Clive Washington

Design and Evaluation of an Emulsion Vehicle for Paclitaxel. I. Physicochemical Properties and Plasma Stability

AbstractPurpose. The current formulation of paclitaxel contains ethanol and Cremophor EL and has been reported to cause serious adverse reactions. The purpose of the present work was to develop an improved emulsion vehicle for paclitaxel and to study the physicochemical properties of such a system.nMethods. Emulsions were prepared by either microfluidization or sonication method and the droplet size characterized by dynamic light scattering and light microscopy.nResults. Stable emulsions could be made using mixtures of lecithin/sodium deoxycholate as the emulsifiers. The formulation was further improved by using a combination of free acid and the sodium salt. Paclitaxel could be loaded into the emulsions at 2.5 mg/ml without the formation of drug crystals. While these emulsions were stable on storage, they flocculated when mixed with plasma. Steric stabilization of the emulsion droplets with poloxamer 188 increased the stability of the emulsions in plasma but promoted the crystallization of paclitaxel. The crystallization tendency could be reduced by using PEG5000PE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[poly (ethylene glycol) 5000]), a less water-soluble stabilizernConclusions. Emulsions with good stability characteristics containing 2.5 mg/ml paclitaxel could be made using bile salt/acid and lecithin, and the excellent stability of these emulsions in plasma was achieved by steric stabilization using PEG5000PE.

An investigation into the efficacy of the pectin based anti-reflux formulation-Aflurax.

The properties of the new pectin-based anti-reflux agent Aflurax (Ferrosan) were studied in vitro and in vivo. Aflurax had a significantly higher in vitro raft strength than the placebo which was matched to the active except for the pectin (4.66+/-2.10 and 0. 22+/-0.04 g, respectively). In the modified Rossett and Rice test, the pectin raft remained above pH 3 for 130 min, whereas the pH in the acid phase remained unchanged. A modification to the stirring speed of the Rossett and Rice test was required to obtain a neutralisation profile for the placebo. The neutralisation profiles for the Aflurax and placebo were the same since both contained 5 mEq of base per tablet. In the in vivo study, subjects were randomly assigned to two groups, which either received radiolabelled food and unlabelled formulation, or unlabelled food and radiolabelled formulations. A pH probe was passed naso-gastrically and placed 5 cm from the cardia, and a small gamma detector was placed on the chest wall, coincident with the pH probe. The subjects received the test meal after an overnight fast. The pectin formulation or placebo was administered 30 min later. Each part of the study was performed as a single-blind two-way cross over with the active versus placebo. The reflux of radiolabel and acid was monitored for three hours postprandially. Aflurax reduced the H(+) concentration (total refluxed hydrogen ion index for Aflurax=3.5 x 10(3)+/-2.1 x 10(3), placebo=29 x 10(3)+/-16 x 10(3)) and amount of radiolabelled food reaching the oesophagus (total refluxed count index of food in counts x 1000 min(-1) Aflurax=19.2+/-2.3, placebo=525+/-423). The mean time for which the oesophageal pH fell below pH 4 was 2.58+/-1. 0 and 0.86+/-0.4 minutes for the placebo and Aflurax groups, respectively. The total amount of radiolabelled formulation which reached the oesophagus was 1000+/-660 for the placebo and 621+/-580 for the Aflurax.

Polyoxyalkylene block copolymers adsorbed in hydrocarbon and fluorocarbon oil-in-water emulsions

Small-angle neutron scattering has been used to investigate the structure of the adsorbed layers formed by three poly(oxyethylene)-poly(oxypropylene) block copolymers (Poloxamer 188, Poloxamer 407 and Poloxamine 908) in two similar oil-in-water emulsions; one with a fluorocarbon oil phase, the other with a hydrocarbon oil phase. We find that the structure of the buoy layer is remarkably similar in the two cases. Since previous work has shown that the fluorocarbon/water interface is impenetrable to these polymers, these new findings also suggest that there cannot be significant penetration of the hydrocarbon/water interface. This is discussed in relation to the findings from other studies. The effects of added electrolyte and temperature on the adsorbed layer structure are also reported.

Polymer bristles: a SANS study

We report the results of a SANS study into the structure of the adsorbed layers formed at the interface in a dilute perfluorodecalinin-water emulsion by five short chain diblock copolymers of oxyethylene (OE) and oxybutylene (OB). The results are discussed in the context of the Marques-Joanny-Leibler scaling description of block copolymer adsorption from selective solvents. The volume fraction profiles are best described by parabolic and, to a lesser extent, Gaussian functional forms. On increasing the temperature the buoy segments of one copolymer were found to contract toward the surface, giving rise to profiles that were more block-like in accordance with the mean-field predictions of Wijmans and Zhulina.