Date of Award
Ph.D. in Pharmaceutical Sciences
Narasimha S. Murthy
N. P. Dhammika Nanayakkara
Blood-brain barrier and blood-cerebrospinal fluid barrier limit the systemic delivery of therapeutics to the brain and cerebrospinal fluid (CSF) respectively. Therapeutic agents targeting CNS are currently being administered by invasive routes which are not patient compliant and do not allow frequent administration. Intranasal delivery of therapeutics to target CSF and brain is a noninvasive route of administration which is patient compliant and allows frequent administration. In the current study, the plausibility of delivering ziconotide and cefotaxime to CSF and brain respectively via intranasal pathway using barrier modulating agents like chitosan was investigated. The ability of chitosan to enhance the permeation of therapeutic agents was investigated across bovine olfactory mucosa and the pharmacokinetics of therapeutic agents administered via intranasal route was investigated in Sprague dawley rats. Overall, it was found that intranasal delivery of therapeutic agents to brain and CSF was significantly enhanced when chitosan was used as a barrier modulating agent. However, the elimination of therapeutic agents was rapid from the Brain/CSF. Therefore to prolong the drug levels in the target tissue fluids, thermosensitive in situ gels were developed using poloxamers. As the poloxamers are poorly cleared from the applied region particularly when multiple applications are executed subsequently, the use of multiblock copolymer which degrades at mucosal pH was explored as an alternative as well. The gel formulations prolonged the brain levels of cefotaxime as well as CSF levels of ziconotide as well. This project has clearly demonstrated that intranasal administration could be used to administer therapeutic agents of interest to target brain or CSF. The bioavailability could be improved using barrier modulating agents and in situ gel formulations.
Manda, Prashanth, "Intranasal delivery of therapeutics targeted to CSF and Brain" (2014). Electronic Theses and Dissertations. 1462.