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Mathematical Modeling and Simulation to Investigate the CNS Transport Characteristics of Nanoemulsion-Based Drug Delivery Following Intranasal Administration

  • Ekta Kadakia
  • Dean Bottino
  • Mansoor AmijiEmail author
Research Paper
  • 254 Downloads

Abstract

Purpose

Despite encouraging preclinical results, mechanisms of CNS drug delivery following intranasal dosing of nanoemulsions remain incompletely understood. Herein, the transport characteristics of intranasally administered nanoemulsions are investigated using mathematical modeling and simulation.

Methods

A compartmental model was developed to describe systemic and brain pharmacokinetics of drug solutions following intranasal dosing in rodents. The association between transport processes and CNS drug delivery was predicted using sensitivity analysis. Published pharmacokinetic data for four drugs; dosed as a nanoemulsion and aqueous solution were modeled to characterize differences in transport processes across formulations.

Results

The intranasal model structure performed in a drug agnostic fashion. Sensitivity analysis suggested that though the extent of CNS drug delivery depends on nasal bioavailability, the CNS targeting efficiency is only sensitive to changes in drug permeability across the nasal epithelium. Modeling results indicated that nanoemulsions primarily improve nasal bioavailability and drug permeability across the olfactory epithelium, with minimal effect on drug permeability across the non-olfactory epithelium.

Conclusions

Using mathematical modeling we outlined dominant transport pathways following intranasal dosing, predicted the association between transport pathways and CNS drug delivery, predicted human CNS delivery after accounting for inter-species differences in nasal anatomy, and quantified the CNS delivery potential of different formulations in rodents.

Key words

Blood-brain barrier CNS targeting intranasal drug delivery modeling and simulation nanoemulsions 

Abbreviations

%

Percentage

2-PMPA

2-(phosphonomethyl)pentanedioic acid

99mTc

Technetium-99 m

AUCall

The area under the curve (AUC) from the time of dosing to the time of the last observation

Ave

Average

cm

Centimeter

CSF

Cerebrospinal fluid

CV

Coefficient of variation

Da

Dalton

g

Gram

hr

Hour

IA

Intra arterial

IN

Intranasal

IP

Intraperitoneal

IV

Intravenous

kg

Kilogram

M

Molar

mg

Milligram

min

Minute

mL

Milliliter

mM

Millimolar

MW

Molecular weight

NA

Not available

NES

Not estimated

ng

Nanogram

nm

Nanometer

NOE

Non-olfactory epithelium

OE

Olfactory epithelium

PDI

Polydispersity index

SA

Surface area

SD

Standard deviation

μCi

Microcurie

μg

Microgram

μL

Microliter

Notes

Acknowledgments and Disclosures

This study was partially supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health through a grant R21-NS066984.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, School of PharmacyNortheastern UniversityBostonUSA
  2. 2.Translational Modeling & Simulation, Quantitative Clinical PharmacologyTakeda PharmaceuticalsCambridgeUSA

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