeability across the blood-brain barrier. Microdialysis probes were implanted in blood and in right and left side of the brain (striatum) in rats. The pharmacokinetics of sodium fluorescein was studied from 0 to 180min following intravenous and unilateral nasal administration without occlusion of the oesophagus. Pharmacokinetic modelling showed a significantly higher absorption rate and lower T(max) in the ipsilateral striatum (0.097min(-1) and 41min) compared with the contralateral side (0.056min(-1) and 54min). The rate of elimination in brain was significantly lower after nasal administration (0.004min(-1)) compared with intravenous administration (0.012min(-1)). However, the brain to plasma area under the curve ratios of model substance were low (2-3%) and not significantly different between right and left side of the brain, regardless of the route of administration. The results obtained by microdialysis were supported by findings in whole brain homogenates where concentrations of fluorescein were approximately 40% higher in the right striatum compared with the left side initially after nasal administration to the right nostril of rats. Despite some indications of olfactory transport to the central rat brain it was concluded that the drug targeting potential of sodium fluorescein and most likely other hydrophilic compounds is limited.

A microdialysis model to examine nasal drug delivery and olfactory absorption in rats using lidocaine hydrochloride as a model drug.

Targeting of the central nervous system by direct drug transport from the nose to the brain has gained increased attention through the last decade. In the present study, a model for olfactory drug absorption has been investigated using intravenous and unilateral nasal administration of lidocaine hydrochloride in rats. To investigate the possible drug delivery aspects of this route of transport to a central part of the brain a microdialysis model using in vivo recovery by calibrator was applied to the systemic blood and to right and left striatum. The integrity of the blood-brain barrier was evaluated following microdialysis probe implantation. The in vivo experiments were carried out as a cross-over study in rats. The drainage from the nasal cavity was not restricted by occlusion. It was found that true unbound lidocaine concentrations could be calculated from in vivo recovery measurements of retrodialysis of prilocaine hydrochloride. The relative in vivo recoveries in striatum (11.3%) and blood (24.0%) were significantly lower than in vitro (31.3 and 44.9%). The blood-brain barrier was found to retain its physical integrity when evaluated one hour after probe implantation. From pharmacokinetic modelling of the time-concentration curves it was found that the absorption rates and area under the curve (AUC) values of lidocaine in left and right striatum were not statistically different following nasal and intravenous administration, respectively. The average nasal bioavailabilities of lidocaine in blood, left and right striatum were 85, 103 and 129%, respectively. It was concluded that no significant olfactory absorption to striatum was evident in the present study. However, the method should be applicable to studies of drug delivery to blood and brain following nasal administration of other drugs.

Sodium glycocholate transport across Caco-2 cell monolayers, and the enhancement of mannitol transport relative to transepithelial electrical resistance.

Ideally, the amount of enhancer remaining at the donor side during an in vitro transport study should be known, in order to know the true enhancer concentration during a permeability study. The purpose of the present study is to estimate the flux of the enhancer, sodium glycocholate (GC), through Caco-2 cell monolayers, and to study the effect of various enhancer concentrations on the permeability of GC itself, the permeability of mannitol and the transepithelial electrical resistance (TEER). Apical to basolateral permeability was measured with various concentrations 0.50% (10.2mM), 0.75% (15.5mM) and 1.00% (20.5mM) of GC. The GC permeabilities (Papp) were 4.7+/-1.1, 12.8+/-2.8 and 25.8+/-4.3 (x10(-7)cms(-1)), respectively. Mannitol transport changed accordingly with the Papp; 8.5+/-0.8, 9.9+/-2.7, 20.4+/-2.8 and 31.0+/-4.9 (x10(-7)cms(-1)) for GR, 0.50, 0.75 and 1.00% GC, respectively, with a TEER after 120min, relative to initial, of 86+/-6, 77+/-10, 61+/-11 and 49+/-7%. In conclusion a low and concentration-dependent permeability was found for GC across the Caco-2 cells. Mannitol transport increased and TEER decreased accordingly with increasing GC concentrations. TEER decreased in less than 10min to a certain level, without further reduction in a 120min period, indicating that the enhancer effect is momentarily, rather than time-dependent. The apical GC concentration and enhancer effect may be considered well defined during the experiment, due to the observed low permeability of GC.

Intranasal bioavailability of diazepam in sheep correlated to rabbit and man.

The purposes of the present study were to estimate the nasal bioavailability of diazepam in sheep and to compare this to earlier results in rabbits and humans. Additional, to compare the absorption during various initial periods in the two animal models and man, due to the importance of early absorption in emergency treatment. In a cross-over design, diazepam was nasally administered (7 mg) and intravenously (3 mg), respectively, to six sheep. Diazepam was solubilised in polyethylene glycol 300 in the nasal formulation. The mean nasal bioavailability, t(max) and C(max) were 15% (S.D.+/-8), 5 min (S.D.+/-3) and 934 ng/ml (S.D.+/-593), respectively. Sheep bioavailability was lower than rabbit 54% (P<0.001) and man 34% (P<0.05). In conclusion, the nasal absorption of diazepam was found to be fast, indicating the potential of nasal delivery in acute treatment. The initial (30 min) nasal bioavailability (30 min) for sheep and rabbit is a factor of 2.3 lower and 1.6 higher than man, respectively. The correlation of bioavailability was not optimal between sheep, man and rabbit with differences both in relation to extend and rate.