Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

Abstract

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.

Intranasal delivery of FSD‐C10, a novel Rho kinase inhibitor, exhibits therapeutic potential in experimental autoimmune encephalomyelitis

“…Unlike intranasal administration of hydrophilic compounds, which typically target only the brain, with low or no systemic exposure, intranasal delivery of a small lipophilic molecule may have systemic exposure, and studies on the efficacy of this approach are lacking. 38 In conclusion, our results demonstrate that, unlike Fasudil, which has a narrow safety window and cannot be used for frequent injections, its derivative, FSD-C10, can easily be delivered by nasal administration and it effectively suppresses EAE by inhibiting neuroinflammation in the CNS and also by regulating immune responses in the periphery and promoting neuroprotection. Thus, our present study using intranasal delivery of the novel ROCK inhibitor represents a cutting-edge approach for the rapid, easy and non-invasive delivery of drugs into the CNS for treatment of EAE, eventually for MS and probably other diseases of the CNS.…”

Delivery of High Solubility Polyols by Vibrating Mesh Nebulizer to Enhance Mucociliary Clearance

“…The chemical information and osmotic equivalence among the three polyols is presented in Tables 1 and 2, (19)(20)(21) respectively. Based on data from a previous publication, (10) 1% saline was chosen as the vehicle for the polyol formulations.…”

Intranasal Delivery of a Peptide with Antidepressant-Like Effect

“…Intranasal (IN) drug delivery offers a noninvasive alternative for getting protein and peptide drugs into the brain by utilizing the olfactory neuronal distribution pathways in the cribriform plate that lead to direct nose-to-brain drug distribution (Dhuria et al, 2010). IN administration can lead to a direct transfer of protein and other types of drugs from the nose to the brain in similar or higher concentrations than can be obtained by systemic administration (Hoekman and Ho, 2011a;Shemesh et al, 2012;Yang et al, 2013). In some cases, IN drug delivery can result in 100-fold increases in protein drug concentration in multiple brain regions (Dhuria et al, 2010).…”