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

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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.

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Acknowledgments

Supported in part by NIH grants AI 077390 and MH086351, and University of Washington Technology Innovation grant TGIF-1001. RJYH is also supported by Milo Gibaldi Endowment.

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  1. Department of Pharmaceutics, University of Washington, Seattle, Washington, 98195-7610, USA

    John Douglas Hoekman & Rodney J. Y. Ho

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  1. John Douglas Hoekman
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Correspondence to Rodney J. Y. Ho.

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Hoekman, J.D., Ho, R.J.Y. Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution. AAPS PharmSciTech 12, 534–543 (2011). https://doi.org/10.1208/s12249-011-9614-1

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