Abstract
Ribavirin is a water-soluble antiviral compound which, owing to its inability to cross the blood–brain barrier, has limited effectiveness in treating viruses affecting the central nervous system. Direct nose-to-brain delivery was investigated for ribavirin in combination with poloxamer 188, an excipient known to enhance the absorption of drug compounds administered intranasally. Composite solid microparticles suitable for intranasal insufflation were prepared by suspending fine crystals of ribavirin in a matrix of poloxamer 188, which were cryogenically milled and characterized to ensure that ribavirin remained stable throughout preparation. In vitro diffusion of ribavirin across a semi-permeable regenerated cellulose membrane showed comparable cumulative drug release after 180 min from both fine solid particles (<20 µm) and 1:1 ribavirin:poloxamer microparticles (d50 = 20 µm); however, the initial release from polymer microparticles was slower, owing to gel formation on the membrane surface. When solid ribavirin was directly deposited on excised olfactory mucosa, either as fine drug particles or 1:1 ribavirin:poloxamer microparticles, permeation was significantly increased from microparticles containing poloxamer 188, suggesting additional interactions between the polymer and olfactory mucosa. These data indicate that for highly water-soluble drugs such as ribavirin or drugs subject to efflux by the nasal mucosa, a formulation of poloxmer-containing microparticles can enhance permeability across the olfactory epithelium and may improve direct nose-to-brain transport.
Highlights
The synthetic nucleoside ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a broad-spectrum antiviral drug [1] that has shown promising in vitro activity [2,3,4]
Neither the melting onset (To ) nor the peak maximum temperature (Tmax ) for the microparticles deviated significantly relative to either pure component, indicating that little to no drug dissolved in the molten polymer during preparation and confirming that a suspension of ribavirin existed in the solidified poloxamer 188 matrix
Solid microparticles comprised of a 1:1 suspension of fine crystalline ribavirin in a poloxamer 188 matrix were developed and tested for their ability to improve nasal absorption drug
Summary
The synthetic nucleoside ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a broad-spectrum antiviral drug [1] that has shown promising in vitro activity [2,3,4]. Owing to its high aqueous solubility and low lipid permeability (BCS Class III), ribavirin does not cross the blood–brain barrier (BBB), which limits its usefulness against viruses that affect the central nervous system (CNS). This was reinforced by studies showing that intraperitoneal, intramuscular, and subcutaneous ribavirin injections were ineffective against several encephalitis viruses in mice [5,6]. Intracranial ribavirin administration in virus-infected hamsters allowed for improved survival against subacute sclerosing panencephalitis (SSPE) [6] This suggests that increasing the CNS bioavailability of ribavirin through alternative routes of administration addresses an important unmet medical need. Direct nose-to-CNS delivery occurs via the olfactory and trigeminal pathways in the nasal cavity, offering several advantages including avoidance of
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