Effects of localized hydrophilic mannitol and hydrophobic nelfinavir administration targeted to olfactory epithelium on brain distribution

Abstract

Many nasally applied compounds gain access to the brain and the central nervous system (CNS) with varying degree. Direct nose-to-brain access is believed to be achieved through nervous connections which travel from the CNS across the cribriform plate into the olfactory region of the nasal cavity. However, current delivery strategies are not targeted to preferentially deposit drugs to the olfactory at cribriform. Therefore, we have developed a pressurized olfactory delivery (POD) device which consistently and non-invasively deposited a majority of drug to the olfactory region of the nasal cavity in rats. Using both a hydrophobic drug, mannitol (log P = -3.1), and a hydrophobic drug, nelfinavir (log P = 6.0), and POD device, we compared brain and blood levels after nasal deposition primarily on the olfactory region with POD or nose drops which deposited primarily on the respiratory region in rats. POD administration of mannitol in rats provided a 3.6-fold (p < 0.05) increase in cortex-to-blood ratio, compared to respiratory epithelium deposition with nose drop. Administration of nelfinavir provided a 13.6-fold (p < 0.05) advantage in cortex-to-blood ratio with POD administration, compared to nose drops. These results suggest that increasing the fraction of drug deposited on the olfactory region of the nasal cavity will result in increased direct nose-to-brain transport.

Fig. 1

Schematic presentation of the pressurized olfactory delivery device. The pressurized nitrogen is controlled by a pneumatic solenoid which releases the gas in increments of 0.1 s. The gas enters the nozzle outlet and mixes with the liquid dose, which flows through the outlet producing a narrow flow with rotational velocity

Fig. 2

Dye deposition of POD or nose drops within rat nasal cavity. Ten microliters (upper panels) or 30 μl (lower panels) of blue dye was administered to the rat nasal cavity using a single dose from the POD device (left panels) or nose drops administered in 5 μl drops every minute (right panels). The blue circle indicates the olfactory epithelium within the rat nasal cavity, while the green circle outlines the respiratory epithelium. The white line indicates the cribriform plate, which is the interface between the nasal cavity and the olfactory bulb area of the brain

Fig. 3

Brain concentrations of mannitol 30 min after a 0.2-mg dose. The brain concentrations in the olfactory bulbs, cortex, diencephalon, and cerebellum were significantly greater when delivered near the cribriform plate with the POD device than when delivered to the respiratory region with nose drops (*p < 0.05)

Fig. 4

Blood-normalized brain concentrations of mannitol 30 min after a 0.2-mg dose. The blood-normalized brain concentrations after nose drop were significantly higher than after IV administration in all brain regions. The blood-normalized olfactory bulb and cortex mannitol concentrations after POD administration were significantly higher than after nose drop (*p < 0.05 compared with nose drop administration)

Fig. 5

Brain concentrations of nelfinavir. The brain concentrations 30 min after a 0.14-mg dose of nelfinavir were significantly greater when delivered near the cribriform plate via POD spray than when delivered to the respiratory region with nose drops (*p < 0.05)

Fig. 6

Blood-normalized brain concentrations of nelfinavir. The blood-normalized brain concentrations 30 min after a 0.14-mg dose of nelfinavir were significantly greater when delivered near the cribriform plate via POD than when delivered to the respiratory region with nose drops (*p < 0.05)

Fig. 7

Blood-normalized drug concentrations 30 min after delivery. The blood-normalized olfactory bulb and brain concentrations of nelfinavir and mannitol were significantly higher after delivery to the olfactory region with the POD device compared to the nose drop treatments (*p < 0.05)

Fig. 8

Histopathology images after POD spray. All images are from septum of nasal cavity in the olfactory region of rat nasal cavity. a, b shows control animals which received no POD spray, c, d received POD spray with a driving pressure of 10 psi, e, f with a driving pressure of 20 psi, and g, h with a driving pressure of 30 psi. No histological damage was observed from the POD spray