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The Oral and Intranasal Delivery of Propofol Using Chitosan Amphiphile Nanoparticles

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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.
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Keywords: Anaesthetic; GCPQ; N; N-dumethyl-N; N-palmitoylation-N-monomethyl-N; Ntrimethyl- 6-O-glycolchitosan; nanoparticles; nasal delivery; oral propofol; propofol

Document Type: Research Article

Publication date: June 1, 2014

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  • Pharmaceutical Nanotechnology publishes original manuscripts, reviews, thematic issues, rapid technical notes and commentaries that provide insights into the synthesis, characterisation and pharmaceutical (or diagnostic) application of materials at the nanoscale. The nanoscale is defined as a size range of below 1 µm. Scientific findings related to micro and macro systems with functionality residing within features defined at the nanoscale are also within the scope of the journal. Manuscripts detailing the synthesis, exhaustive characterisation, biological evaluation, clinical testing and/ or toxicological assessment of nanomaterials are of particular interest to the journal’s readership. Articles should be self contained, centred around a well founded hypothesis and should aim to showcase the pharmaceutical/ diagnostic implications of the nanotechnology approach. Manuscripts should aim, wherever possible, to demonstrate the in vivo impact of any nanotechnological intervention. As reducing a material to the nanoscale is capable of fundamentally altering the material’s properties, the journal’s readership is particularly interested in new characterisation techniques and the advanced properties that originate from this size reduction. Both bottom up and top down approaches to the realisation of nanomaterials lie within the scope of the journal.
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