Oral administration of highly lipophilic, poorly water-soluble drugs often results in poor and highly variable bioavailability due to poor dissolution in vivo. One approach for improving the absorption of these drugs involves the use of self-emulsifying drug delivery systems (SEDDS) (1-6) which rapidly disperse following oral administration yielding an o/w emulsion or microemulsion containing the solubilized drug.

SEDDS formulations are typically developed by an empirical, trial-and-error approach (2,3) although some useful guidelines have emerged from characterization of successful formulations such as the NeoralĀ® formulation of cyclosporine A (7-8). The literature on microemulsion formulations describes a multitude of compositions and functional characteristics producing varying degrees of drug absorption enhancement in both animals and humans (2-4). Formulation scientists are frequently presented with a series of challenging decisions during the development of SEDDS formulations including choice of formulation strategy, excipient selection, solubility and stability assessment, formulation optimization, scale-up and production of the final product.

However, the key consideration in development of a SEDDS formulation involves solubilization of the drug and preventing its precipitation following dilution with aqueous media which requires that the drug molecules remain within the formulation lipid phase following dilution.

Spontaneous generation of a microemulsion following aqueous dilution of a SEDDS requires a high surfactant concentration relative to the other formulation components; an insufficient amount of surfactant can yield a coarse emulsion with increased propensity for drug precipitation. Selection of the lipid component for the SEDDS formulation is commonly based on the physical and/or interfacial characteristics of the resulting formulation (4-5) without understanding the manner in which the lipid influences drug absorption. The selection of a lipid for optimal enhancement of in vivo absorption of the drug is often an iterative, empirical and slow process (2,3).

This chapter describes the design and development of SEDDS formulations with enhanced oral bioavailability as illustrated with two highly lipophilic and poorly soluble drugs, namely, PNU-74006 (Clog P 5.8; water solubility, 50ng/mL, pH 6.5) and Drug X (Clog P~7, water solubility, ~5 ^g/mL, pH 6.5). The influence of the SEDDS formulation variables on the rate and the extent of absorption of lipophilic drugs in animals and in humans is presented along with the in vitro characterization methods employed in determining the emulsifi-cation spontaneity and the dispersibility of the SEDDS formulations. This article describes a systematic approach for developing lipid-based formulations of poorly soluble and lipophilic drugs. In addition, a possible mechanism for the enhanced uptake of the drugs from the SEDDS formulations in the intestine is discussed.

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