(753c) Transport of Drugs Across Surfactant Covered Emulsion Interfaces

About 40% of drug candidates identified through combinatorial screening are highly lipophilic resulting in significant difficulties in formulating the drug. The preponderance of lipophilic molecules can be attributed to the hydrophobic nature of various barriers in the body including the lipid membranes that the drugs must cross before eventual binding to the target, which also frequently lies within hydrophobic bilayers. The most common approach for formulating hydrophobic drugs with very low aqueous solubility involves dissolving the drugs in an oil carrier, followed by dispersing the oil in water using surfactants to form an oil-in-water emulsion or microemulsion. The most critical attributes for an emulsion or microemulsion formulations are stability and the rate of drug release. The release of drugs from these formulations is critically important for intravenous formulations, particularly in cases where the interaction of the drugs with the venous walls could cause toxicity. In such cases, it is important to design a system in which the release duration is sufficiently long to convect the formulation to larger blood vessels before the drug is released. The release of drug from the emulsion or microemulsion formulations can be controlled by either diffusion of the drug across the surfactant covered interface or diffusion through the surrounding bulk liquid. This talk will focus on transport of drug from an emulsion to the bulk liquid under perfect sink conditions. In particular, we are interested in determining whether the surfactant covered interface offers a significant resistance to mass transfer.

Propofol is a very commonly used intravenously injected anesthetic agent with many clinical advantages over other drugs. Commercially formulations of propofol comprise of the drug dissolved in oil-in-water emulsions stabilized by egg lecithin. The lipid stabilized emulsion formulations have several drawbacks including patient pain on injection, limited shelf stability, and potential for hypertriglycemia. In attempts to improve propofol formulations, several studies have successfully formed thermodynamically-stable propofol microemulsions without the need for excipient lipids. While microemulsion formulations improve stability, we propose that these systems may not be suitable for propofol delivery because of the very rapid dissolution immediately after intravenous injection. This talk explores the dissolution of propofol emulsions of various sizes and uses the results to explain why microemulsions are not feasible for propofol. Dissolution times are compared with the predictions from a mass transfer based model to determine whether the rate of transport is controlled by the interface or by diffusion in the boundary larger surrounding the particle.

The rate of drug transport in the emulsions is very rapid, with a total equilibration time of only a few seconds, after immersion in a sink environment. Thus commonly used methods for measuring release profiles such as diffusion cells are not feasible in this case.  We developed a new method based on measuring transient solution turbidity to determine the total dissolution time. Emulsions with droplet size of about 100 ηm or larger appear hazy or opaque. After the emulsions are injected into a perfect sink, the dissolution of the droplets will reduce their size, and the system will slowly turn clear due to the decrease in particle size and eventually complete dissolution. Here, we image injections of emulsions into 7% bovine serum albumin solutions and quantify the turbidity as a function of time. The concentration of the protein was kept sufficiently high to ensure sink conditions. The dissolution times were then estimated from the turbidity data for a range of starting emulsion droplet sizes. The dependence of the dissolution durations on droplet size was compared with a mathematical model. The model was modified to incorporate transport of both the free and drug binding to protein. Separate experiments were conducted to measure drug binding to protein, and diffusivity of the drug and the protein were obtained from literature. The initial sizes of the emulsion droplets were obtained by dynamic light scattering. The model did not use any fitting constants. Experimental data was in good agreement with the model based solely on diffusion in the boundary layer around the particle for small Reynolds numbers. It was determined that the surfactant covered interface does not offer substantial resistance to mass transfer. The results also show that dissolution times for microemulsions in blood would be a fraction of a second, which may be inadequate to convect injections to larger blood vessels before they dissolve.

The proposed approach of imaging the injection of formulations into protein solutions could be a useful approach for measuring very short dissolution times. The microemulsion formulations of propofol will release the entire drug payload in the blood very rapidly elevating the propofol concentration leading to toxicity. Microemulsions are expected to exacerbate the pain on injection than larger droplet emulsions due to their rapid release profiles.