Evaluation of new propofol aqueous solutions for intravenous anesthesia

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The aim of this study was to evaluate the potential of using three new aqueous formulations of propofol for intravenous (i.v.) anesthesia. The first formulation can be prepared by using hydroxypropyl-γ-cyclodextrin (HP-γ-CD) as a solubilizer. Phase-solubility analysis showed a linear increase in the solubility of propofol to a maximum of 16.6 mg/ml in 30% (w/v) HP-γ-CD. Moreover, phase-solubility studies demonstrated that 18% (w/v) HP-β-CD or SBE-β-CD and 24% HP-γ-CD solutions, respectively, are required to dissolve 10 mg of propofol in 1 ml of the vehicle; the corresponding solutions, however, are slightly hypertonic. Autoclaving the 10 mg/ml CD-based formulations for 15 min at 121 °C caused a change in pH which was more evident for the HP-β-CD-based formulation while, in any case, no detectable fall in propofol concentration was observed. The second formulation herein evaluated is a co-solvent mixture (i.e., propylene glycol:water (1:1), v/v) which is able to dissolve 10 mg/ml of the anesthetic agent. However, although it is simple to prepare, the stability of this formulation is limited. The third aqueous formulation can be prepared by using the prolinate ester of propofol and its water-soluble derivative dissolved in water at equimolar concentration. The efficacy of all these formulations as i.v. anesthetic agents was assessed using a pharmacodynamic measure (onset and duration of loss of the righting reflex, LORR), and compared with that of the commercial propofol formulation (Diprivan®, 10 mg/ml) in rats. It was found that minimizing the amount of cyclodextrin in all CD-based formulations, anesthetic effects comparable to those of propofol in Diprivan® were still observed. Moreover, the prolinate ester constituted an effective i.v. anesthetic formulation with the same duration of action but with a longer induction time than Diprivan®.

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