The intravenous anaesthetic propofol acts on gamma amino butyric acid A (GABAA) receptors in the brain.
Propofol is often used as a procedural sedative and is also effective (at sub-anaesthetic doses) against intractable migraine
and non-migraine headaches. However intravenous propofol is associated with pain on injection and with peripherally
mediated hypotension. Here we introduce N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan
(GCPQ) - propofol nanoparticles and demonstrate, for the first time, that propofol nanoparticles are centrally active via
the oral and the intranasal routes. Utilising these routes would abolish the pain on injection and, with respect to the nasal
route, reduce peripheral exposure. The nanoparticles are 40-500 nm in size and stable for 21 days at room temperature.
Brain drug exposure with orally administered GCPQ-propofol nanoparticles (350 mg kg-1 propofol) was not significantly
different from a comparable oral dose of Diprivan. However there was less inter-individual variability with the GCPQ
formulation (brain concentration coefficient of variation at the 5 minute peak time point = 1.24 and 0.72 for the Diprivan
and GCPQ nanoparticle formulations respectively). Furthermore there was increased inter-individual variability in the
pharmacodynamic response to oral Diprivan when compared to oral GCPQ-propofol, as measured by the loss of righting
reflex (LORR) time. The LORR time after oral doses of 250 mg kg-1 and 350 mg kg-1 propofol as Diprivan was 15.7±24.6
minutes and 47.2±35.70 minutes respectively while the LORR time after oral 250 mg kg-1 and 350 mg kg-1 GCPQpropofol
was 0 minutes and 52.7±22.9 minutes respectively. These data have implications for the safety of oral Diprivan.
Via the intranasal route, the LORR time with Diprivan (4mg kg-1 propofol) was not significantly different from that of intranasal
saline, while the intranasal administration of GCPQ-propofol formulations (4 mg kg-1 and 8 mg kg-1 propofol)
produced significantly higher LORR times than when saline was administered. In summary, these animal data demonstrate
that GCPQ-propofol nanoparticles may provide an effective method of administering non-parenteral propofol for
potential use in non-anaesthetic settings.
Keywords: Anaesthetic, GCPQ, nanoparticles, nasal delivery, N-palmitoylation-N-monomethyl-N, N-dumethyl-N, N, Ntrimethyl-
6-O-glycolchitosan, oral propofol, propofol.
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