High throughput screening techniques that are routinely used in modern drug
discovery processes result in a higher prevalence of poorly water-soluble drugs. Such
drugs often have poor bioavailability issues due to their poor dissolution and/or
permeability to achieve sufficient and consistent systemic exposure, resulting in sub-optimal
therapeutic efficacies, particularly via oral administration. Alternative
formulations and delivery routes are demanded to improve their bioavailability.
Nanoparticulate formulations of poorly water-soluble drugs offer improved dissolution
profiles. The physiology of the lung makes it an ideal target for non-invasive local and
systemic drug delivery for poorly water-soluble drugs.
In Chapter 2, a particle engineering process ultra-rapid freezing (URF) was
utilized to produce nanostructured aggregates of itraconazole (ITZ), a BCS class II drug, for pulmonary delivery with approved biocompatible excipients. The obtained
formulation, ITZ:mannitol:lecithin (1:0.5:0.2, w/w), i.e. URF-ITZ, was a solid solution
with high surface area and ability to achieve high magnitude of supersaturation. An
aqueous colloidal dispersion of URF-ITZ was suitable for nebulization, which
demonstrated optimal aerodynamic properties for deep lung delivery and high lung and
systemic ITZ levels when inhaled by mice.
The significantly improved systemic bioavailability of inhaled URF-ITZ was
mainly ascribed to the amorphous morphology that raised the drug solubility. The effect
of supersaturation of amorphous URF-ITZ relative to nanocrystalline ITZ on
bioavailability following inhalation was evaluated in Chapter 3. The nanoparticulate
amorphous ITZ composition resulted in a significantly higher systemic bioavailability
than for the nanocrystalline ITZ composition, as a result of the higher supersaturation that
increased the permeation.
In Chapter 4, pharmacokinetics of inhaled nebulized aerosols of solubilized ITZ
in solution versus nanoparticulate URF-ITZ colloidal dispersion were investigated, under
the hypothesis that solubilized ITZ can be absorbed faster through mucosal membrane
than the nanoparticulate ITZ. Despite similar ITZ lung deposition, the inhaled solubilized
ITZ demonstrated significantly faster systemic absorption across lung epithelium relative
to nanoparticulate ITZ in mice, due in part to the elimination of the phase-to-phase transition of nanoparticulate ITZ. / text
| Identifer | oai:union.ndltd.org:UTEXAS/oai:repositories.lib.utexas.edu:2152/6661 |
| Date | 23 October 2009 |
| Creators | Yang, Wei |
| Source Sets | University of Texas |
| Language | English |
| Detected Language | English |
| Format | electronic |
| Rights | Copyright is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works. |
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