Electronic Theses and Dissertations

Title

Nose to Brain Delivery of Therapeutic Agents

Date of Award

2011

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

Narasimha S. Murthy

Second Advisor

John S. Williamson

Third Advisor

Soumyajit Majumdar

Abstract

The potential treatment approaches for various disorders associated with central nervous system are invasive and do not allow frequent administration. Brain targeting of drugs by intranasal route is a safe and noninvasive method of drug delivery which allows frequent administration and is certainly more patient compliant than the currently followed invasive methods. In this study, the plausibility of delivering neurotrophins [nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF)], neurotrophinogenic agents (ex: carnosic acid) and antibiotics (ex: cefotaxime) to brain via nose-brain pathway using chitosan as barrier modulating agent was investigated. In vitro permeation studies of fluorescein isothiocyanate dextran (FD40k) across bovine olfactory mucosa using different viscosity grades chitosan at different concentrations indicated that medium viscosity grade chitosan (0.25% w/v) enhanced the permeation of FD40k significantly over other grades and concentration of chitosan. Such similar results were observed when medium viscosity grade chitosan (0.25% w/v) was used as barrier modulating agent in studies involving nerve growth factor, brain derived neurotrophic factor, carnosic acid and cefotaxime. The potential of intranasal formulations of therapeutic agents containing medium viscosity grade chitosan (0.25% w/v) was explored by carrying out in vivo studies in male Sprague-Dawley rats. The brain bioavailability of group of rats administered intranasally with NGF and BDNF solution containing chitosan was significantly enhanced by ?14 fold and ?13 fold, respectively,compared to group of rats administered with same concentration of NGF and BDNF solution without chitosan. Pharmacodynamic studies clearly indicated that the immobility time in case of rats subjected to immobilization stress was significantly decreased upon intranasal administration of BDNF solution containing chitosan. In studies involving carnosic acid the neurotrophin levels (NGF and BDNF) were enhanced significantly upon intranasal administration of carnosic acid with chitosan, which was ?1.5–2 fold more over the parenteral route. When carnosic acid with chitosan formulations were administered in the form of nanoparticles only once in contrary to that of solution which was administered daily once for a period of 4 days there was no statistically significant difference in the NGF and BDNF levels. However, when the formulations were administered in the form of solution only once, the NGF and BDNF levels even after 4 days were not statistically significant from the vehicle control group. The results clearly indicated that carnosic acid nanoparticles could reduce the frequency of administration and also could maintain prolonged therapeutic levels due to higher retention time at the site of delivery. The pharmacokinetic studies of cefotaxime indicated that the drug levels attained in the brain following i.v and intranasal administrations were comparable. However, the drug levels in the plasma following intranasal administration were almost an order of magnitude less when compared to that of i.v administration. These results suggested that intranasal administration of cefotaxime along with chitosan is likely to result in less systemic side effects compared to parenteral administration. Nose to brain delivery of therapeutic agents along with chitosan as barrier modulating agent is a potential approach for treating various disorders associated with central nervous system.

Concentration/Emphasis

Pharmaceutics

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