SkyePharma Plc

Because propofol is water insoluble, current formulations of propofol use a soybean oil emulsion. These soybean emulsions cause elevated plasma triglycerides and support bacterial growth. This study compares an alternative formulation of propofol as a 2% emulsion in a medium-chain triglyceride solution (IDD-D Propofol) with Diprivan.

This double-blind, crossover, phase 1 study compared IDD-D Propofol with Diprivan using two consecutive protocols of 12 subjects each. Subjects in protocol 1 received a single bolus of 2.5 mg/kg, and those in protocol 2 received the same induction dose followed by a 30-min infusion at 0.2 mg. kg(-1).min(-1). Venous samples were taken for propofol concentration and biochemical measurements. Induction and emergence times were measured by termination of voluntary counting and responding to command, respectively.

Plasma concentrations were not different between the two formulations. Induction time was 14% longer with IDD-D Propofol than with Diprivan (N = 24, protocols 1 and 2 combined, 53.3 +/- 12.1 s and 46.9 +/- 7.8 s, respectively; P = 0.002). Emergence time was not significantly different for protocol 1 but was marginally longer (P = 0.04) for IDD-D Propofol in protocol 2 (1,197 +/- 445 s [n = 11] and 1,254 +/- 468 s [n = 12], respectively). As expected because of the inherent characteristics of the formulations, plasma triglycerides were elevated for Diprivan but not for IDD-D Propofol; octanoate, a metabolite of medium-chain triglycerides, was elevated only with IDD-D Propofol. Octanoate was elevated to concentrations below those considered toxic. Plasma concentrations of other biochemical markers of medium-chain triglyceride metabolism, ketones, showed no significant changes. Interestingly, there were significant differences between male and female subjects in the propofol plasma concentrations and time to awakening with both drugs.

Differences between the two propofol formulations were slight and not clinically significant. Similar gender differences in plasma concentrations and awaking times were found for both formulations.

A review and discussion.Drug insolubility is one of the most intractable problems in new drug development and in reformulation of existing medications.This article describes a novel approach, Insoluble Drug Delivery (IDD) technol., which has successfully addressed the problem of water-insoluble drug delivery.Without intending a comprehensive review of the latter, this article briefly compares the attributes of the IDD approach and other formulation technologies for water-insoluble drugs.Example formulations employing IDD technol. are discussed, particularly with respect to their ability to improve oral bioavailability.

A method for the anal. of free fatty acids resulting from the degradation of phospholipids was developed using high-performance liquid chromatog.-mass spectrometry with an electrospray ionization source.Separation of fatty acid mol. species was achieved using an isocratic acidified mixture of acetonitrile/water (70:30) on a reversed phased column (C₈).Optimization of the mass spectrometer conditions has allowed the method to sep. and detect the fatty acids mainly as deprotonated mol. species.Separation of all major fatty acids was achieved in less than 6 min.The fatty acids studied provide a linear response over 3 orders of magnitude.Data supporting the validation of this method are also presented.